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Invited Commentary
Gastroenterology and Hepatology
June 7, 2019

Concerns About Direct-Acting Antiviral Agents for Hepatitis C—Cause for Reassurance

Author Affiliations
  • 1Division of General Internal Medicine, Department of Medicine, University of Washington School of Medicine, Seattle
  • 2General Medicine Service, VA Puget Sound Health Care System, Seattle, Washington
JAMA Netw Open. 2019;2(6):e194757. doi:10.1001/jamanetworkopen.2019.4757

The advent of all-oral direct-acting antiviral (DAA) medication for hepatitis C virus (HCV) in 2013 was a substantial breakthrough in the treatment of this chronic viral infection. Many challenges remain in HCV treatment, such as barriers to screening, linkage to care, access to medication, and high pharmaceutical costs. However, the efficacy of DAA drugs is well established and represents a monumental advance over previous interferon-based therapies.1

Direct-acting antiviral drugs have relatively few contraindications, but they do have known risks, including reactivation of hepatitis B virus and several critical drug-drug interactions.2,3 Because most safety information for DAAs came from highly selected cohorts enrolled in DAA drug trials, the field has experienced a dearth of data on rates of adverse events in large, real-world populations. Early alarm was raised in small observational studies about excess risk for hepatocellular carcinoma recurrence after DAA therapy, although this concern was not supported in larger studies.4 The US Food and Drug Administration received hundreds of voluntary postmarketing reports of liver injury and liver failure among patients receiving DAAs, although it is impossible to discern from these cases whether the drugs or the HCV itself were the culprit.

The work of McGlynn and colleagues5 helps address many of these safety concerns. Using a retrospective cohort of insured patients with chronic HCV (n = 33 808) from 3 health systems in the National Patient-Centered Clinical Research Network, McGlynn and colleagues5 examined the rate of adverse clinical events and acute care use among patients during exposed and unexposed time within 180 days of receiving a DAA. The study used a time-to-event approach and benefited from complete data capture within the respective health networks, including laboratory results, diagnosis codes, prescription data, and health care use. The cohort included many individuals who were either excluded from most HCV clinical trials, such as those with decompensated cirrhosis, a history of liver cancer, or significant medical comorbidities, or demographic groups that were underrepresented in clinical trials, such as Hispanic or black individuals.

Because many potential drug-related adverse events may also result from HCV itself (eg, liver transplantation, hepatic decompensation, death), McGlynn and colleagues5 used marginal structural modeling to adjust their analyses for patient characteristics and for the probability of receiving antiviral treatment. Patients who receive DAAs inevitably differ from patients who do not receive DAAs in ways that could potentially affect their risk of experiencing an adverse outcome during the treatment period. The study methods help to overcome biases inherent in large observational studies of drug safety by minimizing the issue of confounding by indication to the extent statistically feasible.

After comparing 7207 person-years of DAA exposure time with 64 823 person-years without DAA exposure, the researchers found no signal that DAA recipients experience higher adverse event rates in any of the categories they examined, which included not only liver-related events but also renal, cardiovascular, and oncologic outcomes. They also found no evidence that DAA exposure was associated with increased use of acute health care services, including emergency department or inpatient care. They examined the rate of clinically significant hepatitis B virus reactivation using 3 different methods and found only a single case of a clinically significant reactivation.

The rates of adverse outcomes were consistently lower in patients with HCV who received treatment compared with individuals who did not receive treatment (death: adjusted odds ratio [aOR], 0.42; 95% CI, 0.30-0.59; multiple organ failure: aOR, 0.67; 95% CI, 0.49-0.90; hepatic decompensation: aOR, 0.61; 95% CI, 0.49-0.76; acute-on-chronic liver event: aOR, 0.71; 95% CI, 0.56-0.91; and arrhythmia: aOR, 0.47; 95% CI, 0.25-0.88) in this large, diverse, nationally representative sample. Patients treated for HCV likely receive more contact with the health care system and closer surveillance with laboratory results, imaging, and other diagnostic testing in the course of their treatment, making the lower observed risk of adverse events in the DAA group even more notable. The authors caution against concluding that DAAs protect against adverse outcomes because the risk of selection bias for receipt of antiviral therapy cannot be fully resolved. However, the results indicate that real-world populations have low risk of adverse events associated with DAA therapy.

The long-term benefits of HCV treatment have been extensively reported and include lower mortality, lower risk of liver cancer, and improved health-related quality of life for patients.6,7 While no retrospective study of adverse drug events can completely eliminate treatment selection bias, the results of McGlynn and colleagues5 may help support clinicians’ confidence that DAA therapy is not associated with excess treatment-related risks to patients.

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Article Information

Published: June 7, 2019. doi:10.1001/jamanetworkopen.2019.4757

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Beste LA. JAMA Network Open.

Corresponding Author: Lauren A. Beste, MD, MSc, VA Puget Sound Health Care System, 1660 S Columbian Way, Seattle, WA 98108 (lauren.beste@va.gov).

Conflict of Interest Disclosures: None reported.

References
1.
Falade-Nwulia  O, Suarez-Cuervo  C, Nelson  DR, Fried  MW, Segal  JB, Sulkowski  MS.  Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review.  Ann Intern Med. 2017;166(9):637-648. doi:10.7326/M16-2575PubMedGoogle ScholarCrossref
2.
Talavera Pons  S, Boyer  A, Lamblin  G,  et al.  Managing drug-drug interactions with new direct-acting antiviral agents in chronic hepatitis C.  Br J Clin Pharmacol. 2017;83(2):269-293. doi:10.1111/bcp.13095PubMedGoogle ScholarCrossref
3.
US Food and Drug Administration. FDA Drug Safety Communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis. https://www.fda.gov/Drugs/DrugSafety/ucm522932.htm. Accessed April 24, 2018.
4.
Waziry  R, Hajarizadeh  B, Grebely  J,  et al.  Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression.  J Hepatol. 2017;67(6):1204-1212. doi:10.1016/j.jhep.2017.07.025PubMedGoogle ScholarCrossref
5.
McGlynn  AE, Adams  JL, Kramer  J,  et al.  Assessing the safety of direct-acting antiviral agents for hepatitis C.  JAMA Netw Open. 2019;2(6): e194765. doi:10.1001/jamanetworkopen.2019.4765Google Scholar
6.
Carrat  F, Fontaine  H, Dorival  C,  et al; French ANRS CO22 Hepather cohort.  Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study.  Lancet. 2019;393(10179):1453-1464. doi:10.1016/S0140-6736(18)32111-1PubMedGoogle ScholarCrossref
7.
Younossi  Z, Papatheodoridis  G, Cacoub  P,  et al.  The comprehensive outcomes of hepatitis C virus infection: a multi-faceted chronic disease.  J Viral Hepat. 2018;25(suppl 3):6-14. doi:10.1111/jvh.13005PubMedGoogle ScholarCrossref
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