Background and Aims
Studies have suggested that tenofovir disoproxil fumarate (TDF) treatment is associated with a significantly lower risk of hepatocellular carcinoma (HCC) occurrence when compared ...with entecavir (ETV) therapy in patients with chronic hepatitis B. We aimed to compare HCC recurrence and survival of patients treated with TDF or ETV after surgical resection for hepatitis B virus (HBV)–related HCC.
Approach and Results
This historical cohort study included 1,695 consecutive patients treated with ETV (n = 813) or TDF (n = 882) after curative‐intent hepatectomy for HBV‐related HCC of Barcelona Clinic Liver Cancer stage 0 or A in Korea between 2010 and 2018. HCC recurrence and overall survival of patients were compared between ETV and TDF groups by propensity score–matched and multivariable‐adjusted Cox regression analyses from the date of hepatectomy for HCC. The mean age of the study patients was 54.8 years, and 1,294 patients (76.3%) were male. During the median follow‐up duration of 37.6 months with continued ETV or TDF therapy, 561 (33.1%) patients developed HCC recurrence, 144 (8.4%) died, and 22 (1.3%) received liver transplant. Compared with ETV, TDF therapy was associated with significantly higher recurrence‐free (P = 0.02) and overall survival (P = 0.03) rates by propensity score–matched analysis. By multivariable‐adjusted analysis, the TDF group was associated with significantly lower rates of HCC recurrence (hazard ratio HR, 0.82; 95% confidence interval, 0.68‐0.98; P = 0.03), and death or transplantation (HR, 0.62; 95% confidence interval, 0.44‐0.88; P = 0.01). TDF therapy was an independent protective factor for both early (<2 years; HR, 0.79; P = 0.03) and late (≥2 years; HR, 0.68; P = 0.03) postoperative HCC recurrence.
Conclusions
Among patients who underwent curative hepatectomy for HBV‐related HCC, TDF therapy was associated with a significantly lower risk of HCC recurrence and better overall patient survival compared with ETV therapy.
Background and Aims
HBsAg seroclearance is considered a realistic goal in patients with chronic hepatitis B (CHB), known as “functional cure.” However, it remains elusive whether nucleos(t)ide ...analogue (NUC)‐induced HBsAg seroclearance, compared with spontaneous HBsAg seroclearance, differs in its association with favorable long‐term clinical outcomes.
Approach and Results
A total of 1,972 CHB patients with confirmed HBsAg seroclearance at least two consecutive times, 6 months apart, were retrospectively analyzed. Risks of HCC development and composite clinical events, including HCC, liver‐related death, and liver transplantation, were compared between spontaneous and NUC‐induced HBsAg seroclearance. Of 1,972 patients, mean patient age was 53.7 years, and 64.4% were men. Cirrhosis was present in 297 (15.1%) patients. HBsAg seroclearance was achieved spontaneously in 1,624 (82.4%) patients and by NUC treatment in 348 (17.6%). HCC developed in 49 patients, with an annual incidence of 0.38 of 100 person‐years (PY) during a median follow‐up of 5.6 years. With 336 propensity‐score–matched pairs, risks of HCC (P = 0.52) and clinical events (P = 0.14) were not significantly different between NUC‐induced and spontaneous HBsAg seroclearance. By multivariable analysis, NUC‐induced HBsAg seroclearance, compared with spontaneous HBsAg seroclearance, was not associated with the significantly higher risk of HCC (adjusted HR AHR, 1.49; P = 0.26) and clinical events (AHR, 1.78; P = 0.06).
Conclusions
Risks of HCC and clinical events were not significantly different between spontaneous and NUC‐induced HBsAg seroclearance. Nonetheless, annual risk of HCC exceeds the recommended cutoff for HCC surveillance even after HBsAg seroclearance, suggesting that continued HCC surveillance is required.
We aimed to determine the surveillance performance of alpha‐fetoprotein (AFP), lectin‐reactive AFP (AFP‐L3), des‐gamma‐carboxy prothrombin (DCP), and their combinations for the early detection of ...hepatocellular carcinoma (HCC) by using prospectively collected longitudinal samples in patients at risk. Among 689 patients with cirrhosis and/or chronic hepatitis B who participated in four prospective studies, 42 HCC cases were diagnosed, selected, and matched with 168 controls for age, sex, etiology, cirrhosis, and duration of follow‐up in a 1:4 ratio. Levels of AFP, AFP‐L3, and DCP at the time of HCC diagnosis, month −6, and month −12 were compared between cases and controls. Of 42 HCC cases, 39 (93%) had cirrhosis, 36 (85.7%) had normal alanine aminotransferase levels, and 31 (73.8%) had very early‐stage HCC (single <2 cm). AFP and AFP‐L3 began to increase from 6 months before diagnosis of HCC in cases (P < 0.05), while they remained unchanged in controls. At HCC diagnosis, the area under the receiver operator characteristic curves (AUROCs) for AFP, AFP‐L3, and DCP were 0.77, 0.73, and 0.71, respectively. Combining AFP and AFP‐L3 showed a higher AUROC (0.83), while adding DCP did not further improve the AUROC (0.86). With the optimal cutoff values (AFP, 5 ng/mL; AFP‐L3, 4%), the sensitivity and specificity of AFP and AFP‐L3 combination were 79% and 87%, respectively. The sensitivity of ultrasonography was 48.6%, which was increased to 88.6% and 94.3% by adding AFP and AFP + AFP‐L3, respectively. Conclusion: Among three biomarkers, AFP showed the best performance in discriminating HCC cases from controls; the AFP and AFP‐L3 combination, adopting cutoff values (5 ng/mL and 4%, respectively), significantly improved the sensitivity for detecting HCC at a very early stage.
Most mortalities from liver disease and liver cancer worldwide are attributable to hepatitis B virus (HBV) and hepatitis C virus. Despite remarkable advances in the treatment of HBV over past ...decades, limited population‐level data are available regarding its impact on burden of liver disease and liver cancer. Mortality data from liver disease and liver cancer were obtained from the national death certificate database of Korea, an HBV‐endemic country, between 1999 and 2013, and were analyzed by Joinpoint analysis. For liver disease, number of annual deaths decreased by 62.3% (95% confidence interval CI, 62.0‐62.6), crude death rate (CDR) decreased by 64.6% (95% CI, 64.3‐64.9) from 21.2 to 7.5 per 100,000 population, and age‐standardized death rate (ADR) declined by 75.0% (95% CI, 74.7‐75.3), between 1999 and 2013. In contrast, for liver cancer, number of annual deaths increased by 17.8% (95% CI, 17.6‐18.0) and CDR increased by 10.2% (95% CI, 10.0‐10.4) from 20.5 to 22.6, although ADR decreased by 26.9% (95% CI, 26.6‐27.2). The annual number of patients receiving oral antiviral agents against HBV increased from 1,716 to 187,226 during the study period. The increase in mean age at death from liver disease was significantly greater than that from liver cancer (8.8 vs. 6.1 years: P = 0.02). Conclusion: Marked reduction in liver disease mortality by widespread use of antiviral treatments against HBV may increase the life expectancy and number of patients at risk of developing liver cancer, inadvertently leading to increased burden of liver cancer in an HBV‐endemic population. The competing nature between death from liver disease and that from liver cancer should be carefully considered in establishing a health care policy. (Hepatology 2017;66:1454–1463).
The most common cause of hepatocellular carcinoma (HCC) worldwide is chronic hepatitis B virus (HBV) infection (CHB). Long-term suppression of HBV replication by antiviral treatment reduces the risk ...of HCC and mortality. Nonetheless, only 2.2% of CHB patients globally received the treatment in 2019. Current international CHB guidelines recommend antiviral treatment only in subsets of patients with clear evidence of liver damage as evidenced by elevation of alanine aminotransferase (ALT). This review aims to provide existing evidence that the risk of HCC is significantly associated with serum levels of HBV DNA, and the association is non-linear parabolic, in both untreated and treated CHB patients, regardless of HBeAg status or ALT levels. Therefore, the decision for the antiviral treatment should be based on serum HBV DNA levels and age, rather than ALT levels or liver biopsy, to reduce or prevent the risk of HCC in CHB patients. The potential impact and cost-effectiveness data on early antiviral treatment initiation were also collated.
Summary
Background
It remains unknown whether antiviral treatment for HBeAg‐negative chronic hepatitis B (CHB) patients having high viral loads without significant elevation of alanine ...aminotransferase (ALT) levels would reduce the risks of clinical events.
Aim
To compare clinical outcomes of high viral load CHB patients untreated for normal or mildly elevated ALT vs those treated for ALT ≥ 2 upper limit of normal (ULN).
Methods
This historical cohort study included 5414 HBeAg‐negative CHB patients without cirrhosis at a tertiary hospital in Korea from 2000 to 2013. Inactive phase was defined as serum hepatitis B virus HBV DNA < 2000 IU/mL and persistently normal ALT (n = 3572). High viral load (HBV DNA ≥ 2000 IU/mL) patients were classified into three phases by ALT levels: Replicative (persistently normal ALT, n = 900); Mildly active (ALT 1‐2ULN, n = 396); and Active (ALT ≥ 2ULN, n = 546) phases. All Active phase patients were treated with nucleos(t)ide analogues.
Results
The mean age of the patients was 47 years without a significant difference among the groups. Compared with the treated Active phase group, the untreated Replicative phase group showed a significantly higher risk of hepatocellular carcinoma (HCC; HR 1.76; 95% CI 1.00 ‐ 3.10, P = 0.05) and death/transplantation (HR 2.14; 5% CI 1.09 ‐ 4.21, P = 0.03) by propensity score‐matched analysis. The untreated mildly active phase patients had further increase in risk of HCC and death/transplantation compared with the treated Active phase group by unadjusted, PS‐matched, competing risks, and multivariable‐adjusted analyses.
Conclusions
Untreated high viral load HBeAg‐negative CHB patients without significant ALT elevation had higher risks of clinical events than treated Active phase patients with elevated ALT.
LINKED CONTENT
This article is linked to Lim et al papers. To view these articles, visit https://doi.org/10.1111/apt.16788 and https://doi.org/10.1111/apt.16854
Summary
Background
Studies have shown a higher risk of hepatocellular carcinoma (HCC) with higher baseline serum hepatitis B virus (HBV) DNA levels in chronic hepatitis B (CHB) patients. However, the ...association between very high HBV DNA levels (>6 log10 IU/mL) and HCC risk remains unclear, especially in middle‐aged and old HBeAg‐positive patients.
Aim
To identify the association between broad‐range HBV DNA levels and HCC risk.
Methods
We conducted a historical cohort study in Korea involving 6949 non‐cirrhotic, treatment‐naïve CHB patients with alanine aminotransferase (ALT) <2× upper limit of normal for >1 year. HBV DNA was >6 log10 IU/mL in 2029 (29.2%) patients. Follow‐up was censored when the antiviral therapy was initiated.
Results
The mean age of the patients was 45 years. During 8.0 years of median follow‐up, 363 patients (5.2%) developed HCC. By multivariable Cox regression analysis, HCC risk was highest with baseline HBV DNA levels of 6‐7 log10 IU/mL (adjusted hazard ratio aHR 4.98; P < 0.001), and lowest with >8 log10 IU/mL (aHR 0.90; P = 0.71) and ≤4 log10 IU/mL (aHR 1.00; reference), which was independent of other predictive factors. The similar association between HBV DNA levels and HCC risk was consistently observed in all age subgroups (age <40, 40‐49 and ≥ 50 years).
Conclusions
HCC risk was highest with moderate serum HBV DNA levels of 6‐7 log10 IU/mL in CHB patients without significant ALT elevation. Extending treatment indication to CHB patients with moderate levels of HBV DNA may be considered to further prevent HCC, regardless of ALT levels.
Background
Current major guidelines for diagnosis of hepatocellular carcinoma (HCC) based on imaging findings are different from each other and do not include clinical risk factors as a diagnostic ...criteria.
Purpose
To developed and validated a new diagnostic score system using MRI and clinical features as applied in chronic hepatitis B patients.
Study Type
Retrospective observational study.
Subject
A total of 418 treatment‐naïve patients (out of 902 patients) with chronic hepatitis B having 556 lesions suspected for HCC which were eligible for curative treatment.
Field Strength/sequence
T1W GRE in‐ and opposed‐phase, T2W FSE, DWI, and T1W 3D‐GRE dynamic contrast‐enhanced sequences at 1.5 T and 3 T.
Assessment
Six radiologists with 7–22 years of experience independently evaluated MR images based on Liver Imaging Reporting and Data System (LI‐RADS) version 2018.
Statistical Tests
Based on logistic regression analysis of MRI features and clinical factors, a risk score system was devised in derivation cohorts (268 patients, 352 lesions) and externally validated (150 patients, 204 lesions). The performance of the new score system was assessed by Harell's c‐index. Using cutoff value of 12, maintaining positive predictive value ≥95%, the diagnostic performances of the score system were compared with those of LR‐5.
Results
The 15‐point diagnostic scoring system used MRI features (lesion size, nonrim arterial phase hyperenhancement, portal venous phase hypointensity, hepatobiliary phase hypointensity, and diffusion restriction) and clinical factors (alpha‐fetoprotein and platelet). It showed good discrimination in the derivation (c‐index, 0.946) and validation cohorts (c‐index, 0.907). Using a risk score of 12 as a cut‐off, this system yielded higher sensitivity than LR‐5 (derivation cohort, 76.8% vs. 52.1%; validation cohort, 73.4% vs. 49.5%) without significant decrease in specificity (derivation cohort, 93.1% vs. 97.2%, P = 0.074; validation cohort, 91.7% vs. 96.1%, P = 0.299).
Data Conclusion
A new score system showed improved sensitivity in chronic hepatitis B patients compared to LI‐RADS without significant compromise in specificity.
Evidence Level
3
Technical Efficacy
Stage 2.
LINKED CONTENT
This article is linked to Wu et al papers. To view these articles, visit
https://doi.org/10.1111/apt.17667
and
https://doi.org/10.1111/apt.17685
