Hepatitis C, Substance Abuse, Intravenous, Substance Use Disorders
Conditions
Keywords
Hepatitis C, HCV, People Who Inject Drugs, PWID, Medication Assisted Therapy, MAT, Needle Exchange Program
Brief summary
hepatitis C virus (HCV) has traditionally been treated in subspecialty health centers given the complexity of older pegylated interferon containing regimens, formerly the standard of care. This model has persisted into the modern era of direct anti-viral agents (DAAs) despite their relative simplicity, creating a bottleneck of human resources necessary to fight the largest infectious epidemic in North America. In addition, stigma and fear over cost has lead payers to restrict treatment in People Who Inject Drugs (PWIDs), even though a majority of new infections occur in this population. This study evaluates the effectiveness of treatment of HCV with elbasvir-grasoprevir in PWIDs in a real world, community health clinic setting. There are two prospective cohorts of PWIDs of 25 patients each, both in primary care-based community health clinics in Portland, Oregon. Cohort one is actively engaged with ambulatory medication assisted therapy with buprenorphine or extended released injectable naltrexone. Cohort two maintains active injection drug use with needle exchange and risk reduction education. These groups are compared to a 50 patient retrospective cohort of people with substance use disorders at tertiary care hepatology-based treatment program. All patients have genotype 1 or 4 HCV and are treated with elbasvir-grasoprevir for 12 weeks. The investigators hypothesize there is no difference in sustained viremic response at 12 or 48 weeks post-completion of treatment (SVR 12, 48) when treating patients in a community health clinic setting as compared to the standard-of-care subspecialty setting.
Detailed description
Hepatitis C has traditionally been treated in subspecialty health centers given the complexity of older pegylated interferon containing regimens, formerly the standard of care. This model has persisted into the modern era of direct anti-viral agents (DAAs) despite their relative simplicity, creating a bottleneck of human resources necessary to fight the largest infectious epidemic in North America. In addition, stigma and fear over cost has lead payers to restrict treatment in People Who Inject Drugs (PWIDs), even though a majority of new infections occur in this population. This study evaluates the effectiveness of treatment of hepatitis C virus (HCV) with elbasvir-grasoprevir in people who inject drugs (PWIDs) in a real world, community health clinic setting. There are two prospective cohorts of PWIDs of 25 patients each, both in primary care-based community health clinics in Portland, Oregon. Cohort one is actively engaged with ambulatory medication assisted therapy with buprenorphine or extended released injectable naltrexone. Cohort two maintains active injection drug use with needle exchange and risk reduction education. These groups are compared to a 50 patient retrospective cohort of people with substance use disorders at tertiary care hepatology-based Academic Health Center. All patients have genotype 1 or 4 HCV and are treated with elbasvir-grasoprevir for 12 weeks. The investigators exclude patients who: are under the age of 18; have a history of liver transplant; have failed past treatment of HCV; have an Aspartate aminotransferase Platelet Ratio Index (APRI) \> 0.7 or APRI \>0.7 but fibrosure/fibroscan of F2 or less; patients with genotype 1a and Nonstructural 5a (NS5a) resistance associated variants (RAVs); have clinical or radiologic evidence of cirrhosis; have aminotransferase levels \>10x upper limit of normal; have a hemoglobin of less than 11g/dL, and are co-infected with hepatitis B or HIV. The investigators hypothesize there is no difference in sustained viremic response at 12 or 48 weeks post-completion treatment (SVR 12, 48) when treating patients with a DAA in a community health clinic setting as compared to the standard-of-care subspecialty setting.
Interventions
DRUGelbasvir-grazoprevir (50 mg/100 mg)
12 week treatment of elbasvir-grazoprevir (50 mg/100 mg)
Sponsors
Oregon Health and Science University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Two parallel investigational groups in different community health clinic treatment settings assigned to treatment with elbasvir-grazoprevir as compared to an academic hepatology clinic retrospective cohort treated with elbasvir-grazoprevir.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Genotype 1b and genotype 1a without baseline NS5A resistance or Genotype 4 * APRI Score \<0.7; if \>0.7 a Fibrosure/Fibrotest or Fibroscan score of F2 or less * No clinical or laboratory evidence of cirrhosis * Readiness for treatment based on ability to make \>2/3 sequential office visits * Patients must be assessed to have decision-making capacity, be capable of consenting, and not be displaying evidence of overt intoxication.
Exclusion criteria
* Clinical or Laboratory Evidence of Cirrhosis * Elevated prothrombin time unrelated to anticoagulation, hemoglobin level less than 12.3 g/L in females and \<14 g/L in males, platelet count \<150 × 109 cells/L), white blood cells (WBC) \<4.0 x103/mm3 , aminotransferase levels more than 10 times the upper limit of normal, or albumin level \<3.5 g/L. * Previous treatment for hepatitis C infection * Hepatocellular carcinoma * HIV or hepatitis B virus co-infection * Subjects taking medications that are contra-indicated to administer with Zepatier including phenytoin, carbamazepine, rifampin, St. John's Wort, and cyclosporine AND unable to change these medications to one without interactions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SVR 12 | 24 weeks post-initiation of treatment (12 weeks post-completion of treatment) | Sustained Viremic Response at 12 weeks post-completion of treatment. SVR12 was determined negative if undetectable (\<20 copies) by polymerase chain reaction and positive if EITHER loss-to-follow up and no lab data or virus was detected greater than 20 copies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SVR 48 | 60 weeks post-initiation of treatment (48 weeks post-completion of treatment) | Sustained Viremic Response at 48 weeks post-completion of treatment (SVR48). Participants Achieving SVR48 had a negative hepatitis C real time polymerase chain reaction (RT-PCR) test at 48 weeks after end of treatment. Participants who Did Not Achieve SVR48 had a positive hepatitis C RT-PCR test at 48 weeks after end of treatment. |
| Discontinuation Rate or Lost To Follow Up | Study duration (60 weeks) | Percentage of patients discontinuing medications prior to completion of 12 weeks or being lost to follow up, defined as inability to reach patient after 3 attempts and patients not following up with primary endpoint labs (SVR 12, 48) |
| NS5A Resistance | At Study Screening/Enrollment | Percentage of patients with genotype 1a and NS5A Resistance-Associated Variants (RAVs) |
| Medication Adherence | 12 weeks (duration of treatment) | Adherence determined by client/subject self-reported medication adherence measured by percentage of pills taken on a monthly basis. Categorically separated into \< 90% adherence, 90-99% adherence, 100% adherence. |
| Injection Drug Use Relapse (IDU) | Duration of study (60 weeks) | Self reported relapse IDU following HCV treatment (MAT arm) |
Countries
United States
Participant flow
Recruitment details
Participants for the medication assisted therapy (MAT) group were all recruited and enrolled from within a single FQHC that provides office based opioid treatment with buprenorphine. Participants in the needle exchange program were similarly recruited in that setting. Retrospective comparison group was an academic hepatology referral clinic.
Pre-assignment details
This is a non-randomized, prospective cohort trial. No washout/run-in occured.
Participants by arm
| Arm | Count |
|---|---|
| Old Town Clinic, Medication Assisted Therapy Group 25 People Who Inject Drugs engaged in a Medication Assisted Therapy treatment program for their substance use disorder, treated for their HCV using elbasvir-grazoprevir (50 mg/100 mg) for 12 weeks.
elbasvir-grazoprevir (50 mg/100 mg): 12 week treatment of elbasvir-grazoprevir (50 mg/100 mg) | 25 |
| Outside In Clinic, Needle Exchange Program 25 People Who Inject Drugs engaged in a Needle Exchange Program with risk reduction education, treated for their HCV using elbasvir-grazoprevir (50 mg/100 mg) for 12 weeks.
elbasvir-grazoprevir (50 mg/100 mg): 12 week treatment of elbasvir-grazoprevir (50 mg/100 mg) | 25 |
| OHSU Hepatology Clinic, Academic Center Retrospective Cohort 50 people with substance use disorder and HCV engaged with an Academic Hepatology Clinic (Oregon Health & Sciences University, OHSU) and treated with elbasvir-grazoprevir (50 mg/100 mg) for 12 weeks.
elbasvir-grazoprevir (50 mg/100 mg): 12 week treatment of elbasvir-grazoprevir (50 mg/100 mg) | 50 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Assessed for Eligibility --> Enrollment | Exclusion Criteria: HIV | 4 | 4 | 0 |
| Assessed for Eligibility --> Enrollment | Exclusion Criteria: NS5a Resistance | 5 | 3 | 0 |
| Assessed for Eligibility --> Enrollment | Exclusion Criteria: Treatment Readiness | 4 | 2 | 0 |
| Assessed for Eligibility --> Enrollment | Inclusion Criteria: Fibrosis > F2 | 18 | 12 | 0 |
| Assessed for Eligibility --> Enrollment | Inclusion Criteria: neg HCV | 28 | 6 | 0 |
| Assessed for Eligibility --> Enrollment | Inclusion Criteria: No active use | 0 | 12 | 0 |
| Assessed for Eligibility --> Enrollment | Inclusion Criteria: No MAT | 40 | 0 | 0 |
| Assessed for Eligibility --> Enrollment | Inclusion Criteria: Wrong Genotype | 15 | 32 | 0 |
| Assessed for Eligibility --> Enrollment | Lost to Follow-up | 17 | 36 | 0 |
| Assessed for Eligibility --> Enrollment | Other Lab exclusion Criteria | 9 | 3 | 0 |
| Enrollment to SVR12 Results | Lost to Follow-up | 1 | 8 | 3 |
Baseline characteristics
| Characteristic | Total | Old Town Clinic, Medication Assisted Therapy Group | Outside In Clinic, Needle Exchange Program | OHSU Hepatology Clinic, Academic Center Retrospective Cohort |
|---|---|---|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 12.9 | 44 years STANDARD_DEVIATION 11.3 | 41 years STANDARD_DEVIATION 11.9 | 60 years STANDARD_DEVIATION 7.5 |
| Drug of choice Alcohol | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Drug of choice Cannabis | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Drug of choice Heroin | 39 Participants | 23 Participants | 16 Participants | 0 Participants |
| Drug of choice Methamphetamines | 9 Participants | 0 Participants | 9 Participants | 0 Participants |
| Established in Primary Care Established in primary care < 1 year | 13 Participants | 6 Participants | 7 Participants | 0 Participants |
| Established in Primary Care Established in primary care > 1 year | 33 Participants | 19 Participants | 14 Participants | 0 Participants |
| Established in Primary Care Not established in primary care | 4 Participants | 0 Participants | 4 Participants | 0 Participants |
| Fibrosis Status APRI < 0.7 | 72 Participants | 19 Participants | 23 Participants | 30 Participants |
| Fibrosis Status APRI > 0.7 | 28 Participants | 6 Participants | 2 Participants | 20 Participants |
| Genotype Genotype 1a | 82 Participants | 22 Participants | 24 Participants | 36 Participants |
| Genotype Genotype 1b | 18 Participants | 3 Participants | 1 Participants | 14 Participants |
| Genotype Genotype 4 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Highest Level of Education Bachelors degree or higher | 5 Participants | 3 Participants | 2 Participants | 0 Participants |
| Highest Level of Education Did not complete highschool | 5 Participants | 1 Participants | 4 Participants | 0 Participants |
| Highest Level of Education High school completion | 29 Participants | 18 Participants | 11 Participants | 0 Participants |
| Highest Level of Education Trade school completion | 11 Participants | 3 Participants | 8 Participants | 0 Participants |
| Housing Status Houseless / Unstable Housing | 12 Participants | 4 Participants | 8 Participants | 0 Participants |
| Housing Status Transitional / Stable Housing | 38 Participants | 21 Participants | 17 Participants | 0 Participants |
| Income 0-50% Federal Poverty Level | 29 Participants | 10 Participants | 19 Participants | 0 Participants |
| Income > 101% Federal Poverty Level | 9 Participants | 6 Participants | 3 Participants | 0 Participants |
| Income 51-100% Federal Poverty Level | 12 Participants | 9 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Black / African American | 2 participants | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Latinx | 2 participants | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Native American | 2 participants | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized White | 84 participants | 22 participants | 22 participants | 50 participants |
| Sex: Female, Male Female | 63 Participants | 15 Participants | 15 Participants | 33 Participants |
| Sex: Female, Male Male | 37 Participants | 10 Participants | 10 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 | 0 / 0 |
| other Total, other adverse events | 15 / 25 | 18 / 25 | 0 / 0 |
| serious Total, serious adverse events | 1 / 25 | 0 / 25 | 0 / 0 |
Outcome results
Primary
SVR 12
Sustained Viremic Response at 12 weeks post-completion of treatment. SVR12 was determined negative if undetectable (\<20 copies) by polymerase chain reaction and positive if EITHER loss-to-follow up and no lab data or virus was detected greater than 20 copies.
Time frame: 24 weeks post-initiation of treatment (12 weeks post-completion of treatment)
Population: All participants enrolled were analyzed using intention to treat (ITT) methodology for sustained viremic response at 12 weeks after end of treatment (SVR12).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Old Town Clinic, Medication Assisted Therapy Group | SVR 12 | SVR12 negative, intention to treat | 24 Participants |
| Old Town Clinic, Medication Assisted Therapy Group | SVR 12 | SVR12 positive, intention to treat | 1 Participants |
| Outside In Clinic, Needle Exchange Program | SVR 12 | SVR12 negative, intention to treat | 15 Participants |
| Outside In Clinic, Needle Exchange Program | SVR 12 | SVR12 positive, intention to treat | 10 Participants |
| OHSU Hepatology Clinic, Academic Center Retrospective Cohort | SVR 12 | SVR12 negative, intention to treat | 47 Participants |
| OHSU Hepatology Clinic, Academic Center Retrospective Cohort | SVR 12 | SVR12 positive, intention to treat | 3 Participants |
Secondary
Discontinuation Rate or Lost To Follow Up
Percentage of patients discontinuing medications prior to completion of 12 weeks or being lost to follow up, defined as inability to reach patient after 3 attempts and patients not following up with primary endpoint labs (SVR 12, 48)
Time frame: Study duration (60 weeks)
Population: All participants analyzed for this variable
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Old Town Clinic, Medication Assisted Therapy Group | Discontinuation Rate or Lost To Follow Up | Discontinued therapy, or incomplete SVR12 labs | 1 Participants |
| Old Town Clinic, Medication Assisted Therapy Group | Discontinuation Rate or Lost To Follow Up | Completed therapy and SVR12 lab confirmation | 24 Participants |
| Outside In Clinic, Needle Exchange Program | Discontinuation Rate or Lost To Follow Up | Discontinued therapy, or incomplete SVR12 labs | 9 Participants |
| Outside In Clinic, Needle Exchange Program | Discontinuation Rate or Lost To Follow Up | Completed therapy and SVR12 lab confirmation | 16 Participants |
| OHSU Hepatology Clinic, Academic Center Retrospective Cohort | Discontinuation Rate or Lost To Follow Up | Discontinued therapy, or incomplete SVR12 labs | 3 Participants |
| OHSU Hepatology Clinic, Academic Center Retrospective Cohort | Discontinuation Rate or Lost To Follow Up | Completed therapy and SVR12 lab confirmation | 47 Participants |
Secondary
Injection Drug Use Relapse (IDU)
Self reported relapse IDU following HCV treatment (MAT arm)
Time frame: Duration of study (60 weeks)
Population: These data were not collected. The study group determined that the definition of relapse was inappropriate for the study population given the nature of ongoing use in the MAT group and the lack of comparison with the outside in group, that was currently using drugs by definition. Scientific value of these data was thought to be limited.
Secondary
Medication Adherence
Adherence determined by client/subject self-reported medication adherence measured by percentage of pills taken on a monthly basis. Categorically separated into \< 90% adherence, 90-99% adherence, 100% adherence.
Time frame: 12 weeks (duration of treatment)
Population: Enrolled study participants in prospective arms initiating therapy. Self report combined will pharmacist pill count adherence data assessed by study pharmacist at q4week study visits, including end of treatment. Retrospective comparison group at OHSU did not collect adherence data.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Old Town Clinic, Medication Assisted Therapy Group | Medication Adherence | 100% adherence | 23 Participants |
| Old Town Clinic, Medication Assisted Therapy Group | Medication Adherence | 90 - 99% adherence | 2 Participants |
| Old Town Clinic, Medication Assisted Therapy Group | Medication Adherence | Less than 90% Adherence | 0 Participants |
| Outside In Clinic, Needle Exchange Program | Medication Adherence | 100% adherence | 17 Participants |
| Outside In Clinic, Needle Exchange Program | Medication Adherence | Less than 90% Adherence | 8 Participants |
| Outside In Clinic, Needle Exchange Program | Medication Adherence | 90 - 99% adherence | 0 Participants |
| OHSU Hepatology Clinic, Academic Center Retrospective Cohort | Medication Adherence | 100% adherence | 0 Participants |
| OHSU Hepatology Clinic, Academic Center Retrospective Cohort | Medication Adherence | 90 - 99% adherence | 0 Participants |
| OHSU Hepatology Clinic, Academic Center Retrospective Cohort | Medication Adherence | Less than 90% Adherence | 0 Participants |
Secondary
NS5A Resistance
Percentage of patients with genotype 1a and NS5A Resistance-Associated Variants (RAVs)
Time frame: At Study Screening/Enrollment
Population: 165 potential participants in medication assisted therapy group and 135 potential participants in needle exchange group were analyzed for Non-Structural Protein 5a (NS5a) resistance. OHSU Hepatology cohort only included treated individuals and NS5a resistance data were not collected.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Old Town Clinic, Medication Assisted Therapy Group | NS5A Resistance | NS5a Resistance to Elbasvir-Grazoprevir Detected | 5 Participants |
| Old Town Clinic, Medication Assisted Therapy Group | NS5A Resistance | NS5a Resistance to Elbasvir-Grazoprevir Absent | 160 Participants |
| Outside In Clinic, Needle Exchange Program | NS5A Resistance | NS5a Resistance to Elbasvir-Grazoprevir Detected | 3 Participants |
| Outside In Clinic, Needle Exchange Program | NS5A Resistance | NS5a Resistance to Elbasvir-Grazoprevir Absent | 132 Participants |
| OHSU Hepatology Clinic, Academic Center Retrospective Cohort | NS5A Resistance | NS5a Resistance to Elbasvir-Grazoprevir Detected | 0 Participants |
| OHSU Hepatology Clinic, Academic Center Retrospective Cohort | NS5A Resistance | NS5a Resistance to Elbasvir-Grazoprevir Absent | 0 Participants |
Secondary
SVR 48
Sustained Viremic Response at 48 weeks post-completion of treatment (SVR48). Participants Achieving SVR48 had a negative hepatitis C real time polymerase chain reaction (RT-PCR) test at 48 weeks after end of treatment. Participants who Did Not Achieve SVR48 had a positive hepatitis C RT-PCR test at 48 weeks after end of treatment.
Time frame: 60 weeks post-initiation of treatment (48 weeks post-completion of treatment)
Population: Limitations in study funding and delayed recruitment prevented both prospective groups from collecting full SVR48 data. Therefore, PER PROTOCOL (PP) data presented below. Analysis framework for this secondary outcome was not pre-specified but PP analysis most appropriate given reasons for lacking data. OHSU comparison did not collect SVR48 data.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Old Town Clinic, Medication Assisted Therapy Group | SVR 48 | Achieved SVR48 | 17 Participants |
| Old Town Clinic, Medication Assisted Therapy Group | SVR 48 | Did Not Achieve SVR48 | 0 Participants |
| Outside In Clinic, Needle Exchange Program | SVR 48 | Achieved SVR48 | 3 Participants |
| Outside In Clinic, Needle Exchange Program | SVR 48 | Did Not Achieve SVR48 | 4 Participants |
| OHSU Hepatology Clinic, Academic Center Retrospective Cohort | SVR 48 | Achieved SVR48 | 0 Participants |
| OHSU Hepatology Clinic, Academic Center Retrospective Cohort | SVR 48 | Did Not Achieve SVR48 | 0 Participants |