Hepatitis C, Chronic
Conditions
Keywords
Drug-Related Side Effects and Adverse Reactions, Antiviral Agents / Adverse Effects, Antiviral Agents / Toxicity, Simeprevir, Sofosbuvir, Ledipasvir, Ombitasvir, Paritaprevir, Ritonavir, Dasabuvir, Daclatasvir, Elbasvir, Grazoprevir, Velpatasvir, Ribavirin
Brief summary
The investigators will assess whether patients with the Hepatitis C virus (HCV) who are prescribed direct-acting antiviral (DAA) medications experience higher rates of adverse events than patients with HCV who are untreated. The investigators hypothesize that patients receiving DAAs do not experience higher rates of adverse events compared to patients who have not received DAAs. The study population is adults between the ages of 18 and 88 with any indication of a diagnosis of HCV. An intervention group (those receiving a DAA) and comparison group (those who are not treated) will be created using medication dispensing data. Eligibility for the study will be determined from January 1, 2011 through December 31, 2017. Covariates will be collected from January 1, 2011 through December 31, 2017. Individual study sites may have access to historical data prior to 2011 that can be used as covariates or to identify individuals with HCV. The primary outcomes of interest include acute myocardial infarction, neurological outcomes (e.g. acute stroke, intracranial bleed), acute kidney failure, acute on chronic liver failure, hepatic decompensation, multiple organ dysfunction syndrome, cancer, bradyarrhythmia, and death. The secondary outcomes include decompensated cirrhosis, hospitalization, emergency department visit, and arrhythmia. Outcomes will be assessed from January 1, 2011 through December 31, 2017. The investigators will use two different analytic approaches to answer the question of interest: a Poisson regression model and marginal structural modeling (MSM). The simpler Poisson model is an extension of tabular rate of event analysis. The more complicated MSM model incorporates modeling of the treatment decision to more flexibly control for confounding by indication. For each outcome, the investigators will only record the first date an outcome occurs. Each outcome will be modeled separately.
Interventions
The time period during which a patient is dispensed the medication and for up to 180 days after initiation of the medication.
Sponsors
OneFlorida Clinical Research Consortium
Patient-Centered Outcomes Research Institute
Kaiser Permanente
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 88 Years
Inclusion criteria
* HCV viral load * HCV genotype * HCV qualitative * HCV antibody * HCV drug * Continuously enrolled 12 months
Exclusion criteria
* Each outcome will be analyzed separately as time to first event, thus people who experience an outcome prior to their study start date are ineligible for analyses related to that particular outcome. The results will be examined for sensitivity to the following possible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Acute Myocardial Infarction (AMI) | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | Inpatient encounter with an ICD-9 diagnosis code of 410.xx or ICD-10 diagnosis code of I21.xx. |
| Incidence of Acute on Chronic Liver Failure | Labs and diagnoses collected from clinical encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | An acute change in MELD (model for end stage liver disease) score of 5 or more and the change is deemed to have persisted (defined as meeting one of the following criteria: MELD continues to be elevated 3 months later, liver transplant, death). The minimum value for the MELD is 6.43, but there is no maximum value. Higher scores mean a worse outcome. |
| Incidence of Acute Kidney Failure (AKF) | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | Encounters with an ICD-9 diagnosis code of 584.xx or ICD-10 diagnosis code of N17.xx. |
| Incidence of Multiple Organ Dysfunction Syndrome (MODS) | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | Inpatient encounters with ICD-9 diagnosis code of 995.92, 995.94, 785.52 or ICD-10 code of R65.11 or R65.2x. |
| Death | Death dates will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | Date of death in one or more records. Death data comes from medical records, Social Security, or state databases. |
| Incidence of Ischemic Stroke | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | Inpatient encounters with ICD-9 diagnosis code of 433.xx, 434.xx or ICD-10 code of I63.xx, I65.xx. |
| Incidence of Hemorrhagic Stroke | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | Inpatient encounters with ICD-9 diagnosis code of 430.xx-432.xx or ICD-10 code of I60.xx-I62.xx |
| Incidence of Decompensated Cirrhosis | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | A patient will be characterized as having decompensated cirrhosis from an encounter indicating jaundice (ICD-9 diagnosis code of 782.4 or ICD-10 code of R17), ascites (ICD-9 diagnosis code of 789.5, 789.51, 789.59 or ICD-10 diagnosis code of R18.0, R18.8, K71.51, K70.11, or K70.31), or varices (ICD-9 diagnosis code of 456.0, 456.20 or ICD-10 diagnosis code of I85.01 or I85.11, or a medication dispense of lactulose or rifaximin along with a diagnosis of cirrhosis. |
| Rate of Hospitalizations | Hospitalizations will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | An encounter in which the place of service is an inpatient hospitalization. |
| Rate of Emergency Department Visits | ED visits will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | An encounter in which the place of service is an emergency department or urgent care center. |
| Incidence of Arrhythmia | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | Inpatient encounters with an ICD-9 diagnosis code of 427.1, 427.42, 427.5, 427.9 or an ICD-10 diagnosis code of I47.2, I49.01, I49.02, I46.9, I49.9. |
| Incidence of Liver Cancer | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | Encounters with ICD-9 diagnosis code of 155.xx or ICD-10 code of C22.xx. |
| Incidence of Cancers Other Than Liver Cancer | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | Encounters with ICD-9 codes 140.xx through 208.xx, except 155.xx or ICD-10 coes C00-C97 except C22.xx. |
| Incidence of HBV Reactivation | Labs will be for up to 180 days following the initiation of a DAA. | We identified HBV reactivations in three different ways \[Di Bisceglie et al., 2015; Yanny et al., 2018\]: (1) patients who had a history of Hepatitis B core antibody (HBcAb) positive and were Hepatitis B surface antigen (HBsAg) negative at the time of initiating DAA therapy who became HBsAg positive within 180 days after receiving a DAA; (2) patients with undetectable levels of HBV DNA at the time of initiating DAA therapy who had a numerical result within 180 days after receiving a DAA; (3) patients with a numerical HBV DNA result at the time of initiating DAA therapy whose viral load increased by a factor of 10 within 180 days after receiving a DAA. For all methods of detecting a reactivation, we required that the reactivations be clinically significant: bilirubin at least 3, aspartate aminotransferase (AST) at least 400, or alanine aminotransferase (ALT) at least 500. |
Participant flow
Pre-assignment details
This is a retrospective observational study, thus patients are not assigned and no one is excluded from the study after they become eligible.
Participants by arm
| Arm | Count |
|---|---|
| Direct Acting Antivirals Patients who receive a direct acting antiviral enter the DAA cohort at the time of initiation of the drug.
Direct Acting Antivirals: The time period during which a patient is dispensed the medication and for up to 180 days after initiation of the medication. | 15,524 |
| Comparison The exposure time of patients who have not received a direct acting antiviral (patients can change from the comparison to the DAA group once they receive the medication) | 18,284 |
| Total | 33,808 |
Baseline characteristics
| Characteristic | Direct Acting Antivirals | Comparison | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3175 Participants | 3646 Participants | 6821 Participants |
| Age, Categorical Between 18 and 65 years | 12349 Participants | 14638 Participants | 26987 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 112 Participants | 116 Participants | 228 Participants |
| Race (NIH/OMB) Asian | 891 Participants | 772 Participants | 1663 Participants |
| Race (NIH/OMB) Black or African American | 2699 Participants | 3838 Participants | 6537 Participants |
| Race (NIH/OMB) More than one race | 700 Participants | 720 Participants | 1420 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 49 Participants | 51 Participants | 100 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2403 Participants | 2895 Participants | 5298 Participants |
| Race (NIH/OMB) White | 8670 Participants | 9892 Participants | 18562 Participants |
| Region of Enrollment United States | 15524 Participants | 18284 Participants | 33808 Participants |
| Sex: Female, Male Female | 6092 Participants | 6962 Participants | 13054 Participants |
| Sex: Female, Male Male | 9432 Participants | 11322 Participants | 20754 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 77 / 15,524 | 2,186 / 18,284 |
| other Total, other adverse events | 0 / 15,524 | 0 / 18,284 |
| serious Total, serious adverse events | 0 / 15,524 | 0 / 18,284 |
Outcome results
Primary
Death
Date of death in one or more records. Death data comes from medical records, Social Security, or state databases.
Time frame: Death dates will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population is equivalent to the baseline population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Death | 10.7 Events per 1000 person years |
| Comparison | Death | 33.7 Events per 1000 person years |
p-value: <0.0195% CI: [0.3, 0.59]Marginal Structural Model
Primary
Incidence of Acute Kidney Failure (AKF)
Encounters with an ICD-9 diagnosis code of 584.xx or ICD-10 diagnosis code of N17.xx.
Time frame: Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population consists of the subset of patients without a prior diagnosis of AKF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Incidence of Acute Kidney Failure (AKF) | 24.2 Events per 1000 person years |
| Comparison | Incidence of Acute Kidney Failure (AKF) | 33.7 Events per 1000 person years |
p-value: 0.3995% CI: [0.75, 1.12]Marginal Structural Model
Primary
Incidence of Acute Myocardial Infarction (AMI)
Inpatient encounter with an ICD-9 diagnosis code of 410.xx or ICD-10 diagnosis code of I21.xx.
Time frame: Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population consists of the subset of patients without a prior diagnosis of MI.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Incidence of Acute Myocardial Infarction (AMI) | 3.3 Events per 1000 person years |
| Comparison | Incidence of Acute Myocardial Infarction (AMI) | 5.2 Events per 1000 person years |
p-value: 0.6895% CI: [0.3, 2.2]Marginal Structural Model
Primary
Incidence of Acute on Chronic Liver Failure
An acute change in MELD (model for end stage liver disease) score of 5 or more and the change is deemed to have persisted (defined as meeting one of the following criteria: MELD continues to be elevated 3 months later, liver transplant, death). The minimum value for the MELD is 6.43, but there is no maximum value. Higher scores mean a worse outcome.
Time frame: Labs and diagnoses collected from clinical encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population consists of the subset of patients with MELD scores less than 15 at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Incidence of Acute on Chronic Liver Failure | 16.5 Events per 1000 person years |
| Comparison | Incidence of Acute on Chronic Liver Failure | 24.1 Events per 1000 person years |
p-value: 0.0195% CI: [0.56, 0.91]Marginal Structural Model
Primary
Incidence of Arrhythmia
Inpatient encounters with an ICD-9 diagnosis code of 427.1, 427.42, 427.5, 427.9 or an ICD-10 diagnosis code of I47.2, I49.01, I49.02, I46.9, I49.9.
Time frame: Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population consists of the subset of patients without a past diagnosis of arrhythmia.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Incidence of Arrhythmia | 3.2 Events per 1000 person years |
| Comparison | Incidence of Arrhythmia | 4.7 Events per 1000 person years |
p-value: 0.0295% CI: [0.25, 0.88]Marginal Structural Model
Primary
Incidence of Cancers Other Than Liver Cancer
Encounters with ICD-9 codes 140.xx through 208.xx, except 155.xx or ICD-10 coes C00-C97 except C22.xx.
Time frame: Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population consists of the subset of patients without a prior diagnosis of cancer.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Incidence of Cancers Other Than Liver Cancer | 20.7 Events per 1000 person years |
| Comparison | Incidence of Cancers Other Than Liver Cancer | 26.4 Events per 1000 person years |
p-value: 0.1195% CI: [0.63, 1.05]Marginal Structural Model
Primary
Incidence of Decompensated Cirrhosis
A patient will be characterized as having decompensated cirrhosis from an encounter indicating jaundice (ICD-9 diagnosis code of 782.4 or ICD-10 code of R17), ascites (ICD-9 diagnosis code of 789.5, 789.51, 789.59 or ICD-10 diagnosis code of R18.0, R18.8, K71.51, K70.11, or K70.31), or varices (ICD-9 diagnosis code of 456.0, 456.20 or ICD-10 diagnosis code of I85.01 or I85.11, or a medication dispense of lactulose or rifaximin along with a diagnosis of cirrhosis.
Time frame: Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population consists of the subset of patients without prior diagnosis of jaundice, ascites, hemorrhagic varices or medication dispense of lactulose or rifaximin.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Incidence of Decompensated Cirrhosis | 23.8 Events per 1000 person years |
| Comparison | Incidence of Decompensated Cirrhosis | 38.6 Events per 1000 person years |
p-value: <0.0195% CI: [0.49, 0.76]Marginal Structural Model
Primary
Incidence of HBV Reactivation
We identified HBV reactivations in three different ways \[Di Bisceglie et al., 2015; Yanny et al., 2018\]: (1) patients who had a history of Hepatitis B core antibody (HBcAb) positive and were Hepatitis B surface antigen (HBsAg) negative at the time of initiating DAA therapy who became HBsAg positive within 180 days after receiving a DAA; (2) patients with undetectable levels of HBV DNA at the time of initiating DAA therapy who had a numerical result within 180 days after receiving a DAA; (3) patients with a numerical HBV DNA result at the time of initiating DAA therapy whose viral load increased by a factor of 10 within 180 days after receiving a DAA. For all methods of detecting a reactivation, we required that the reactivations be clinically significant: bilirubin at least 3, aspartate aminotransferase (AST) at least 400, or alanine aminotransferase (ALT) at least 500.
Time frame: Labs will be for up to 180 days following the initiation of a DAA.
Population: At the time of initiating DAA therapy, at least one of the following had to be true (1) Hepatitis B core antibody (HBcAb) positive and Hepatitis B surface antigen (HBsAg) negative (2) Hepatitis B core antibody (HBcAb) positive and undetectable levels of HBV DNA; (3) numerical HBV DNA result
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Direct Acting Antivirals | Incidence of HBV Reactivation | 1 Participants |
Primary
Incidence of Hemorrhagic Stroke
Inpatient encounters with ICD-9 diagnosis code of 430.xx-432.xx or ICD-10 code of I60.xx-I62.xx
Time frame: Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population consists of the subset of patients without a prior diagnosis of a stroke.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Incidence of Hemorrhagic Stroke | 1.5 Events per 1000 person years |
| Comparison | Incidence of Hemorrhagic Stroke | 3.1 Events per 1000 person years |
p-value: 0.3495% CI: [0.22, 1.7]Marginal Structural Model
Primary
Incidence of Ischemic Stroke
Inpatient encounters with ICD-9 diagnosis code of 433.xx, 434.xx or ICD-10 code of I63.xx, I65.xx.
Time frame: Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population consists of the subset of patients without a prior diagnosis of a stroke.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Incidence of Ischemic Stroke | 3.6 Events per 1000 person years |
| Comparison | Incidence of Ischemic Stroke | 5.8 Events per 1000 person years |
p-value: 0.1295% CI: [0.42, 1.1]Marginal Structural Model
Primary
Incidence of Liver Cancer
Encounters with ICD-9 diagnosis code of 155.xx or ICD-10 code of C22.xx.
Time frame: Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population consists of the subset of patients without a prior diagnosis of liver cancer.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Incidence of Liver Cancer | 9.3 Events per 1000 person years |
| Comparison | Incidence of Liver Cancer | 14.9 Events per 1000 person years |
p-value: 0.0795% CI: [0.37, 1.03]Marginal Structural Model
Primary
Incidence of Multiple Organ Dysfunction Syndrome (MODS)
Inpatient encounters with ICD-9 diagnosis code of 995.92, 995.94, 785.52 or ICD-10 code of R65.11 or R65.2x.
Time frame: Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population consists of the subset of patients without a prior diagnosis of MODS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Incidence of Multiple Organ Dysfunction Syndrome (MODS) | 9.7 Events per 1000 person years |
| Comparison | Incidence of Multiple Organ Dysfunction Syndrome (MODS) | 17.2 Events per 1000 person years |
p-value: 0.0195% CI: [0.49, 0.9]Marginal Structural Model
Primary
Rate of Emergency Department Visits
An encounter in which the place of service is an emergency department or urgent care center.
Time frame: ED visits will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population is the same as the baseline population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Rate of Emergency Department Visits | 551.2 Events per 1000 person years |
| Comparison | Rate of Emergency Department Visits | 853.4 Events per 1000 person years |
p-value: <0.0195% CI: [0.77, 0.87]Poisson Regression
Primary
Rate of Hospitalizations
An encounter in which the place of service is an inpatient hospitalization.
Time frame: Hospitalizations will be examined through study completion, or up to 180 days from the day the patient initiated a DAA.
Population: The analysis population is the same as the baseline population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Direct Acting Antivirals | Rate of Hospitalizations | 162.8 Events per 1000 person years |
| Comparison | Rate of Hospitalizations | 325.0 Events per 1000 person years |
p-value: <0.0195% CI: [0.6, 0.84]Poisson Regression