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

Safety of Direct-Acting Antiviral Medications for Hepatitis C

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.

Study Overview

• Status: Completed
• Conditions: Hepatitis C, Chronic
• Intervention / Treatment: Drug: Direct Acting Antivirals

• Study Type: Observational
• Enrollment (Actual): 33808

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The groups/cohorts will consist of all HCV patients from Kaiser Permanente Southern California region, Kaiser Permanente Northern California region, and the OneFlorida Clinical Research Consortium.

Description

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)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Direct Acting Antivirals; Patients who receive a direct acting antiviral enter the DAA cohort at the time of initiation of the drug.	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.
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)

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Kaiser Permanente
• Collaborators: Patient-Centered Outcomes Research Institute; OneFlorida Clinical Research Consortium
• Investigators: Principal Investigator: Elizabeth A McGlynn, PhD, Kaiser Permanente

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2011
• Primary Completion (Actual): December 31, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: January 31, 2018
• First Submitted That Met QC Criteria: January 31, 2018
• First Posted (Actual): February 6, 2018

Study Record Updates

• Last Update Posted (Actual): August 7, 2019
• Last Update Submitted That Met QC Criteria: August 5, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Simeprevir; Ritonavir; Sofosbuvir; Daclatasvir; Ribavirin; Drug-Related Side Effects and Adverse Reactions; Ombitasvir; Paritaprevir; Ledipasvir; Dasabuvir; Velpatasvir; Grazoprevir; Elbasvir; Antiviral Agents / Adverse Effects; Antiviral Agents / Toxicity
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Anti-Infective Agents; Antiviral Agents
• Other Study ID Numbers: RI-RCR-1000

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Current plan is to make a de-identified data set available to investigators under specified conditions.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes