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HBV Treatment Reduces HCC. Editorial: Re-assessing antiviral treatment criteria for chronic hepatitis B
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Download the PDF here
Download the PDF here
Lok, James; Dusheiko, Geoffrey
Hepatology May 30, 2023.
International HBV guidelines are due for renewal, and the manuscript by Huang helps energise the debate around expanding antiviral therapy (and simplifying treatment paradigms). In the HBeAg negative population, HBV DNA titres ≥2000 IU/ml are generally considered to be the threshold for initiating treatment as prospective and retrospective studies have shown this ceiling to be an important relative predictor of cirrhosis and HCC. Many experts now advocate for a more liberal and expanded approach to antiviral therapy to accommodate patients' preferences, and the argument for expanding treatment is supported by the tolerability, affordability, and relative safety of nucleos(t)ide analogues. Ultimately, a patient centred approach should be adopted that carefully considers virological parameters, risk factors for disease progression, age, as well as individual preferences.
In this issue of Hepatology, Huang et al. report a retrospective analysis of outcomes in 855 patients with CHB infection.6 The cumulative HCC incidence was compared between those who received antiviral therapy versus those who remained off-treatment. 59% were male, 20% were HBeAg-positive and the baseline mean HBV DNA was 4.5 ± 2.1 log10 IU/ml. All patients were classified into an "indeterminate" category of chronic hepatitis B if they failed to meet the criteria for the standard phases of infection specified in 2018 American Association for the Study of Liver Diseases (AASLD) guidelines. The study was conducted across 14 sites in the U.S.A, Europe and Asia between August 1992 and November 2021
(total follow-up of 4,714 person-years). Two percent of treatment naïve individuals transitioned to the "immune active" phase by year 10 of follow-up and were censored at the point of transition. Amongst the treated population in this "indeterminate" group, the 5-, 10- and 15-year incidence of HCC was 2.5%, 3.9% and 9.4%, respectively, compared with 2.7%, 14.7% and 19.1% in the untreated cohort.6 Antiviral therapy was a strong predictor of reduced HCC risk (adjusted hazard ratio 0.3, 95% CI 0.1-0.6, p=0.001), but the protective effect was mainly observed in males, HBeAg-positive individuals, those aged >35 years and possibly patients with HBV DNA concentrations of >1000 IU/ml. The incidence of HCC was low in both groups (5.2 per 1000 person years in the treated group; 11.6 per 1000 person years in the untreated group) and five years of antiviral treatment was required to achieve a significant reduction in oncogenic risk (years 0-5 p=0.67; year 5 onwards p=0.007). A reduction was not observed amongst females or HBeAg-negative individuals, and larger studies may be required to explore these lower risk populations.6
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Original
Antiviral therapy substantially reduces hepatocellular carcinoma risk in chronic Hepatitis B patients in the indeterminate phase
In this large, multinational study consisting of indeterminate phase CHB patients without advanced fibrosis from 14 sites in the U.S., Europe, and Asia, we determined that antiviral therapy was associated with a 70% reduction in the incidence of HCC after adjusting for relevant confounders using comparative groups that were well balanced by IPTW. In the IPTW cohort, the cumulative HCC incidence in treated versus untreated patients at 5-, 10- and 15-years were 3%, 4%, and 9% versus 3%, 15%, and 19%, respectively, with the benefits only apparent after five years of antiviral therapy as determined by our landmark analysis, consistent with previous literature14. Lower HCC incidence was observed in several patient subgroups that received antiviral therapy: male patients, those older than 35 years, those with positive HBeAg, and those with HBV DNA >1,000 IU/mL. Notably, significantly lower HCC incidence was also observed in treated patients with ALTULN as compared to untreated patients.
These data have important clinical implications. Given that a substantial proportion of patients with CHB are in the indeterminate phase, this represents a major proportion of CHB patients at increased risk of HCC 4 that can be mitigated by well-tolerated antiviral therapy as shown in this study. Therefore, treatment indications for CHB may be expanded to include indeterminate patients at higher risk such as male patients, those older than 35 years, positive HBeAg, and patients with HBV DNA>1,000 IU/mL regardless of ALT levels, especially given the favorable side effect profile and efficacy of current first-line nucleos(t)ide agents 10,22-28. Additionally, these data may be helpful to simplify the management of CHB, an unmet need that has been highlighted by a recent systematic review of the literature by the World Health Organization27. Inconsistencies between CHB guidelines and complicated treatment algorithms may be burdensome for care providers and likely contribute to suboptimal linkage to care for patients with CHB24,25
Abstract
Background & Aims:
Hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) is higher in the indeterminate phase compared to the inactive phase. However, it is unclear if antiviral therapy reduces HCC risk in this population. We aimed to evaluate the association between antiviral therapy and HCC risk in the indeterminate phase.
Approach & Results:
We analyzed 855 adult (59% male), treatment-naïve CHB patients without advanced fibrosis in the indeterminate phase at 14 centers (U.S., Europe, and Asia). Inverse probability of treatment weighting (IPTW) was used to balance the treated (n = 405) and untreated (n = 450) groups. The primary outcome was HCC development. The mean age was 46 ± 13 years, the median ALT was 38 (IQR, 24 - 52) U/L, the mean HBV DNA was 4.5 ± 2.1 log10 IU/mL and 20% were HBeAg positive. The two groups were similar after IPTW. After IPTW (n = 819), the 5-, 10- and 15-year cumulative HCC incidence was 3%, 4%, and 9% among treated patients (n = 394) versus 3%, 15%, and 19%, among untreated patients(n = 425), respectively (p = 0.02), with consistent findings in subgroup analyses for age > 35 years, males, HBeAg positive, HBV DNA > 1,000 IU/mL, and ALT < upper limit of normal. In multivariable Cox proportional hazards analysis adjusted for age, sex, HBeAg, HBV DNA, ALT, diabetes, and platelets, antiviral therapy remained an independent predictor of reduced HCC risk (adjusted HR 0.3, 95%CI 0.1 - 0.6, p = 0.001).
Conclusion:
Antiviral therapy reduces HCC risk by 70% among indeterminate phase CHB patients. These data have important implications for the potential expansion of CHB treatment criteria.
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