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Aim: This retrospective study aimed to investigate the impact of proton pump inhibitor treatment (PPI) and antibiotic treatment on the therapeutic outcomes of hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/Bev). Methods: The present study included a total of 441 HCC patients who were treated with Atez/Bev in 20 Japanese institutions from September 2020 to April 2022. We adopted the inverse probability of treatment weight to adjust for imbalance in the baseline characteristics of patients with and without PPI treatment as well as patients with and without antibiotic treatment. Results: The progression‐free survival (PFS) and overall survival (OS) of patients with and without PPI treatment did not differ to a statistically significant extent. In the weighted cohort, the difference in PFS and OS between the patients with and without PPI did not reach statistical significance (median PFS, 7.0 vs. 6.5 months, p = 0.07; 1‐year survival rate 66.3% and 73.8%, p = 0.9). The PFS and OS in patients with antibiotic treatment were worse in comparison to patients without antibiotic treatment (median PFS, 3.8 vs. 7.0 months, p = 0.007; 1‐year survival rate 58.8% and 70.3%, p = 0.01). In the weighted cohort, the PFS and OS of the two groups did not differ to a statistically significant extent (median PFS, 3.8 vs. 6.7 months, p = 0.2; 1‐year survival rate, 61.8% and 71.0%, p = 0.6). Conclusions: The therapeutic outcomes of Atez/Bev in HCC patients did not differ between patients with and without PPI treatment or between patients with and without antibiotic treatment. [ABSTRACT FROM AUTHOR]

Aim: The present study focused on the association of early bevacizumab (Bev) interruption with the clinical outcome of atezolizumab plus bevacizumab. Methods: This retrospective study included 239 patients with advanced hepatocellular carcinoma receiving atezolizumab/Bev from September 2020 to June 2021 at 16 different institutions in Japan. We conducted a 9‐week landmark analysis to investigate the association of Bev interruption due to adverse events with the therapeutic efficacy. Results: The median age was 73.0 (68.0–80.0) years old, with 195 (81.6%) men. The objective response rate was significantly higher in patients without Bev interruption than in those with it (34.5% vs. 17.3%, p = 0.038). The median progression‐free survival (PFS) was 6.5 months (95% confidence interval [CI] 4.5–9.7) and 9.0 months (95% CI 7.1–not applicable) in patients with and without Bev interruption, respectively, with statistical significance (p = 0.021). The 12‐month overall survival (OS) rates in patients with and without Bev interruption were 49.4% (CI 27.7%–67.9%) and 82.2% (95% CI 70.3%–89.6%), respectively, showing a significant difference (p = 0.004). The presence of Bev interruption was a significant factor associated with the PFS (p = 0.021) and OS (p = 0.008). A multivariate analysis showed that modified albumin–bilirubin 2b (p < 0.001) and later‐line treatment (p = 0.018) were unfavorable factors associated with Bev interruption. Liver injury, appetite loss, protein urea, and ascites or hepatic edema were more frequently found in patients with Bev interruption than in those without it. Conclusions: Early Bev interruption was an unfavorable factor associated with the PFS and OS. Good liver function and treatment settings may be associated with maintaining Bev treatment. [ABSTRACT FROM AUTHOR]

Aim: Multiple molecular agents have been developed for treating unresectable hepatocellular carcinoma. This study aimed to elucidate the clinical efficacy of sequential treatment with lenvatinib after regorafenib failure. Methods: From June 2017 to October 2020, 63 patients with Child–Pugh A and treated with regorafenib followed by sorafenib were enrolled (median age 71 years, 52 men, Barcelona Clinic Liver Cancer B:C = 23:40). They were divided into two groups, those treated with lenvatinib after regorafenib treatment (R‐L group, n = 47) and those who did not receive lenvatinib after regorafenib (non‐R‐L group, n = 16). Prognostic factors were retrospectively analyzed after adjustment with inverse probability weighting. Results: Serum albumin level at the start of regorafenib and reasons for discontinuation of regorafenib were significantly different between the R‐L and non‐R‐L groups, whereas the albumin‐bilirubin score, Child–Pugh class, and tumor burden were not. Progression‐free survival was also not significantly different (median 4.1 vs. 3.8 months, p = 0.586). As for overall survival, the R‐L group showed better prognosis after introducing regorafenib and after introducing sorafenib, following inverse probability weighting adjustment (MST 19.7 vs. 10.3 months, 33.8 vs. 15.3 months, p < 0.001 and p = 0.022, respectively). Modified albumin‐bilirubin grade 2b (score >−2.27) at the start of regorafenib (HR 2.074, p = 0.041) and the presence of lenvatinib treatment after regorafenib failure (HR 0.355, p = 0.004) were found to be significant prognostic factors in Cox proportional hazards multivariate analysis, after inverse probability weighting adjustment. Conclusion: These results show that lenvatinib is a good sequential treatment option after progression under regorafenib therapy in unresectable hepatocellular carcinoma patients with better hepatic reserve function. [ABSTRACT FROM AUTHOR]

Aim: Lenvatinib has become available as first‐line therapy for patients with unresectable hepatocellular carcinoma (HCC). However, the safety and efficacy of lenvatinib in elderly patients with HCC has not been sufficiently investigated. We compared the frequency of adverse events and prognosis between elderly and non‐elderly patients with HCC who received lenvatinib. Methods: A total of 100 patients with HCC who received lenvatinib were selected using propensity score matching: 50 patients were elderly (age ≥75 years) and 50 patients were non‐elderly. Results: In the elderly group, >20% of patients experienced fatigue (36.0%), decreased appetite (26.0%), hypothyroidism (24.0%), proteinuria (22.0%), palmar‐plantar erythrodysesthesia (22.0%), and hypertension (20.0%) of any grade as treatment‐related adverse events. In addition, >10% of patients experienced grade ≥3 treatment‐related fatigue (12.0%). In the non‐elderly group, >20% of patients experienced palmar‐plantar erythrodysesthesia (42.0%), fatigue (28.0%), decreased appetite (22.0%), and diarrhea (20.0%) of any grade as treatment‐related adverse events. In addition, >10% of patients experienced grade ≥3 treatment‐related proteinuria (10.0%). There were no significant differences between the elderly and non‐elderly groups in the frequency of adverse events. Regarding overall and progression‐free survival, there were no significant differences between the elderly and non‐elderly groups (hazard ratio 0.972, 95% confidence interval 0.374–2.529; and hazard ratio 1.362, 95% confidence interval 0.687–2.700, respectively). Palmar‐plantar erythrodysesthesia (hazard ratio 0.117, 95% confidence interval 0.015–0.916) was independently associated with overall survival in a multivariate analysis. Conclusions: Lenvatinib can be used safely and efficaciously regardless of age in patients with HCC. [ABSTRACT FROM AUTHOR]

Aim: Although the development of new direct‐acting antivirals (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection has markedly advanced, the effects of cirrhosis on DAA treatment remain unclear. We aimed to clarify the impact of cirrhosis on DAA treatment of patients infected with HCV. Methods: This large‐scale, multicenter, retrospective study consisted of 2130 HCV genotype 1b‐infected patients who were treated with one of the following DAA combination therapies: asunaprevir/daclatasvir (ASV/DCV), ledipasvir/sofosbuvir (LDV/SOF), or paritaprevir/ombitasvir/ritonavir (PTV/OBV/r). Ninety‐two patients (4.3%) previously received DAA‐based treatment. Seven hundred and forty‐five patients (34.9%) had cirrhosis. Results: Overall, the sustained virologic response (SVR) rate was 93.0%. The SVR rates in patients who received ASV/DCV, LDV/SOF, or PTV/OBV/r were 90.0%, 96.9%, and 97.6%, respectively. The SVR rate in patients with cirrhosis (89.1%) was significantly lower than that in patients without cirrhosis (95.1%, P = 6.94 × 10–7). In the multivariate analysis for the overall cohort, absence of cirrhosis (P = 1.26 × 10–3), no previous DAA‐based treatment (P = 2.54 × 10–14), low HCV‐RNA levels (P = 1.64 × 10–6), wild‐type non‐structural protein 5A L31/Y93 (P = 7.33 × 10–13), and DAA regimen (LDV/SOF or PTV/OBV/r) (P = 1.92 × 10–14) were independent factors contributing to SVR. Except for patients with DAA‐based treatment history, absence of cirrhosis (P = 2.15 × 10–3; odds ratio, 2.51) was an independent factor contributing to SVR in 2038 DAA‐naïve patients. Conclusion: This study suggests that the presence of cirrhosis reduces the SVR rate of DAA treatment, regardless of the type of DAA treatment. [ABSTRACT FROM AUTHOR]

Aim: Lenvatinib (LEN) has recently become available as a first‐line tyrosine‐kinase inhibitor (TKI) for unresectable hepatocellular carcinoma (u‐HCC). In patients who showed intolerability or failure in other TKI treatments, alternative treatment options are needed. This retrospective study evaluated the therapeutic potential of LEN in clinical practice. Methods: We enrolled 57 u‐HCC patients treated with LEN from March to June 2018. Lenvatinib was given orally to patients weighing <60 kg at 8 mg/day and at 12 mg/day to those ≥60 kg. Following the exclusion of patients whose initial LEN dose was reduced, 49 patients were evaluated in regard to their characteristics and early therapeutic response using modified Response Evaluation Criteria in Solid Tumors for findings of follow‐up computed tomography (CT)/magnetic resonance imaging (MRI) examinations at 4 weeks after introducing LEN. Results: The average patient age was 72.4 ± 9.3 years and 38 (77.6%) were men. The LEN dose was 8 and 12 mg in 32 and 17 patients, respectively. Twenty‐nine (59.2%) had history of treatment with sorafenib and six of them (20.7%) with regorafenib. Of the 49 patients, 27 were evaluated using findings obtained by enhanced CT/MRI at 4 weeks after introducing LEN. Partial response was shown in 11, stable disease in 12, and progressive disease in four (overall response rate [ORR], 40.7%; disease control rate [DCR], 85.2%). The ORR and DCR of TKI‐naïve patients (n = 8) were 50.0% and 87.5%, respectively, whereas those of TKI‐experienced patients (n = 19) were 36.8% and 84.2%, respectively (P = 0.675 and P = 1.00, respectively). Conclusion: Early therapeutic response to LEN was favorable. This new TKI could have therapeutic potential both in patients with and without past TKI treatments. [ABSTRACT FROM AUTHOR]

Aim Although interferon-free therapy with direct-acting antivirals has developed as a standard of care for chronic hepatitis C, the existence of resistance-associated variants (RAVs) has a negative impact on treatment results. Recently, several studies indicated a relationship between chronic hepatitis C and serum vitamin D levels. However, the relationship between RAVs at the hepatitis C virus non-structure 5A (NS5A) region and serum vitamin D level has not yet been examined. Methods Among patients with genotype 1 chronic hepatitis C who were enrolled in a multicenter cooperative study, our subjects comprised 247 patients in whom it was possible to measure RAVs at the NS5A region. These RAVs were measured using a direct sequencing method. Results The median age of patients was 70 years (range, 24-87 years), and the number of female patients was 135 (54.7%). The median serum 25(OH) D3 level was 22 ng/mL (range, 6-64 ng/mL). L31 and Y93 RAVs at the NS5A region were detected in 3.7% (9/247) and 13.4% (33/247) of patients, respectively. Multivariate analysis identified vitamin D deficiency (serum 25(OH) D3 ≤ 20 ng/mL) ( P = 5.91 × 10⁻5, odds ratio = 5.015) and elderly age (>70 years) ( P = 1.85 × 10−3, odds ratio = 3.364) as contributing independent factors associated with the presence of the L31 and/or Y93 RAVs. The Y93H RAV was detected in 25.9% (29/112) of patients with a vitamin D deficiency, and in 8.9% (12/135) of those with a serum 25(OH) D3 level >20 ng/mL ( P = 4.90 × 10−3). Conclusion We showed that RAVs at the NS5A region are associated with vitamin D deficiency and elderly age, which may have a negative influence on innate/adaptive immune responses to hepatitis C virus infection. [ABSTRACT FROM AUTHOR]

Aim Protease inhibitors with pegylated interferon (PEG IFN)/ribavirin improve a sustained virological response (SVR) rate to approximately 90% in chronic hepatitis C genotype 1b patients with IL28B rs8099917 genotype TT, but yield only approximately 50% in those with the unfavorable non-TT. Among such treatment-refractory patients, serum vitamin D levels could influence the SVR rate. This randomized controlled trial was conducted to assess the effect of native vitamin D supplementation in simeprevir with PEG IFN/ribavirin for 1b patients with non-TT. Methods Patients were randomly assigned to receive simeprevir (100 mg/day) for 12 weeks plus PEG IFN/ribavirin for 24 weeks (control group, n = 58), or vitamin D (2000 IU/day) for 16 weeks including a lead-in phase plus PEG IFN/ribavirin for 24 weeks (vitamin D group, n = 57). The primary end-point was sustainably undetectable viremia 24 weeks after the end of treatment (SVR). Results SVR rates were 37.9% in the control group and 70.2% in the vitamin D group. In subgroup analysis, SVR rates of prior null responders were 11.8% and 54.5%, respectively. SVR rates for advanced fibrosis were 28.6% and 65.4%. SVR rates for patients with vitamin D3 deficiency at the baseline were 25.0% in the control group and 66.7% in the vitamin D group. Overall, the SVR rate was significantly higher in patients with high serum 25(OH)D3 levels at the beginning of combination therapy than in those with low serum 25(OH)D3 levels. Conclusion Native vitamin D3 supplementation improved SVR rates in simeprevir with PEG IFN/ribavirin for chronic hepatitis C genotype 1b patients with refractory factors. [ABSTRACT FROM AUTHOR]

Aim Much is unknown about the effect of 25-hydroxyvitamin D3 levels on the outcome of pegylated interferon/ribavirin ( PEG IFN/ RBV) therapy for hepatitis C virus-related cirrhosis. The purpose of the present study was to analyze and elucidate factors, including 25-hydroxyvitamin D3, that contribute to a sustained virological response ( SVR) in patients with cirrhosis. Methods We analyzed whether 25-hydroxyvitamin D3 contributes to the response to PEG IFN/ RBV therapy among 134 cirrhotic patients. Results SVR was achieved in 43 patients. The median 25-hydroxyvitamin D3 level was 20 ng/mL. Univariate analysis showed that the following factors contributed to SVR: low-density lipoprotein cholesterol, albumin, 25-hydroxyvitamin D3, core a.a.70 (a.a.70) substitutions, the number of mutations at the interferon sensitivity-determining region and IL28B genotype. Multivariate analysis identified IL28B genotype and 25-hydroxyvitamin D3 as independent factors contributing to SVR. Subsequently, SVR rate was examined by using 25-hydroxyvitamin D3 and other important factors. The SVR rate was 51.8% in patients with core a.a.70 wild and ≥15 ng/mL of 25-hydroxyvitamin D3, whereas the SVR rate was 7.1% in patients with core a.a.70 wild and <15 ng/mL of 25-hydroxyvitamin D3. The SVR rate was 56.9% in patients with IL28B major genotype and ≥15 ng/mL of 25-hydroxyvitamin D3. Surprisingly, the SVR rate was 0% in patients with IL28B minor genotype and <15 ng/mL of 25-hydroxyvitamin D3. Conclusion IL28B genotype and 25-hydroxyvitamin D3 were identified as independent factors contributing to SVR. Stratified analyses according to core a.a.70 substitution and IL28B genotype suggested that 25-hydroxyvitamin D3 influences the outcome of PEG IFN/ RBV therapy for cirrhosis. [ABSTRACT FROM AUTHOR]