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  The Liver Meeting
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Washington on 04-08
November 2022
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HBV Therapy Slices HCC Risk in HBV's Indeterminate Phase
  AASLD-The Liver Meeting, November 4-8, 2022, Washington, DC
Mark Mascolini
Antiviral therapy for chronic hepatitis B virus (HBV) infection in the indeterminate phase sliced HCC risk by 70% through 15 years of follow-up [1]. Researchers from the National University of Singapore and REAL-B Consortium colleagues across the world believe their findings may support expansion of chronic HBV treatment criteria.
Chronic HBV infection accounts for more cases of HCC than hepatitis C, alcohol, or nonalcoholic steatohepatitis (NASH) [2,3]. As many as 40% of chronic HBV patients fit into the indeterminate phase, which includes anyone not classified as immune tolerant, immune active, or inactive. Prior research showed that HCC incidence stands significantly higher in the indeterminate phase than in the inactive phase [4].
The new multicenter study aimed to explore potential associations between anti-HBV therapy and HCC risk in HBV's indeterminate phase. This retrospective analysis of people with chronic HBV took place at 14 sites in the United States, Europe, and Asia. Participants had to be at least 18 years old and naive to anti-HBV therapy. Researchers confirmed their indeterminate phase status by two consecutive sets of alanine aminotransferase (ALT) and HBV DNA assessments, plus a test for HBeAg, the HBV protein indicating ongoing HBV replication.
A long list of patient characteristics and liver measures could exclude a person from the analysis: less than 1 year of follow-up, HCC developing within 6 months of the index date, coinfection with HCV or HIV, transplantation, FIB-4 above 3.25, transient elastography above 12.5 kPA, liver stiffness by magnetic resonance elastography above 4.63 kPA, or liver biopsy indicating stage 3 or 4 fibrosis. The investigators relied on World Health Organization HBV prevention and treatment guidelines [5] to categorize chronic HBV as immune tolerant, immune active, inactive, or indeterminate.
The researchers balanced baseline characteristics between the antiviral treated and untreated groups by inverse probability of treatment weighting for age, sex, ALT, aspartate aminotransferase (AST), HBV DNA, HBeAg, platelet count, presence of diabetes, and follow-up time. Univariable and multivariable Cox proportional hazards regression estimated hazard ratios for factors associated with HCC development.
After applying inclusion and exclusion criteria to 29,400 people with chronic HBV in the REAL-B consortium [6], the researchers ended up with 855 people for the current analysis, 405 of them treated for HBV and 450 untreated.
Before inverse probability of treatment weighting, the treated group differed significantly from the untreated group in age (average 47.4 vs 45.6, P = 0.05), proportion of men (65.7% vs 52.9%, P < 0.001), proportion HBeAg-positive (28.4% vs 13.1%, P < 0.001), HBV DNA log10 IU/mL (5.2 vs 3.8, P < 0.0001), ALT (median 43 vs 33, P < 0.0001), proportion with FIB-4 below 1.45 (62.0% vs 72.2%, P = 0.001), proportion with FIB-4 1.45 to 3.25 (38% vs 27.8%, P = 0.001), and time between ALT measurement in months (5.5 vs 7.5, P < 0.0001). Inverse probability of treatment weighting erased all these differences, creating balanced groups of 394 treated people and 425 untreated people.
HCC incidence in HBV's indeterminate phase proved significantly lower in the antiviral-treated group through 15 years (9.4% vs 19.1%, P = 0.02). Incidence per 1000 person-years stood at 5.2 in the treated group and 11.6 in the untreated group. In the inverse probability of treatment weighting cohort, treatment cut chances of HCC 70% (adjusted hazard ratio [aHR] 0.30, 95% confidence interval [CI] 0.10 to 0.60, P = 0.001). All other independent predictors of HCC raised the risk: age over 45 years (aHR 4.6, 95% CI 2.1 to 10.1, P < 0.001), male sex (aHR 32.5, 95% CI 3.5 to 304.5, P = 0.002), ALT above versus below the upper limit of normal (aHR 2.4, 95% CI 1.0 to 5.6, P = 0.05), and HBeAg-positive (aHR 3.7, 95% CI 1.8 to 7.7, P < 0.001).
The impact of treatment in lowering HCC incidence remained significant through 15 years for the subgroup older than 45 but not for the younger subgroup. Antiviral treatment significantly lowered HCC incidence through 15 years regardless of whether ALT was above or below the upper limit of normal. Treatment significantly cut HCC incidence through 15 years when HBV DNA stood above but not below 1000 IU/mL.
Although the study group was multinational, most people were Asian, so the researchers cautioned that findings may not apply to other ethnic groups.
Because results may favor expansion of chronic HBV treatment criteria, the investigators see a need to study the cost-effectiveness of wider treatment recommendations.
1. Huang DQ, Tran A, Yeh M-L, et al. Antiviral therapy reduces hepatocellular carcinoma risk among HBV patients in the indeterminate phase. AASLD-The Liver Meeting, November 4-8, 2022, Washington, DC. Abstract 36.
2. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209-249. doi: 10.3322/caac.21660.
3. Huang DQ, Singal AG, Kono Y, et al. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab. 2022 5;34:969-977.e2. doi: 10.1016/j.cmet.2022.05.003.
4. Huang DQ, Li X, Le MH, et al. Natural history and hepatocellular carcinoma risk in untreated chronic hepatitis B patients with indeterminate phase. Clin Gastroenterol Hepatol. 2022;20:1803-1812.e5. doi: 10.1016/j.cgh.2021.01.019. https://pubmed.ncbi.nlm.nih.gov/33465482/
5. World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. 1 March 2015. https://www.who.int/publications/i/item/9789241549059
6. Yang H-I, Yeh M-L, Wong G, et al. Cochrane Library. REAL-B (Real-world Effectiveness from the Asia Pacific Rim Liver Consortium for HBV) risk score for the prediction of hepatocellular carcinoma in chronic hepatitis B patients treated with oral antiviral therapy. https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01989952/full?