Systematic review and meta-analysis: impact of anti-viral therapy on portal hypertensive complications in HBV patients with advanced chronic liver disease.
Abstract:
BACKGROUND
The efficacy of nucleos(t)ide analogs (NAs) in non-cirrhotic chronic hepatitis B (CHB) patients is well-established. However, their impact on complications of portal hypertension in advanced chronic liver disease (ACLD) is less well characterized.
METHODS
MEDLINE/PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and abstracts of major international hepatology meetings were searched for publications from Jan 1, 1995 to Nov 30, 2021. Randomized control trials and observational studies reporting the efficacy of NAs in ACLD patients were eligible. Pooled risk ratios (RRs) for outcomes of interest were calculated with a random-effect or fixed-effect model, as appropriate.
RESULTS
Thirty-nine studies including 14,212 ACLD patients were included. NA treatment was associated with reduced risks of overall hepatic decompensation events (RR, 0.51; 95% confidence interval [CI]: 0.37-0.71), such as variceal bleeding (RR, 0.44; 95% CI: 0.26-0.74) and ascites (RR, 0.10; 95% CI: 0.01-1.59), on a trend-wise level. Moreover, the risks of hepatocellular carcinoma (HCC) (RR, 0.48; 95% CI: 0.30-0.75) and liver transplantation/death (RR, 0.36; 95% CI: 0.25-0.53) were also reduced by NA treatment and the first-line NAs were superior to non-first-line NAs in improving these outcomes (RR, 0.85; 95% CI: 0.75-0.97 and RR, 0.85; 95% CI: 0.73-0.99, respectively).
CONCLUSION
NA therapy lowers the risk of portal hypertension-related complications, including variceal bleeding, HCC, and liver transplantation/death.
© 2022. Asian Pacific Association for the Study of the Liver.
Keywords: Advanced chronic liver disease, Antiviral therapy, Meta-analysis, Systematic review
References: Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1211–1259
Polaris OC. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol. 2018;3:383–403
Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386:1546–1555
Franchis DR, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C, Baveno VII Faculty. Baveno VII—renewing consensus in portal hypertension. J Hepatol. 2021;2021:0168
Wu X, Zhou J, Xie W, Ding H, Ou X, Chen G, et al. Entecavir monotherapy versus de novo combination of lamivudine and adefovir for compensated hepatitis B virus-related cirrhosis: a real-world prospective multicenter cohort study. Infect Drug Resistance. 2019;12:745–757
Sun Y, Zhou J, Wang L, Wu X, Chen Y, Piao H, et al. New classification of liver biopsy assessment for fibrosis in chronic hepatitis B patients before and after treatment. Hepatology. 2017;65:1438–1450
Wang FY, Li B, Li Y, Liu H, Qu WD, Xu HW, et al. Entecavir for patients with hepatitis B decompensated cirrhosis in China: a meta-analysis. Sci Rep. 2016;6:32722
Ye XG, Su QM. Effects of entecavir and lamivudine for hepatitis B decompensated cirrhosis: meta-analysis. World J Gastroenterol. 2013;19:6665–6678
Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M. A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med. 1995;333:1657–1661
Robertson C, Ramsay C, Gurung T, Mowatt G, Pickard R, Sharma P, et al. Practicalities of using a modified version of the Cochrane Collaboration risk of bias tool for randomised and non-randomised study designs applied in a health technology assessment setting. Res Synth Methods. 2014;5:200–211
Sterne JA, Hernan MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355: i4919
Marcellin P, Chang TT, Lim SG, Tong M, Sievert W, Shiffman M, et al. Adefovir dipivoxil (Adv) Results in a consistent and significant improvement in liver histology and clinical status regardless of baseline Knodell fibrosis score in patients with Hbeag+ Chronic Hepatitis B. Digest Dis Week Abstr Itinerary Planner. 2003;2003:507
Mak LY, Seto WK, Hui RW, Fung J, Wong DK, Lai CL, et al. Fibrosis evolution in chronic hepatitis B e antigen-negative patients across a 10-year interval. J Viral Hepat. 2019;26:818–827
Wang JL, Du XF, Chen SL, Yu YQ, Wang J, Hu XQ, et al. Histological outcome for chronic hepatitis B patients treated with entecavir vs lamivudine-based therapy. World J Gastroenterol. 2015;21:9598–9606
Manolakopoulos S, Triantos C, Theodoropoulos J, Vlachogiannakos J, Kougioumtzan A, Papatheodoridis G, et al. Antiviral therapy reduces portal pressure in patients with cirrhosis due to HBeAg-negative chronic hepatitis B and significant portal hypertension. J Hepatol. 2009;51:468–474
Thabut D, Bureau C, Layese R, Bourcier V, Hammouche M, Cagnot C, et al. Validation of Baveno VI criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy. Gastroenterology. 2019;156:997-1009.e5
Lampertico P, Invernizzi F, Viganò M, Loglio A, Mangia G, Facchetti F, et al. The long-term benefits of nucleos(t)ide analogs in compensated HBV cirrhotic patients with no or small esophageal varices: A 12-year prospective cohort study. J Hepatol. 2015;63:1118–1125
Das K, Das K, Datta S, Pal S, Hembram JR, Dhali GK, et al. Course of disease and survival after onset of decompensation in hepatitis B virus-related cirrhosis. Liver Int. 2010;30:1033–1042
He L, Ye X, Ma J, Li P, Jiang Y, Hu J, et al. Antiviral therapy reduces rebleeding rate in patients with hepatitis B-related cirrhosis with acute variceal bleeding after endotherapy. BMC Gastroenterol. 2019;19:101
Kim CH, Um SH, Seo YS, Jung JY, Kim JD, Yim HJ, et al. Prognosis of hepatitis B-related liver cirrhosis in the era of oral nucleos(t)ide analog antiviral agents. J Gastroenterol Hepatol. 2012;27:1589–1595
Li CZ, Cheng LF, Li QS, Wang ZQ, Yan JH. Antiviral therapy delays esophageal variceal bleeding in hepatitis B virus-related cirrhosis. World J Gastroenterol. 2013;19:6849–6856
Liaw YF, Farrell G, Sung JJY, Chow WC, Shue K, Keene ON, et al. Disease progression in chronic hepatitis B with advanced fibrosis or cirrhosis. J Hepatol. 2005;42:183
Liu K, Choi J, Le A, Wong VWS, Chan SL, Chl Y, et al. Tenofovir disoproxil fumarate reduces hepatocellular carcinoma, decompensation and death in chronic hepatitis B patients with cirrhosis. Aliment Pharmacol Ther. 2019;50:1037–1048
Su TH, Hu TH, Chen CY, Huang YH, Chuang WL, Lin CC, et al. Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients. Liver Int. 2016;36:1755–1764
Park JY, Kim SG, Tak WY, Yim HJ, Jang BK, Kim MY, et al. Entecavir versus lamivudine for prevention of liver-related events in patients with HBV-related advanced liver disease: a multicenter, prospective study. Journal of hepatology. In Conference: 51st annual meeting of the european association for the study of the liver, international liver congress 2016. Barcelona spain. Conference start: 20160413. Conference end: 20160417. Conference publication: (var.pagings) 2016;64:S595
Wan YM, Li YH, Wu HM, Yang J, Xu Y, Yang LH, et al. Telbivudine versus lamivudine and entecavir for treatment-naïve, decompensated hepatitis B virus-related cirrhosis. Clin Exp Med. 2017;17:233–241
Pan HY, Pen HY, Yan J, Liu H, Chen L, Chen CR, et al. Comparison of clinical outcomes in cirrhotic chronic hepatitis B patients treated with Entecavir or Lamivudine plus Adefovir dipivoxil for 144 weeks. Hepatology. 2013;58:690A
Koklu S, Tuna Y, Gulsen MT, Demir M, Koksal AS, Kockar MC, et al. Long-term efficacy and safety of lamivudine, entecavir, and tenofovir for treatment of hepatitis B virus-related cirrhosis. Clin Gastroenterol Hepatol. 2013;11:88–94
Tsai MC, Yu HC, Hung CH, Lee CM, Chiu KW, Lin MT, et al. Comparing the efficacy and clinical outcome of telbivudine and entecavir naïve patients with hepatitis B virus-related compensated cirrhosis. J Gastroenterol Hepatol. 2014;29:568–575
Jang JW, Choi JY, Kim YS, Woo HY, Choi SK, Lee CH, et al. Long-term effect of antiviral therapy on disease course after decompensation in patients with hepatitis B virus-related cirrhosis. Hepatology. 2015;61:1809–1820
Jiang XY, Huang B, Huang DP, Wei CS, Zhong WC, Peng DT, et al. Long-term follow-up of cumulative incidence of hepatocellular carcinoma in hepatitis B virus patients without antiviral therapy. World J Gastroenterol. 2021;27:1101–1116
Li L, Liu W, Chen YH, Fan CL, Dong PL, Wei FL, et al. Antiviral drug resistance increases hepatocellular carcinoma: a prospective decompensated cirrhosis cohort study. World J Gastroenterol. 2013;19:8373–8381
Wong GL, Chan HL, Mak CW, Lee SK, Ip ZM, Lam AT, et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology. 2013;58:1537–1547
Jiang JN, Li SH, Su MH, Zhong SH, Wang BJ, Wu XL, et al. The clinical outcomes of the CHB and LC patients treated with long term nucleos(t)ide analogs under whole-course management: a real-life cohort study. J Hepatol. 2014;60:S428
Nguyen MH, Yang HI, Le A, Henry L, Nguyen N, Lee MH, et al. Reduced Incidence of hepatocellular carcinoma in cirrhotic and noncirrhotic patients with chronic hepatitis B treated with tenofovir-A propensity score-matched study. J Infect Dis. 2019;219:10–18
Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58:98–107
Li T, Qu YD, Wang Y, Lin CL, Yang BH, Wang L. Entecavir and low genetic barrier antiviral agents for hepatocellular carcinoma in hepatitis B Viral Cirrhosis: propensity score matching. JCPSP-J Coll Phys Surg Pak. 2019;29:317–323
Kim HR, Yim HJ, Kang S, Suh SJ, Kim SY, Hyun JJ, et al. Efficacy of telbivudine compared with entecavir in hepatitis B virus-related cirrhosis: 2 year follow-up data. Liver Int. 2015;35:860–869
Hou JL, Zhao W, Lee C, Hann HW, Peng CY, Tanwandee T, et al. Outcomes of long-term treatment of chronic HBV infection with entecavir or other agents from a randomized trial in 24 countries. Clin Gastroenterol Hepatol. 2020;18(457–467): e21
Cheinquer H, Raptopoulou-Gigi M, Sarin SK, Tanwandee T, Leung N, Peng CY, et al. Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with evidence of hepatic decompensation: week 96 results. Hep Intl. 2011;5:272
Liaw YF, Raptopoulou-Gigi M, Cheinquer H, Sarin SK, Tanwandee T, Leung N, et al. Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: a randomized, open-label study. Hepatology. 2011;54:91–100
Papatheodoridis GV, Manolakopoulos S, Touloumi G, Nikolopoulou G, Raptopoulou-Gigi M, Gogos C, et al. Hepatocellular carcinoma risk in HBeAg-negative patients with cirrhosis treated with entecavir or lamivudine: results of the nationwide HepNet. Greece cohort study. Hepatol Int. 2013;7:S306–S307
Wang Y, Li T, Han ZL, Qu YD, Lin CL, Wang L, et al. Incidence and predictors of hepatocellular carcinoma in Chinese hepatitis B virus-related cirrhotic patients receiving antiviral therapy: a retrospective cohort study. Int J Clin Exp Med. 2018;11:9462–9472
Lee J, Sinn DH, Kim JH, Gwak GY, Kim HS, Jung SH, et al. Hepatocellular carcinoma risk of compensated cirrhosis patients with elevated HBV DNA levels according to serum aminotransferase levels. J Korean Med Sci. 2015;30:1618–1624
Kumada T, Toyoda H, Yasuda S, Miyake N, Ito T, Tanaka J. Long-term prognosis with or without nucleot(s)ide analogue therapy in hepatitis B virus-related decompensated cirrhosis. J Viral Hepat. 2021;28:508–516
Yao FY, Terrault NA, Freise C, Maslow L, Bass NM. Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort. Hepatology. 2001;34:411–416
Zhao G, Hu P, Zhou H, Tang W, Xie Q. Effects of uncleoside analog on long term outcomes of treatment naïve patients with HBV related decompensated cirrhosis a retrospective cohort study. Hep Intl. 2015;9:S334
Lian JS, Zeng LY, Chen JY, Jia HY, Zhang YM, Xiang DR, et al. De novo combined lamivudine and adefovir dipivoxil therapy vs entecavir monotherapy for hepatitis B virus-related decompensated cirrhosis. World J Gastroenterol. 2013;19:6278–6283
Hsu YC, Mo LR, Chang CY, Perng DS, Tseng CH, Lo GH, et al. Entecavir versus lamivudine in the treatment of chronic hepatitis B patients with hepatic decompensation. Antivir Ther. 2012;17:605–612
Thiele M, Gluud LL, Krag A. Antiviral therapy in hepatitis B has no effect on mortality and decreases incidence of HCC only in patients with cirrhosis. A meta-analysis of 27 trials and 7034 patients. Hepatology. 2012;56:642A-643A
Singal AK, Fontana RJ. Meta-analysis: oral anti-viral agents in adults with decompensated hepatitis B virus cirrhosis. Aliment Pharmacol Ther. 2012;35:674–689
Mandorfer M, Kozbial K, Schwabl P, Chromy D, Semmler G, Stättermayer AF, et al. Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy. Hepatology. 2020;71:1023–1036
Wang HY, Wen B, Chang XY, Wu Q, Wen W, Zhou F, et al. Baveno VI criteria and spleen stiffness measurement rule out high-risk varices in virally suppressed HBV-related cirrhosis. J Hepatol. 2021;74:584–592
Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381:468–475
Jachs M, Hartl L, Bauer D, Simbrunner B, Stättermayer AF, Strassl R, et al. Long-term outcome of HBV-infected patients with clinically significant portal hypertension achieving viral suppression. J Pers Med. 2022;12:239
Authors
- Sha Chen |
- Sven Francque |
- Jidong Jia |
- Yuanyuan Kong |
- Sabela Lens |
- Min Li |
- Tingting Lv |
- Mattias Mandorfer |
- Tongtong Meng |
- Shiv K Sarin |
- Emmanouil Tsochatzis |
- Wei Wei |
- Shanshan Wu |
- Hitoshi Yoshiji |
- Hong You |
- Qian Zhang |
- Lianghui Zhao |
Springer
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Journal Title: Hepatology international
Journal ISSN: 1936-0541
Journal ISO Abbreviation: Hepatol Int
Publication Date: 2022-10-01
DOI: 10.1007/s12072-022-10369-w
Volume: 16
Issue: 5
Start Page: 1052
End Page: 1063