Hepatocellular carcinoma (HCC) is prevalent worldwide with suboptimal therapeutic outcomes. The advancement of therapeutic options and the development of new systemic therapies expand the ...armamentarium to tackle HCC. Treatment options should be provided based on the hierarchy of efficacy in a multidisciplinary perspective, instead of the traditional stage‐guided scheme. In advanced HCC, lenvatinib has a comparable efficacy as sorafenib for the first‐line therapy of HCC; while regorafenib, cabozantinib, and ramucirumab have been approved as second‐line therapy after the failure of sorafenib. Immune checkpoint inhibitor therapy prolongs response rate and survival and enables long‐term cure. Atezolizumab plus bevacizumab is superior to sorafenib as the first‐line therapy for advanced HCC. Several emerging regimens by the combination of various systemic therapies are currently under clinical trials. Systemic therapy may be used in the neoadjuvant, adjuvant or even as initial therapy for intermediate‐stage HCC. The paradigm shift of HCC treatment will improve patient outcomes.
Abstract
Aim
Alpha‐fetoprotein (AFP) checkup with abdominal ultrasonography for hepatocellular carcinoma (HCC) surveillance remains controversial. We evaluated a serial AFP‐increase and high AFP ...levels in the prediction of HCC.
Methods
At‐risk patients with chronic liver disease underwent HCC surveillance with trimonthly AFP measurement were included and categorized into HCC and non‐HCC groups. Their AFP levels at 12, 9, and 6 months (−6M) before the outcome date were evaluated. Group‐based trajectory analysis and multivariable regression analysis were performed to identify AFP trajectories as risk predictors for HCC.
Results
Overall, 2776 patients were included in the HCC (
n
= 326) and non‐HCC (
n
= 2450) groups. Serial AFP levels were significantly higher in the HCC than the non‐HCC groups. Trajectory analysis identified AFP‐increase group (11%) increased 24‐fold risks of HCC compared with the AFP‐stable (89%) group. Compared with patients without the AFP‐increase, a serial 3‐month AFP‐increase ≥10% elevated HCC risk by 12.1‐fold (95% CI: 6.5–22.4) in 6 months, and the HCC risks increased 13–60 fold in patients with cirrhosis, hepatitis B, or C receiving antiviral therapy, or AFP levels <20 ng/ml. Combining serial AFP‐increase ≥10% and AFP ≥20 ng/ml at −6M significantly increased 41.7‐fold (95% CI: 13.8–126.2) HCC risks. In patients who underwent biannual AFP checkups, those with both 6‐month AFP‐increase ≥10% and AFP ≥20 ng/ml increased 22.1‐fold (95% CI: 12.52–39.16) HCC risks in 6 months. Most HCCs were detected at an early stage.
Conclusions
Serial 3–6‐month AFP‐increase of ≥10% previously and AFP level of ≥20 ng/ml significantly increased HCC risks in 6 months.
Summary Background Whether sequential treatment can replace triple therapy as the standard treatment for Helicobacter pylori infection is unknown. We compared the efficacy of sequential treatment for ...10 days and 14 days with triple therapy for 14 days in first-line treatment. Methods For this multicentre, open-label, randomised trial, we recruited patients (≥20 years of age) with H pylori infection from six centres in Taiwan. Using a computer-generated randomisation sequence, we randomly allocated patients (1:1:1; block sizes of six) to either sequential treatment (lansoprazole 30 mg and amoxicillin 1 g for the first 7 days, followed by lansoprazole 30 mg, clarithromycin 500 mg, and metronidazole 500 mg for another 7 days; with all drugs given twice daily) for either 10 days (S-10) or 14 days (S-14), of 14 days of triple therapy (T-14; lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg for 14 days; with all drugs given twice daily). Investigators were masked to treatment allocation. Our primary outcome was the eradication rate in first-line treatment by intention-to-treat (ITT) and per-protocol (PP) analyses. This trial is registered with ClinicalTrials.gov , number NCT01042184. Findings Between Dec 28, 2009, and Sept 24, 2011, we enrolled 900 patients: 300 to each group. The eradication rate was 90·7% (95% CI 87·4–94·0; 272 of 300 patients) in the S-14 group, 87·0% (83·2–90·8; 261 of 300 patients) in the S-10 group, and 82·3% (78·0–86·6; 247 of 300 patients) in the T-14 group. Treatment efficacy was better in the S-14 group than it was in the T-14 group in both the ITT analysis (number needed to treat of 12·0 95% CI 7·2–34·5; p=0·003) and PP analyses (13·7 8·3–40, p=0·003). We recorded no significant difference in the occurrence of adverse effects or in compliance between the three groups. Interpretation Our findings lend support to the use of sequential treatment as the standard first-line treatment for H pylori infection. Funding National Taiwan University Hospital and National Science Council.
Background. Comparable sustained virologic response (SVR) rates have been documented between Asian patients who received 24 weeks of pegylated interferon (IFN) plus ribavirin and white patients who ...received 48 weeks of combination therapy for hepatitis C virus genotype 1 (HCV-1) infection. Whether a 48-week course of combination therapy shows a better SVR rate than a 24-week course of such therapy among Asian patients with HCV-1 infection has not been confirmed in multicenter, randomized studies. Methods. In this multicenter, randomized trial, 308 treatment-naive HCV-1-infected Asian patients were randomly assigned to receive either 24 or 48 weeks of pegylated IFN-α-2a (180 µg per week) plus ribavirin (1000–1200 mg/day) therapy. The primary end point was SVR, defined as an undetectable serum HCV RNA level 24 weeks after discontinuation of therapy. In addition, rapid virologic response (RVR) was defined as an undetectable serum HCV RNA level at week 4 of therapy, and complete early virologic response was defined as an undetectable serum HCV RNA level at 12 weeks of therapy in the absence of RVR. Results. By intention-to-treat analysis, patients who received 48 weeks of therapy had a significantly higher SVR rate than did those who received 24 weeks of therapy (76% vs. 56%; P<.001). Among patients with a baseline serum HCV RNA level <800,000 IU/mL and RVR, SVR rates were comparable between 24- and 48-week courses of therapy (94% vs. 100%; P=.13). In contrast, 48 weeks of therapy was associated with a significantly higher SVR rate than was 24 weeks of therapy among patients without RVR (39% vs.16%; P=.01) and among those who achieved a complete early virologic response (44% vs. 20%; P=.02). Conclusions. In treatment-naive Asian patients with HCV-1 infection, 48 weeks of pegylated IFN-α-2a plus ribavirin therapy is associated with a higher SVR rate, compared with 24 weeks of such therapy. Patients with a baseline serum HCV RNA level <800,000 IU/mL and who have achieved an RVR can receive a 24-week course of therapy without compromising the SVR rates; however, those who have not achieved an RVR but who have achieved a complete early virologic response should receive a 48-week course of therapy. Clinical trials registration. NCT00495131.
Background
Ropeginterferon alfa-2b is a novel mono-pegylated interferon that has only one major form as opposed to 8–14 isomers of other on-market pegylated interferon, allowing injection every two ...or more weeks with higher tolerability. It received European Medicines Agency and Taiwan marketing authorization in 2019 and 2020, for treatment of polycythemia vera. This phase I/II study aimed to have preliminary evaluation of safety and efficacy in chronic hepatitis B.
Methods
Thirty-one HBeAg-positive and 31 HBeAg-negative were stratified by HBeAg status and randomized at 1:1:1 ratio to q2w ropeginterferon alfa-2b 350 μg (group 1), q2w 450 μg (group 2) or q1w PEG-IFN alfa-2a 180 μg (group 3). Each patient received 48-week treatment (TW48) and 24-week post-treatment follow-up (FW24).
Results
The baseline demographics were comparable among the three groups, except for mean HBeAg in HBeAg-positive patients (2.90, 2.23, 2.99 log
10
S/CO, respectively). Cumulative HBeAg seroconversion rate at follow-up period was 27.3% (3/11), 36.4% (4/11), and 11.1% (1/9) with time to HBeAg seroconversion starting from TW24, TW16, and TW48 in group 1, 2, and 3, respectively. The rate of HBV DNA < 2000 IU/mL and HBsAg levels < 1500 IU/mL at FW24 were comparable in all groups. Ropeginterferon alfa-2b (group 1 & 2) had numerically lower incidence of rash (9.5% and 4.5%) as compared to PEG-IFN alfa-2a (36.8%). Ropeginterferon alfa-2b 350 μg (group 1) had more ALT elevation (38.1%), however the rate was comparable in group 2 (9.1%) and group 3 (10.5%).
Conclusion
In this preliminary study, ropeginterferon alfa-2b, although in only half the number of injections, is as safe and effective as pegylated interferon alfa-2a for chronic hepatitis B.
Graphic abstract
Although interferon (IFN)-based therapy has been shown to reduce hepatocellular carcinoma (HCC) development once patients with chronic hepatitis C virus (HCV) infection achieve sustained virologic ...response (SVR), IFN-based therapy is limited by its multiple adverse effects, non-oral administration, and unsatisfactory SVR rate. In recent years, IFN-free all-oral direct-acting antivirals (DAAs) have replaced IFN-based therapy as the standard of care for HCV infection worldwide because of the higher SVR rate and lower incidence of adverse effects. By using currently approved DAA regimens, HCV can be eradicated in more than 95% of infected hosts, regardless of their disease severity. Since 2016, the risk of de novo occurrence or recurrence of HCC in hepatitis C patients receiving DAAs has been debatable because of a report addressing an unexpected high early tumor recurrence rate. To solve this important, interesting, yet controversial issue, we thus reviewed the latest and most relevant articles on this subject and proposed recommendations to manage such patients for healthcare providers.
ABSTRACT
Background and Aim
Ropeginterferon alfa‐2b (P1101) is a novel long‐acting mono‐PEGylated recombinant proline interferon (IFN) conjugated to a 40 kDa branched polyethylene glycol (PEG) chain ...at its N‐terminus, allowing every‐two‐week injection. It received European Medicines Agency and Taiwan marketing authorization for the treatment of polycythemia vera in 2019 and 2020, respectively. This phase 2 study aimed to evaluate the pharmacokinetics, safety, and preliminary efficacy of ropeginterferon alfa‐2b as compared with PEG‐IFN‐α2a in patients with chronic hepatitis C virus genotype 1 infection.
Methods
One hundred six treatment naive patients were enrolled in this phase 2 study and randomized to four treatment groups: subcutaneous weekly PEG‐IFN‐α2a 180 μg (group 1), weekly ropeginterferon alfa‐2b 180 μg (group 2), weekly ropeginterferon alfa‐2b 270 μg (group 3), or biweekly ropeginterferon alfa‐2b 450 μg (group 4) plus ribavirin for 48 weeks.
Results
After multiple weekly administration, serum exposure (AUC0‐τ) in ropeginterferon alfa‐2b 180 μg was approximately 41% greater and the accumulation ratio of 2‐fold greater than PEG‐IFN‐α2a 180 μg. The incidences of flu‐like symptoms were 66.7% (18/27), 53.3% (16/30), 55.0% (11/20), and 48.3% (14/29), anxiety were 14.8% (4/27), 6.7% (2/30), 0%, and 0%, and depression were 25.9% (7/27), 13.3% (4/30), 0%, and 3.4% (1/29), for groups 1–4, respectively. Two grade 2 of 3 depression were noted in PEG‐IFN‐α2a arm, but none in ropeginterferon arms. The SVR24 rates were 77.8% (21/27), 66.7% (20/30), 80% (16/20), and 69% (20/29), respectively.
Conclusions
Ropeginterferon alfa‐2b showed longer effective half‐life and superior safety profile than PEG‐IFN‐α2a. Biweekly injection of ropeginterferon alfa‐2b will be studied in larger viral hepatitis patient population.
Ropeginterferon alfa‐2b (P1101) is a novel mono‐PEGylated recombinant proline‐interferon alfa‐2b with a 40 kDa branched polyethylene glycol (PEG) chain conjugated predominantly at its N‐terminus. Ropeginterferon alfa‐2b showed longer effective half‐life and superior safety profile than pegylated interferon alfa‐2a. Ropeginterferon alfa‐2b will be developed to fill the gap of the need for chronic hepatitis B treatment and is exceptionally needed for chronic hepatitis D.
Objective
Chronic hepatitis B (CHB) and metabolic dysfunction-associated fatty liver disease (MAFLD) are the leading causes of hepatocellular carcinoma (HCC). We aim to explore the impact of ...concurrent MAFLD on the risk of HCC in CHB.
Methods
Patients with CHB were consecutively recruited from 2006 to 2021. MAFLD was defined by steatosis and either obesity, diabetes mellitus, or other metabolic abnormalities. The cumulative incidence of HCC and associated factors were compared between the MAFLD and non-MAFLD groups.
Results
10,546 treatment-naïve CHB patients were included with a median follow-up of 5.1 years. CHB patients with MAFLD (
n
= 2212) had fewer hepatitis B e antigen (HBeAg)-positivity, lower HBV DNA levels, and Fibrosis-4 index compared with the non-MAFLD group (
n
= 8334). MAFLD was independently associated with a 58% reduced risk of HCC (adjusted hazard ratio aHR 0.42, 95% confidence interval CI 0.25–0.68,
p
< 0.001). Furthermore, steatosis and metabolic dysfunction had distinct effects on HCC. Steatosis was protective against HCC (aHR 0.45, 95% CI 0.30–0.67,
p
< 0.001), while a greater burden of metabolic dysfunction increased the risk (aHR 1.40 per dysfunction increase, 95% CI 1.19–1.66,
p
< 0.001). The protective effect of MAFLD was further confirmed in analysis with inverse probability of treatment weighting (IPTW), patients who had undergone antiviral therapy, those with probable MAFLD, and after multiple imputation for missing data.
Conclusions
Concurrent hepatic steatosis is independently associated with a lower risk of HCC, whereas the increasing burden of metabolic dysfunction aggravates the risk of HCC in untreated CHB patients.
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