Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Dec;75(6):1312-1322.
doi: 10.1016/j.jhep.2021.07.021. Epub 2021 Jul 29.

Protease inhibitor-based direct-acting antivirals are associated with increased risk of aminotransferase elevations but not hepatic dysfunction or decompensation

Jessie Torgersen  1 , Craig W Newcomb  2 , Dean M Carbonari  2 , Christopher T Rentsch  3 , Lesley S Park  4 , Alyssa Mezochow  5 , Rajni L Mehta  6 , Lynn Buchwalder  6 , Janet P Tate  6 , Norbert Bräu  7 , Debika Bhattacharya  8 , Joseph K Lim  6 , Tamar H Taddei  6 , Amy C Justice  9 , Vincent Lo Re 3rd  10
Affiliations

Protease inhibitor-based direct-acting antivirals are associated with increased risk of aminotransferase elevations but not hepatic dysfunction or decompensation

Jessie Torgersen et al. J Hepatol. 2021 Dec.

Abstract

Background & aims: Cases of acute liver injury (ALI) have been reported among chronic HCV-infected patients receiving protease inhibitor (PI)-based direct-acting antiviral (DAA) regimens, but no analyses have compared the risk of ALI in patients receiving PI- vs. non-PI-based DAAs. Thus, we compared the risk of 3 ALI outcomes between patients (by baseline Fibrosis-4 [FIB-4] group) receiving PI-based or non-PI-based DAAs.

Methods: We conducted a cohort study of 18,498 patients receiving PI-based DAA therapy (paritaprevir/ritonavir/ombitasvir±dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir) matched 1:1 on propensity score to those receiving non-PI-based DAAs (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir) in the 1945-1965 Veterans Birth Cohort (2014-2019). During exposure to DAA therapy, we determined development of: i) alanine aminotransferase (ALT) >200 U/L, ii) severe hepatic dysfunction (coagulopathy with hyperbilirubinemia), and iii) hepatic decompensation. We used Cox regression to determine hazard ratios (HRs) with 95% CIs for each ALI outcome within groups defined by baseline FIB-4 (≤3.25; >3.25).

Results: Among patients with baseline FIB-4 ≤3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR 3.98; 95% CI 2.37-6.68), but not severe hepatic dysfunction (HR 0.67; 95% CI 0.19-2.39) or hepatic decompensation (HR 1.01; 95% CI 0.29-3.49), compared to those receiving non-PI-based regimens. For those with baseline FIB-4 >3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR, 2.15; 95% CI 1.09-4.26), but not severe hepatic dysfunction (HR, 1.23 [0.64-2.38]) or hepatic decompensation (HR, 0.87; 95% CI 0.41-1.87), compared to those receiving non-PI-based regimens CONCLUSION: While risk of incident ALT elevations was increased in those receiving PI-based DAAs in both FIB-4 groups, the risk of severe hepatic dysfunction and hepatic decompensation did not differ between patients receiving PI- or non-PI-based DAAs in either FIB-4 group.

Lay summary: Cases of liver injury have been reported among patients treated with protease inhibitor-based direct-acting antivirals for hepatitis C infection, but it is not clear if the risk of liver injury among people starting these drugs is increased compared to those starting non-protease inhibitor-based therapy. In this study, patients receiving protease inhibitor-based treatment had a higher risk of liver inflammation than those receiving a non-protease inhibitor-based treatment, regardless of the presence of pre-treatment advanced liver fibrosis/cirrhosis. However, the risk of severe liver dysfunction and decompensation were not higher for patients treated with protease inhibitor-based regimens.

Keywords: acute liver injury; direct-acting antivirals; hepatitis C; protease inhibitor.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest D.B. has received research support to the NIH AIDS Clinical Trials Group (ACTG) from Abbvie and Regeneron for an ACTG-sponsored trial. All other authors declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

Fig. 1.
Fig. 1.. Selection of hepatitis C virus-infected patients from the 1945–1965 Veterans Birth Cohort for study inclusion.
ALI, acute liver injury; DAA, direct acting antiviral; DOAC, direct oral anticoagulant; HCV, hepatitis C virus; VA, Veterans Administration. * Index date was defined as the date that the DAA was initially dispensed in the VA on or after January 1, 2014. † Hepatitis B virus coinfection was defined by the presence (ever) of a positive HBV surface antigen.
Fig. 2.
Fig. 2.. Median alanine aminotransferase (ALT) with interquartile range (IQR) among propensity score-matched protease inhibitor (PI) and non-protease inhibitor-based direct-acting antiviral (DAA) initiators who had an ALI event defined by ALT >200 U/L, by baseline FIB-4.
(A) Median ALT among initiators of PI-based (elbasvir/grazoprevir, glecaprevir/pibrentasvir, or PRO/PROD) and non-PI-based (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir) DAA regimens with baseline FIB-4 ≤3.25. (B) Median ALT among initiators of PI-based and non-PI-based DAA regimens with baseline FIB-4 >3.25.
Fig. 3.
Fig. 3.. Hazard ratios (HRs) with 95% confidence intervals of specified acute liver injury outcomes for propensity score-matched cohorts of protease inhibitor (PI) and non-protease inhibitor-based direct-acting antiviral (DAA) initiators, by baseline advanced hepatic fibrosis/cirrhosis status by FIB-4.
Comparison of initiators of PI-based DAA regimens (elbasvir/grazoprevir, glecaprevir/pibrentasvir, or PRO/PROD) to non-PI-based regimens (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir).
See this image and copyright information in PMC

Comment in

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): 637–48. - PMC - PubMed
    1. United States Food and Drug Administration. FDA Drug Safety Communication: FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie. Oct 22, 2015. Accessed at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-c.... Accessed on March 28, 2021.
    1. United States Food and Drug Administration. FDA Drug Safety Communication: FDA warns about rare occurrence of serious liver injury with use of hepatitis C medicines Mavyret, Zepatier, and Vosevi in some patients with advanced liver disease. Accessed at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-r.... Accessed on March 28, 2021.
    1. Mak LY, Seto WK, Lai CL, Yuen MF. An update on the toxicological considerations for protease inhibitors used for hepatitis C infection. Expert Opin Drug Metab Toxicol 2018; 14(5): 483–91. - PubMed
    1. American Association for the Study of Liver Diseases/Infectious Diseases Society of America. HCV Guidance: Recommendations for testing m, and treating hepatitis C. Accessed at: https://www.hcvguidelines.org. Accessed on March 28, 2021.

Publication types

MeSH terms