Highly sensitive Lens culinaris agglutinin‑reactive fraction of α‑fetoprotein is a predictive marker for hepatocarcinogenesis in long‑term observation of patients with chronic liver disease

Highly sensitive Lens culinaris agglutinin‑reactive fraction of α‑fetoprotein (hs‑AFP‑L3) is a specific marker for hepatocellular carcinoma (HCC) and has been reliable in cases with a low serum α‑fetoprotein (AFP) level. However, the biomarkers that contribute to hepatocarcinogenesis during the long‑term observation are not yet clear. The present study reported the clinical utility of hs‑AFP‑L3 in the long‑term observation of patients with chronic liver disease. The subjects were 106 patients with chronic liver disease without HCC or a history of HCC treatment and who had been followed for >12 months. hs‑AFP‑L3 was measured using cryopreserved serum. The factors contributing to hepatocarcinogenesis were examined using univariate and multivariate analyses. The median observation period was 88 months (15‑132 months). The cumulative incidence of HCC was 10.5% at 5 years and 19.6% at 10 years. The univariate analysis revealed that age ≥55 years old, platelet count ≤13.1x104/µl, hyaluronic acid ≥80.8 ng/ml, alanine transaminase ≥47 U/l, AFP ≥6.3 ng/ml, hs‑AFP‑L3 ≥3.5% and des‑γ‑carboxy prothrombin (DCP) ≥25 mAU/ml were significant factors. In the multivariate analysis, platelet count ≤13.1x104/µl [hazard ratio (HR), 4.966; 95% confidence interval (CI), 1.597‑15.437; P=0.006] and hs‑AFP‑L3 ≥3.5% (HR, 5.450; 95% CI, 1.522‑19.512; P=0.009) were extracted as significant factors contributing to hepatocarcinogenesis. In addition, for cases with AFP <20 ng/ml, a multivariate analysis revealed that hs‑AFP‑L3 ≥4.9% (HR, 11.608; 95% CI, 2.422‑55.629; P=0.002) and DCP ≥25 mAU/ml (HR, 3.936; 95% CI, 1.088‑14.231; P=0.037) were significant factors contributing to hepatocarcinogenesis. hs‑AFP‑L3 is a useful marker for predicting hepatocarcinogenesis in the long‑term observation of patients with chronic liver disease. Kazuaki Tabu, Seiichi Mawatari, Kohei Oda, Ohki Taniyama, Ai Toyodome, Sho Ijuin, Haruka Sakae, Kotaro Kumagai, Shuji Kanmura, Akio Ido Highly sensitive Lens culinaris agglutinin‑reactive fraction of α‑fetoprotein is a predictive marker for hepatocarcinogenesis in long‑term observation of patients with chronic liver disease MOLECULAR AND CLINICAL ONCOLOGY 15: 174, 2021 https://doi.org/10.3892/mco.2021.233

Analysis of the susceptibility of refractory hepatitis C virus resistant to nonstructural 5A inhibitors

Abstract Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs

Clinical Effect of Lenvatinib Re-Administration after Transcatheter Arterial Chemoembolization in Patients with Intermediate Stage Hepatocellular Carcinoma

The present study clarified the prognosis of intermediate-stage hepatocellular carcinoma (HCC) patients who received lenvatinib (LEN) followed by transcatheter arterial chemoembolization (TACE) on demand. We retrospectively evaluated 88 intermediate-stage HCC patients who received LEN. The median age was 74 (range: 47–92) years old, 67 patients were male, and 82 were classified as Child-Pugh A. LEN was administered until disease progression or discontinuation due to adverse events (AEs). The mean duration of LEN treatment was 7.0 months. The response and disease control rates were 51.1% and 89.8%, respectively. The median progression-free survival and overall survival (OS) after the initiation of LEN were 6.8 months and 29.9 months, respectively. The OS in patients for whom LEN was re-administered after TACE (TACE-LEN) was better than that in patients who received other therapies (e.g., only TACE, TACE-other therapy, or only other therapy) even with propensity score matching (p = 0.008). A Cox proportional hazard analysis showed that TACE-LEN was most strongly associated with the OS (hazard ratio: 0.083, 95% confidence interval: 0.019–0.362, p = 0.001). LEN was administered for approximately 11.1 months after TACE. In intermediate-stage HCC patients who can tolerate LEN without discontinuation due to AEs, TACE-LEN may prolong the prognosis

The co-existence of NS5A and NS5B resistance-associated substitutions is associated with virologic failure in Hepatitis C Virus genotype 1 patients treated with sofosbuvir and ledipasvir

<div><p>Objective</p><p>The present study aimed to reveal the factors associated with virologic failure in sofosbuvir and ledipasvir (SOF/LDV)-treated patients, and identify baseline NS5A or NS5B resistance-associated substitutions (RASs).</p><p>Methods</p><p>Four hundred ninety-three patients with Hepatitis C Virus (HCV) genotype 1b infection were treated with SOF/LDV; 31 had a history of interferon (IFN)-free treatment with daclatasvir and asunaprevir. The effect of baseline RASs on the response to SOF/LDV therapy was analyzed.</p><p>Results</p><p>Overall, a sustained virologic response at 12 weeks (SVR12) was achieved in 476 patients (96.6%). The SVR12 rates in the patients with IFN-free treatment-naïve and retreatment were 97.6% and 80.6%, respectively. HCV elimination was not achieved in 17 patients, 11 (including 5 with IFN-free retreatment) of whom had virologic failure. Eight patients had coexisting NS5A RASs of Q24, L28 and/or R30, L31, or Y93 and one patient had coexisting NS5A RASs of P32L and A92K. Interestingly, 10 and 8 patients had NS5B A218S and C316N RAS respectively. According to a multivariate analysis, coexisting NS5A RASs, NS5A P32 RAS, NS5B A218 and/or C316 RASs, and γ-glutamyltranspeptidase were associated with virologic failure. In the naïve patients, all patients without NS5B A218 and/or C316 RAS achieved an SVR12. Notably, the SVR12 rates of patients with coexisting NS5A and NS5B RASs were significantly lower (83.3%).</p><p>Conclusions</p><p>Although SOF/LDV therapy resulted in a high SVR12 rate, coexisting NS5A and NS5B RASs were associated with virologic failure. These results might indicate that the coexisting baseline RASs influence the therapeutic effects of SOF/LDV.</p></div

The virologic response rates (intention-to-treat analysis).

<p>The sustained virologic response (SVR) 12 rates of the IFN-free treatment-naïve patients and IFN-free retreatment patients were 97.6% and 80.6% respectively.</p

The baseline resistance-associated substitutions (RASs) and virologic failure in patients treated with sofosbuvir and ledipasvir.

<p>The baseline resistance-associated substitutions (RASs) and virologic failure in patients treated with sofosbuvir and ledipasvir.</p

The reasons for the discontinuation of sofosbuvir/lediprevir.

<p>The reasons for the discontinuation of sofosbuvir/lediprevir.</p

The sustained virologic response (SVR) 12 rate in the patients with co-existing NS5A and NS5B RASs.

<p>The interferon (IFN) free-naïve patients with coexisting resistance-associated substitutions (RASs) of Q24, L28, and/or R30, L31, or Y93 and NS5B A218 and/or C316 had a significantly lower sustained virologic response (SVR) 12 rate in comparison to the patients without these RASs.</p

The multivariate logistic regression analysis of factors associated with virologic failure in patients treated with sofosbuvir and ledipasvir.

<p>The multivariate logistic regression analysis of factors associated with virologic failure in patients treated with sofosbuvir and ledipasvir.</p