HIV, Hepatitis C, Cirrhosis
Conditions
Keywords
HIV, Hepatitis C, Liver Disease, HCV Treatment, transplant
Brief summary
Retrospective/Prospective, open-label study using sofosbuvir based DAA therapy to treat HIV/HCV coinfected pre or post liver transplant participants
Detailed description
Approximately fifty HIV/HCV coinfected patients with decompensated liver disease will be enrolled in the study. Ten (up to twenty) subjects will be treated with FDC SOF/LDV pre or post liver transplant and followed prospectively. Forty + subjects will be enrolled retrospectively with the intent to capture all patients who have been exposed to sofosbuvir based DAA therapies at participating sites since 1/2014, and to mirror the population being enrolled prospectively. In addition, participants in the retrospective arm will be contacted to consent to one prospective study visit for liver staging to determine rates of reversal of decompensation, reversal of cirrhosis and improvements in graft survival post treatment, and for future contact by the NIH Clinical Center to assess longer term outcomes when this study ends.
Interventions
DRUGHarvoni
Treatment of Hepatitis C with sofosbuvir based HCC therapy
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Icahn School of Medicine at Mount Sinai
Columbia University
University of Pennsylvania
University of Maryland, College Park
Georgetown University
Johns Hopkins University
National Institutes of Health Clinical Center (CC)
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
RETROSPECTIVE ARM INCLUSION CRITERIA The intent of the Retrospective Arm is to capture all HIV/HCV coinfected patients exposed to sofosbuvir based DAA therapy since 2014, to mirror the population enrolled in the Prospective Arm. Liver transplant candidates (listed) and decompensated cirrhotics (not listed) for liver transplant 1. Treated with sofosbuvir based DAA for any duration since 2014 2. Age \>18 years at time of treatment 3. Pre-treatment Child's Pugh score of 7 or greater 4. Pre-treatment laboratory MELD \>=6 and \<=0 5. Survived at least 12 weeks after start of treatment 6. HIV-positive on stable ART for at least 4 weeks pre-treatment 7. Chronic HCV infection with at least one measurement of plasma HCV RNA \>= 1,000 IU/mL prior to treatment with sofosbuvir based DAA therapy 8. HCV genotype 1, 4, 5 or 6 Liver transplant recipients 1. Treated with sofosbuvir based DAA post liver transplant for any duration since 2014 2. Liver transplant from 2000 to current 3. Age \>18 years at time of treatment 4. Treated initiated at least 1 month post-liver transplant 5. Post-LT stage of liver disease documented within the prior year of treatment start date by standard of care methods of liver staging 6. Survived at least 12 weeks after start of treatment 7. HIV-positive on stable ART for at least 4 weeks pre-treatment 8. Chronic HCV infection with at least one measurement of plasma HCV RNA \>= 1,000 IU/mL prior to treatment with sofosbuvir based DAA therapy 9. Fibrosis staging done within 1 year of start of DAA therapy 10. HCV genotype 1, 4, 5 or 6 PROSPECTIVE ARM INCLUSION/
Exclusion criteria
Pre-liver transplant candidates * Enrollment will be targeted to occur at least 12 weeks prior to anticipated transplant date. * Screening laboratory MELD \>=6 and \<=20 (NIH) or \<=30 (non-NIH sites) Post-liver transplant recipients * Recipients with evidence of recurrent HCV viremia * Subjects with compensated and decompensated liver disease * Screening laboratory MELD \>=6 and \<=20 (NIH) or \<=30 (non-NIH sites) * Life expectation of \>12 weeks Inclusion Criteria 1. Over 18 years of age at screening 2. Female participants of child bearing potential must have a negative urine pregnancy test at day 0 prior to dosing. 3. Has received a liver transplant for HCV or has decompensated cirrhosis (Child's Pugh score of 7 or greater) 4. Have HIV-1 infection and either: 1. On HIV medications (antiretrovirals) for at least 4 weeks WITH * An HIV viral load less than the level of detection OR 2. On no HIV medications for at least 8 weeks WITH: * A CD4 count of 500 cells/mm3 or more OR * HIV viral load of \< 500 copies/mL with a stable CD4 count for at least 3 months 5. Chronic HCV infection as documented by at least one measurement of plasma HCV RNA \>= 1,000 IU/mL during screening and at least one of the following: A positive anti-HCV antibody, HCV RNA, or an HCV genotype test at least 12 months prior to baseline (Day 0) visit together with positive HCV RNA test 6. HCV genotype 1, 4, 5 or 6 7. The use of an anti-HCV positive donor is allowed for participants who have detectable HCV RNA at the time of transplant. 8. The use of an HIV+ donor is allowed if the participant is enrolled in an IRB approved HOPE Act protocol at the transplant site. If the HIV+ donor is also HCV co-infected, then the recipient must have detectable HCV RNA at the time of transplant. 9. Able to effectively communicate with the Investigator and other center personnel. 10. Willing to give written informed consent and comply with the study restrictions and requirements. 11. Willingness to allow stored blood or tissue samples to be used in the future for studying liver disease and immune function. 12. Willingness to permit HLA typing to be performed. 13. Have a transplant team available for all primary and transplant-related care. 14. If not yet transplanted: expected to be at least 12 weeks prior to transplant in order to complete treatment course. 15. If not yet transplanted: Must have prior standard of care liver staging consistent with F4. 16. If not yet transplanted: For pre-LT patients with HCC, they must meet Milan criteria at time of enrollment to be eligible 17. If post-liver transplant, must be at least 1 month since transplant procedure to begin treatment. 18. If post-liver transplant, liver disease staging must be documented within the prior year by standard of care methods of liver staging
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Sustained Virologic Response (SVR) | Median time from end of treatment was 38.5 months | Sustained virologic response (SVR) defined by hepatitis C virus (HCV) RNA less than the lower level limit of quantification (LLOQ) of \<15 IU/ml at a median time of 38.5 months after the end of sofosbuvir-based direct-acting antiviral (DAA) therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reversal in Decompensation | Median months from baseline to last MELD measurement is 48 months | Number of participants with an improved, worsened or unchanged MELD (Model for End-stage Liver Disease) score. A MELD score ranges from 6 to 40. The higher the number, the worse the liver disease. |
| Change in Liver Fibrosis | Median months from baseline to last APRI measurement is 41 months Median months from baseline to last FIB-4 measurement is 41 months | Change in AST to Platelet Ratio Index (APRI) where negative values indicate improvement in liver fibrosis score and positive values indicate worsening of fibrosis score. There is no upper or lower limit for change. Change in Fibrosis-4 (FIB-4) where negative values indicate improvement in liver fibrosis score and positive values indicate worsening of fibrosis score. There is no upper or lower limit for change. |
| HIV Viral Breakthrough or Relapse | Median months from baseline to last HIV follow-up is 38 months | Number of participants with a detectable HIV viral load after sofosbuvir-based HCV therapy |
| Number of Subjects Treated With Sofosbuvir-based DAA Therapy Who Had Alanine Aminotransferase (ALT) Normalization Post Treatment (Normal Reference Range: 7 - 55 IU/L) | Median months from baseline to last ALT measurement is 41 months | Change in ALT after sofosbuvir based DAA therapy |
Countries
United States
Participant flow
Recruitment details
STOP-CO is a multi-center prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV coinfected participants pre- or post-LT.
Pre-assignment details
The study was designed to prospectively assign ledipasvir-sofosbuvir to participants awaiting transplant or ≥1 month post-transplant. During the course of the trials, DAAs became widely available and the standard of care for the target study population. Only 7 participants could be enrolled in the prospective arm of this study with ledipasvir-sofosbuvir. Therefore in 2017 the study was amended to include retrospective participants treated with any sofosbuvir-based therapy after 2014.
Participants by arm
| Arm | Count |
|---|---|
| Adults With HIV and Chronic HCV and End-stage Liver Disease (ESLD) Pre-liver Transplant The study was implemented at 7 designated sites across the United States. Participants were HIV-positive on a stable antiretroviral (ART) regimen for at least 4 weeks pre-treatment. The retrospective portion of the study enrolled participants treated with sofosbuvir-based DAAs for any duration since 2014 were eligible. HCV genotypes 1, 4, 5 or 6 were included with at least one serum HCV RNA ≥ 1000 IU/mL prior to treatment. Pre-LT participants had a pre-treatment Child's Pugh Turcotte (CPT) score ≥ 7 and a pre-treatment laboratory MELD ≥ 6 and ≤ 30 and included both listed LT candidates and participants who had decompensated cirrhosis not listed for LT. Inclusion criteria for post-LT participants were a LT after 2000 and DAA treatment initiated ≥ 1 month after LT. Prospective participants were accrued from 12/2016-11/2018. Additional exclusion criteria for prospective participants were chronic hepatitis B infection, a history of any other clinically active chronic liver disease, and prior treatment for HCV within one month of screening. Retrospective participants were enrolled between 4/2018 and 6/2019. Information about type of SOF-based therapy in the retrospective participants was not collected for this study. | 42 |
| Adults With HIV With Chronic HCV and Any Stage of Liver Disease Post-liver Transplant The study was implemented at 7 designated sites across the United States. Participants were HIV-positive on a stable antiretroviral (ART) regimen for at least 4 weeks pre-treatment. The retrospective portion of the study enrolled participants treated with sofosbuvir-based DAAs for any duration since 2014 were eligible. HCV genotypes 1, 4, 5 or 6 were included with at least one serum HCV RNA ≥ 1000 IU/mL prior to treatment. Pre-LT participants had a pre-treatment Child's Pugh Turcotte (CPT) score ≥ 7 and a pre-treatment laboratory MELD ≥ 6 and ≤ 30 and included both listed LT candidates and participants who had decompensated cirrhosis not listed for LT. Inclusion criteria for post-LT participants were a LT after 2000 and DAA treatment initiated ≥ 1 month after LT. Prospective participants were accrued from 12/2016-11/2018. Additional exclusion criteria for prospective participants were chronic hepatitis B infection, a history of any other clinically active chronic liver disease, and prior treatment for HCV within one month of screening. Retrospective participants were enrolled between 4/2018 and 6/2019. Information about type of SOF-based therapy in the retrospective participants was not collected for this study. | 26 |
| Total | 68 |
Baseline characteristics
| Characteristic | Adults With HIV and Chronic HCV and End-stage Liver Disease (ESLD) Pre-liver Transplant | Total | Adults With HIV With Chronic HCV and Any Stage of Liver Disease Post-liver Transplant |
|---|---|---|---|
| Age, Continuous | 56.4 years | 56.6 years | 57.2 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants | 32 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 9 Participants | 3 Participants |
| Race (NIH/OMB) White | 13 Participants | 24 Participants | 11 Participants |
| Region of Enrollment United States | 42 participants | 68 participants | 26 participants |
| Sex: Female, Male Female | 11 Participants | 15 Participants | 4 Participants |
| Sex: Female, Male Male | 31 Participants | 53 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 42 | 3 / 26 |
| other Total, other adverse events | 2 / 42 | 4 / 26 |
| serious Total, serious adverse events | 18 / 42 | 7 / 26 |
Outcome results
Primary
Number of Participants With Sustained Virologic Response (SVR)
Sustained virologic response (SVR) defined by hepatitis C virus (HCV) RNA less than the lower level limit of quantification (LLOQ) of \<15 IU/ml at a median time of 38.5 months after the end of sofosbuvir-based direct-acting antiviral (DAA) therapy
Time frame: Median time from end of treatment was 38.5 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Adults With HIV and Chronic HCV and End-stage Liver Disease (ESLD) Pre-liver Transplant | Number of Participants With Sustained Virologic Response (SVR) | 38 Participants |
| Adults With HIV With Chronic HCV and Any Stage of Liver Disease Post-liver Transplant | Number of Participants With Sustained Virologic Response (SVR) | 25 Participants |
Secondary
Change in Liver Fibrosis
Change in AST to Platelet Ratio Index (APRI) where negative values indicate improvement in liver fibrosis score and positive values indicate worsening of fibrosis score. There is no upper or lower limit for change. Change in Fibrosis-4 (FIB-4) where negative values indicate improvement in liver fibrosis score and positive values indicate worsening of fibrosis score. There is no upper or lower limit for change.
Time frame: Median months from baseline to last APRI measurement is 41 months Median months from baseline to last FIB-4 measurement is 41 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Adults With HIV and Chronic HCV and End-stage Liver Disease (ESLD) Pre-liver Transplant | Change in Liver Fibrosis | Change in Fibrosis-4 (FIB-4) | -2.76 units on a scale |
| Adults With HIV and Chronic HCV and End-stage Liver Disease (ESLD) Pre-liver Transplant | Change in Liver Fibrosis | Change in AST to platelet ratio index (APRI) | -0.71 units on a scale |
| Adults With HIV With Chronic HCV and Any Stage of Liver Disease Post-liver Transplant | Change in Liver Fibrosis | Change in AST to platelet ratio index (APRI) | -0.72 units on a scale |
| Adults With HIV With Chronic HCV and Any Stage of Liver Disease Post-liver Transplant | Change in Liver Fibrosis | Change in Fibrosis-4 (FIB-4) | -1.06 units on a scale |
Comparison: APRI change from baseline to last follow-upp-value: <0.01Kruskal-Wallis
Comparison: APRI change from baseline to last follow-upp-value: <0.01Kruskal-Wallis
Comparison: FIB4 change from baseline to last follow-upp-value: <0.01Kruskal-Wallis
Comparison: FIB4 change from baseline to last follow-upp-value: <0.01Kruskal-Wallis
Secondary
HIV Viral Breakthrough or Relapse
Number of participants with a detectable HIV viral load after sofosbuvir-based HCV therapy
Time frame: Median months from baseline to last HIV follow-up is 38 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Adults With HIV and Chronic HCV and End-stage Liver Disease (ESLD) Pre-liver Transplant | HIV Viral Breakthrough or Relapse | 0 Participants |
| Adults With HIV With Chronic HCV and Any Stage of Liver Disease Post-liver Transplant | HIV Viral Breakthrough or Relapse | 0 Participants |
Secondary
Number of Subjects Treated With Sofosbuvir-based DAA Therapy Who Had Alanine Aminotransferase (ALT) Normalization Post Treatment (Normal Reference Range: 7 - 55 IU/L)
Change in ALT after sofosbuvir based DAA therapy
Time frame: Median months from baseline to last ALT measurement is 41 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Adults With HIV and Chronic HCV and End-stage Liver Disease (ESLD) Pre-liver Transplant | Number of Subjects Treated With Sofosbuvir-based DAA Therapy Who Had Alanine Aminotransferase (ALT) Normalization Post Treatment (Normal Reference Range: 7 - 55 IU/L) | 31 Participants |
| Adults With HIV With Chronic HCV and Any Stage of Liver Disease Post-liver Transplant | Number of Subjects Treated With Sofosbuvir-based DAA Therapy Who Had Alanine Aminotransferase (ALT) Normalization Post Treatment (Normal Reference Range: 7 - 55 IU/L) | 20 Participants |
p-value: <0.001Wilcoxon (Signed Rank Test)
Secondary
Reversal in Decompensation
Number of participants with an improved, worsened or unchanged MELD (Model for End-stage Liver Disease) score. A MELD score ranges from 6 to 40. The higher the number, the worse the liver disease.
Time frame: Median months from baseline to last MELD measurement is 48 months
Population: participants treated pre-liver transplant, who had MELD scores available pre and post treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Adults With HIV and Chronic HCV and End-stage Liver Disease (ESLD) Pre-liver Transplant | Reversal in Decompensation | Participants who MELD score improved from baseline | 19 Participants |
| Adults With HIV and Chronic HCV and End-stage Liver Disease (ESLD) Pre-liver Transplant | Reversal in Decompensation | Participants who MELD score worsened from baseline | 11 Participants |
| Adults With HIV and Chronic HCV and End-stage Liver Disease (ESLD) Pre-liver Transplant | Reversal in Decompensation | Participants who MELD score was unchanged | 3 Participants |