Abstract
Direct-acting antivirals (DAA) have become the treatment of choice for hepatitis C. Nevertheless, efficacy of DAA in preventing hepatitis C complications remains uncertain. We evaluated the impact of DAA on hepatocellular carcinoma (HCC) occurrence and recurrence, all-cause mortality, liver decompensation and liver transplantation as compared to non-DAA treated hepatitis C and the association to baseline liver status. A systematic search for articles from March 1993 to March 2022 was conducted using three electronic databases. Randomized, case-control and cohort studies with comparison to non-DAA treatment and reporting at least one outcome were included. Meta-analysis and sub-group meta-analysis based on baseline liver status were performed. Of 1497 articles retrieved, 19 studies were included, comprising of 266,310 patients (56.07% male). DAA reduced HCC occurrence significantly in non-cirrhosis (RR 0.80, 95% CI 0.69–0.92) and cirrhosis (RR 0.39, 95% CI 0.24–0.64) but not in decompensated cirrhosis. DAA treatment lowered HCC recurrence (RR 0.71, 95% CI 0.55–0.92) especially in patients with baseline HCC and waiting for liver transplant. DAA also reduced all-cause mortality (RR 0.43, 95% CI 0.23–0.78) and liver decompensation (RR 0.52, 95% CI 0.33–0.83) significantly. However, DAA did not prevent liver transplantation. The study highlighted the importance of early DAA initiation in hepatitis C treatment for benefits beyond sustained virological response. DAA therapy prevented HCC particularly in non-cirrhosis and compensated cirrhosis groups indicating benefits in preventing further worsening of liver status. Starting DAA early also reduced HCC recurrence, liver decompensation, and all-cause mortality.
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The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.
References
American Association for the Study of Liver Diseases (2022). Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 27 Feb 2023.
Baumert TF, Juhling F, Ono A, Hoshida Y (2017) Hepatitis C-related hepatocellular carcinoma in the era of new generation antivirals. BMC Med 15:52. https://doi.org/10.1186/s12916-017-0815-7
Butt AA, Yan P (2021) Natural history of hepatitis C virus infection in a large national seroconversion cohort in the direct-acting antiviral agent era: results from ERCHIVES. J Viral Hepat 28:916–924. https://doi.org/10.1111/jvh.13507
Cabibbo G, Celsa C, Calvaruso V et al (2019) Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients. J Hepatol 71:265–273. https://doi.org/10.1016/j.jhep.2019.03.027
Carrat F, Fontaine H, Dorival C et al (2019) Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study. Lancet 393(10179):1453–1464. https://doi.org/10.1016/s0140-6736(18)32111-1
Cheung MCM, Walker AJ, Hudson BE et al (2016) Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol 65:741–747. https://doi.org/10.1016/j.jhep.2016.06.019
Conti F, Buonfiglioli F, Scuteri A et al (2016) Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol. 65:727–733. https://doi.org/10.1016/j.jhep.2016.06.015
Crossan C, Tsochatzis EA, Longworth L et al (2015) Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation. Health Technol Assess. 19:1–409. https://doi.org/10.3310/hta19090
Denford S, Frost J, Dieppe P, Cooper C, Britten N (2014) Individualisation of drug treatments for patients with long-term conditions: a review of concepts. BMJ Open 4:e004172. https://doi.org/10.1136/bmjopen-2013-004172
Fourati S, Feld JJ, Chevaliez S, Luhmann N (2018) Approaches for simplified HCV diagnostic algorithms. J Int AIDS Soc 21:e25058. https://doi.org/10.1002/jia2.25058
Frenette CT, Isaacson AJ, Bargellini I, Saab S, Singal AG (2019) A practical guideline for hepatocellular carcinoma screening in patients at risk. Mayo Clin Proc Innov Qual Outcomes 3:302–310. https://doi.org/10.1016/j.mayocpiqo.2019.04.005
Fujiwara N, Friedman SL, Goossens N, Hoshida Y (2018) Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 68:526–549. https://doi.org/10.1016/j.jhep.2017.09.016
Gastroenterological Society of Australia (2022) Australian recommendations for the management of hepatitis C virus infection: a consensus statement. https://www.hepcguidelines.org.au/
Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor-Robinson SD (2008) Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol 14:4300–4308. https://doi.org/10.3748/wjg.14.4300
Hanafy AS, Bassiony MA, Basha MAA (2019) Management of HCV-related decompensated cirrhosis with direct-acting antiviral agents: who should be treated? Hepatol Int. 13:165–172. https://doi.org/10.1007/s12072-019-09933-8
Harrer M, Cuijpers P, Furukawa T, Ebert D (2021) Doing meta-analysis with R: a hands-on guide. 1st ed. Chapman and Hall/CRC
Hill LA, Delmonte RJ, Andrews B et al (2018) Treatment of hepatitis C with direct-acting antivirals significantly reduces liver-related hospitalizations in patients with cirrhosis. Eur J Gastroenterol Hepatol 30:1378–1383. https://doi.org/10.1097/meg.0000000000001195
Hsu CS, Chao YC, Lin HH, Chen DS, Kao JH (2015) Systematic review: impact of interferon-based therapy on HCV-related hepatocellular carcinoma. Sci Rep 5:9954. https://doi.org/10.1038/srep09954
Huang AC, Mehta N, Dodge JL, Yao FY, Terrault NA (2018) Direct-acting antivirals do not increase the risk of hepatocellular carcinoma recurrence after local-regional therapy or liver transplant waitlist dropout. Hepatology 68:449–461. https://doi.org/10.1002/hep.29855
Ikeda K, Kawamura Y, Kobayashi M et al (2017) Direct-acting antivirals decreased tumor recurrence after initial treatment of hepatitis C virus-related hepatocellular carcinoma. Dig Dis Sci 62:2932–2942. https://doi.org/10.1007/s10620-017-4739-z
Imai Y, Kawata S, Tamura S et al (1998) Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Osaka Hepatocellular Carcinoma Prevention Study Group. Ann Intern Med 129:94–99. https://doi.org/10.7326/0003-4819-129-2-199807150-00005
Lai MM (2002) Hepatitis C virus proteins: direct link to hepatic oxidative stress, steatosis, carcinogenesis and more. Gastroenterology 122:568–571. https://doi.org/10.1053/gast.2002.31474
Lazarus JV, Pericas JM, Picchio C et al (2019) We know DAAs work, so now what? Simplifying models of care to enhance the hepatitis C cascade. J Intern Med 286:503–525. https://doi.org/10.1111/joim.12972
Leong TY, Leong AS (2005) Epidemiology and carcinogenesis of hepatocellular carcinoma. HPB (Oxford) 7(1):5–15. https://doi.org/10.1080/13651820410024021
Lo Re V, Lim JK, Goetz MB et al (2011) Validity of diagnostic codes and liver-related laboratory abnormalities to identify hepatic decompensation events in the Veterans Aging Cohort Study. Pharmacoepidemiol Drug Saf 20:689–699. https://doi.org/10.1002/pds.2148
Louro J, Posso M, Hilton Boon M et al (2019) A systematic review and quality assessment of individualised breast cancer risk prediction models. Br J Cancer 121:76–85. https://doi.org/10.1038/s41416-019-0476-8
Lusivika-Nzinga C, Fontaine H, Dorival C, Simony M, Pol S, Carrat F (2019) The dynamic effect of direct-acting antiviral treatments on the risk of hepatocellular carcinoma in patients with cirrhosis and chronic hepatitis C. J Viral Hepat 26:1489–1492. https://doi.org/10.1111/jvh.13186
McGlynn KA, Petrick JL, El-Serag HB (2021) Epidemiology of hepatocellular carcinoma. Hepatology 73:4–13. https://doi.org/10.1002/hep.31288
Mettke F, Schlevogt B, Deterding K et al (2018) Interferon-free therapy of chronic hepatitis C with direct-acting antivirals does not change the short-term risk for de novo hepatocellular carcinoma in patients with liver cirrhosis. Aliment Pharmacol Ther. 47(4):516–525. https://doi.org/10.1111/apt.14427
Moher D, Shamseer L, Clarke M et al (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:1. https://doi.org/10.1186/2046-4053-4-1
Park H, Jiang X, Song HJ et al (2021) The impact of direct-acting antiviral therapy on end-stage liver disease among individuals with chronic hepatitis C and substance use disorders. Hepatology 74:566–581. https://doi.org/10.1002/hep.31732
Park H, Wang W, Henry L, Nelson DR (2019) Impact of all-oral direct-acting antivirals on clinical and economic outcomes in patients with chronic hepatitis C in the United States. Hepatology 69:1032–1045. https://doi.org/10.1002/hep.30303
Preda CM, Baicus C, Sandra I et al (2019) Recurrence rate of hepatocellular carcinoma in patients with treated hepatocellular carcinoma and hepatitis C virus-associated cirrhosis after ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin therapy. United European Gastroenterol J 7:699–708. https://doi.org/10.1177/2050640619841254
Roche B, Coilly A, Duclos-Vallee JC, Samuel D (2018) The impact of treatment of hepatitis C with DAAs on the occurrence of HCC. Liver Int. 38:139–145. https://doi.org/10.1111/liv.13659
Singal AG, Rich NE, Mehta N et al (2019) Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a Multicenter North American Cohort Study. Gastroenterology 156(1683-1692):e1681. https://doi.org/10.1053/j.gastro.2019.01.027
Singer AW, Reddy KR, Telep LE et al (2018) Direct-acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: a retrospective cohort study. Aliment Pharmacol Ther 47:1278–1287. https://doi.org/10.1111/apt.14593
Smith-Palmer J, Cerri K, Valentine W (2015) Achieving sustained virologic response in hepatitis C: a systematic review of the clinical, economic and quality of life benefits. BMC Infect Dis 15:19. https://doi.org/10.1186/s12879-015-0748-8
Sterne JA, Hernan MA, Reeves BC et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 355:i4919. https://doi.org/10.1136/bmj.i4919
Tse CS, Yang JD, Mousa OY et al (2021) Direct-acting antiviral therapy in liver transplant patients with hepatocellular carcinoma and hepatitis C. Transplant Direct 7(1):e635. https://doi.org/10.1097/txd.0000000000001049
Virlogeux V, Pradat P, Hartig-Lavie K et al (2017) Direct-acting antiviral therapy decreases hepatocellular carcinoma recurrence rate in cirrhotic patients with chronic hepatitis C. Liver Int 37:1122–1127. https://doi.org/10.1111/liv.13456
Warzyszyńska K, Jonas M, Wasiak D, Kosieradzki M, Małkowski P (2017) Accelerated hepatocellular carcinoma recurrence rate after postoperative direct-acting antivirals treatment - preliminary report. Clin Exp Hepatol 3:194–197. https://doi.org/10.5114/ceh.2017.71483
World Health Organisation (WHO) (2022) Hepatitis C. https://www.who.int/news-room/fact-sheets/detail/hepatitis-c. Accessed 11 June 2022
World Health Organisation (WHO) (2018) Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. https://www.ncbi.nlm.nih.gov/books/NBK531733. Accessed 31 August 2023.
Zanetto A, Shalaby S, Vitale A et al (2017) Dropout rate from the liver transplant waiting list because of hepatocellular carcinoma progression in hepatitis C virus-infected patients treated with direct-acting antivirals. Liver Transpl 23:1103–1112. https://doi.org/10.1002/lt.24790
Zoratti MJ, Siddiqua A, Morassut RE et al (2020) Pangenotypic direct acting antivirals for the treatment of chronic hepatitis C virus infection: a systematic literature review and meta-analysis. EClinicalMedicine 18:100237. https://doi.org/10.1016/j.eclinm.2019.12.007
Zhu RX, Seto WK, Lai CL, Yuen MF (2016) Epidemiology of hepatocellular carcinoma in the Asia-Pacific region. Gut Liver 10:332–339. https://doi.org/10.5009/gnl15257
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The authors express their gratitude towards the Director General of Health, Ministry of Health Malaysia for the permission to publish.
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K.C. Yew conceptualized, designed, and supervised the study. Q.R. Tan, P.C. Lim, and W.Y. Low performed formal analysis, investigation, data curation, wrote the original draft, and edited and reviewed the manuscript. P.C. Lim did the quality assessment of the included studies and prepared Fig. 1 and Table 1. C.Y. Lee performed the meta-analyses; produced Figs. 2, 3, 4, and 5; and edited and reviewed the manuscript. The authors confirm that no paper mill and artificial intelligence was used.
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Yew, K.C., Tan, Q.R., Lim, P.C. et al. Assessing the impact of direct-acting antivirals on hepatitis C complications: a systematic review and meta-analysis. Naunyn-Schmiedeberg's Arch Pharmacol 397, 1421–1431 (2024). https://doi.org/10.1007/s00210-023-02716-x
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DOI: https://doi.org/10.1007/s00210-023-02716-x