An Observational Study of the Safety of Direct-acting Antivirals in Patients With Hepatitis C

Study Overview
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Brief Summary
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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.

Official Title
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Safety of Direct-Acting Antiviral Medications for Hepatitis C

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: Direct Acting Antivirals


Participation Criteria
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Eligibility Criteria
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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 exclusion criteria: Achieved SVR-12 prior to index date HCV treatment experienced prior to index date No visit in GI, Infectious Disease, or Liver Transplant / Hepatology No positive HCV test (genotype, viral load, or qualitative) No recent positive HCV test (genotype, viral load or qualitative)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 88 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Direct Acting Antivirals<br>Patients who receive a direct acting antiviral enter the DAA cohort at the time of initiation of the drug. | Drug: Direct Acting Antivirals<br>* The time period during which a patient is dispensed the medication and for up to 180 days after initiation of the medication.<br>|
| Comparison<br>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) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | 
| 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. | 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. | 
| Incidence of Acute Kidney Failure (AKF) | Encounters with an ICD-9 diagnosis code of 584.xx or ICD-10 diagnosis code of N17.xx. | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | 
| 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. | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | 
| Death | Date of death in one or more records. Death data comes from medical records, Social Security, or state databases. | Death dates will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | 
| 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. | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | 
| 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 | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | 
| 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. | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | 
| Rate of Hospitalizations | An encounter in which the place of service is an inpatient hospitalization. | Hospitalizations will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | 
| Rate of Emergency Department Visits | An encounter in which the place of service is an emergency department or urgent care center. | ED visits will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | 
| 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. | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | 
| Incidence of Liver Cancer | Encounters with ICD-9 diagnosis code of 155.xx or ICD-10 code of C22.xx. | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | 
| 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. | Patient diagnoses collected from encounters will be examined through study completion, or up to 180 days from the day the patient initiated a DAA. | 
| 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. | Labs will be for up to 180 days following the initiation of a DAA. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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