Prognostic nutritional index after introduction of atezolizumab with bevacizumab predicts prognosis in advanced hepatocellular carcinoma: A multicenter study.

INTRODUCTION: Atezolizumab plus bevacizumab (Atez/Bev) is the preferred treatment for advanced hepatocellular carcinoma (HCC). However, biomarkers of therapeutic efficacy have remained unclear. We took a retrospective approach to explore the role of prognostic nutritional index (PNI) for predicting the outcomes of Atez/Bev treatment. METHODS: One hundred twenty-five HCC patients were enlisted; these patients received Atez/Bev treatment and underwent dynamic computerized tomography/magnetic resonance imaging to determine the treatment response on at least one occasion between October 2020 and January 2023, and their PNI before treatment and at the beginning of the second cycle (PNI-2c) was evaluated. RESULTS: During the initial evaluation, 2 (2%), 28 (22%), 70 (56%), and 25 (20%) patients exhibited a complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), respectively. Patients with non-PD tended to have higher PNI at baseline and PNI-2c than those with PD (p = 0.245 and 0.122, respectively), with optimal baseline PNI and PNI-2c cut-off values of 42.6 and 40.4, respectively. PNI at baseline could not be used to predict overall survival (OS) or progression-free survival (PFS). However, PNI-2c predicted OS and PFS (PNI-2c ≥ 40.4 vs. < 40.4: 25.3 vs. 16.2 months, P = 0.008 for OS; 12.7 vs. 8.4 months, P = 0.036 for PFS). A multivariate analysis showed a significant association between PNI-2c and OS. CONCLUSIONS: PNI-2c is a predictor of prognosis in HCC patients treated with Atez/Bev therapy.

The neutrophil-to-lymphocyte ratio at the start of the second course during atezolizumab plus bevacizumab therapy predicts therapeutic efficacy in patients with advanced hepatocellular carcinoma: A multicenter analysis.

AIM: Atezolizumab plus bevacizumab (Atez/Bev) therapy is expected to have good therapeutic efficacy for patients with advanced hepatocellular carcinoma (HCC). However, the clinical indicators that predict therapeutic efficacy have not been established. We retrospectively investigated whether the neutrophil-to-lymphocyte ratio (NLR) during Atez/Bev therapy could predict therapeutic efficacy. METHOD: In total, 110 patients with HCC were enrolled; they were treated with Atez/Bev therapy and evaluated for their initial response by dynamic CT or MRI at least once between October 2020 and July 2022. RESULTS: Of the 110 patients with HCC at the initial evaluation, two (2%) showed a complete response (CR), 22 (20%) partial response (PR), 62 (56%) stable disease (SD), and 24 (21%) progressive disease (PD). The NLR at the start of the second course (NLR-2c) increased from CR + PR to SD to PD. There was no significant association between the baseline NLR and the initial therapeutic response. Patients with CR + PR had lower NLR-2c values than those with SD + PD (p < 0.001) and the optimal cut-off value of NLR-2c was 1.97. Patients with NLR-2c <1.97 had better overall survival and progression-free survival (PFS) than those with NLR-2c ≥1.97 (p = 0.005 for overall survival; p < 0.001 for PFS). A multivariate analysis showed that female sex, higher PIVKA-II levels at baseline, and higher values of NLR-2c were significantly associated with poorer PFS. CONCLUSIONS: The NLR-2c value predicts the initial therapeutic response and prognosis of patients with HCC treated with Atez/Bev therapy.

A novel glycobiomarker, Wisteria floribunda agglutinin macrophage colony-stimulating factor receptor, for predicting carcinogenesis of liver cirrhosis.

Recently, we identified a novel liver fibrosis glycobiomarker, Wisteria floribunda agglutinin (WFA)-reactive colony stimulating factor 1 receptor (WFA(+) -CSF1R), using a glycoproteomics-based strategy. The aim of this study was to assess the value of measuring WFA(+) -CSF1R levels for the prognosis of carcinogenesis and outcome in liver cirrhosis (LC) patients with hepatitis C virus (HCV). WFA(+) -CSF1R and Total-CSF1R levels were measured in serum samples from 214 consecutive HCV-infected patients to evaluate their impact on carcinogenesis and the survival of LC patients. Serum WFA(+) -CSF1R levels were significantly higher in LC patients than chronic hepatitis (CH) patients (p < 0.001). The AUC of WFA(+) -CSF1R for predicting overall survival, calculated by time-dependent ROC analysis, was 0.691 and the HR (per 1-SD increase) was 1.80 (95% CI, 1.23-2.62, p < 0.001). Furthermore, the survival rate of LC patients with high WFA(+) -CSF1R levels (≥ 310 ng/ml) was significantly worse than those with lower levels (p < 0.01). The AUC of WFA(+) /total-CSF1R percentage (WFA(+) -CSF1R%) for predicting the cumulative carcinogenesis rate was 0.760, with an HR of 1.66 (95% CI 1.26-2.20, p < 0.001). In fact, the carcinogenesis rate was significantly higher in LC patients with a high WFA(+) -CSF1R% (≥ 35%, p = 0.006). Assessing serum levels of WFA(+) -CSF1R has diagnostic value for predicting carcinogenesis and the survival of LC patients.

[A case of gastric cancer with peritoneal dissemination who achieved long survival from control of ascites for over 2 years by successive treatments with S-1 in combination with docetaxel as first-line followed by irinotecan in combination with cisplatin as second-line].

The patient was a 66-year-old male, admitted and diagnosed as having advanced gastric cancer with peritoneal dissemination, leading to ascites and obstructive jaundice. After reducing the degree of obstructive jaundice, combination chemotherapy of S-1 80mg/m2/day(2 weeks administration and 1 week rest)and docetaxel(TXT)40mg/m2(day 1)was administered from February, 2008. After 3 courses of this regimen, CT revealed no evidence of ascites, and this chemotherapy was successively continued on an outpatient basis until June, 2009. After the relapse of ascites from July, 2009, combination chemotherapy of irinotecan(CPT-11)60mg/m2 and cisplatin(CDDP)30mg/m2 biweekly was performed as second-line chemotherapy, and the ascites disappeared again after around 2 courses of this regimen. This chemotherapy was continued on an outpatient basis until February, 2010. No major adverse reaction to either chemotherapy was observed. This case suggests that these chemotherapies, such as the combination chemotherapy of S-1 plus TXT as a first-line treatment and CPT-11 plus CDDP as the following second-line treatment, can be administered to an outpatient, can keep good patient's QOL and can be one of the effective chemotherapy options for advanced gastric cancer with peritoneal dissemination.

Subclinical hepatitis E virus (HEV) infection detected by nucleic acid amplification test on blood donation: short-term positivity for immunoglobulin G class of antibody against HEV.

A case of subclinical hepatitis E virus (HEV) infection was detected by nucleic acid amplification test on blood donation. The patient was followed-up until day 220 after the blood donation but showed no symptoms throughout the observation period. Aspartate aminotransferase and alanine aminotransferase levels reached the maximum values on day 37 with a slight increase but remained in normal ranges from day 67 to 220. The quantity of HEV RNA at the initial examination on day 13 was 1.1 × 102 copies/mL, which increased to 2.8 × 103 copies/mL by day 37. It was not detected from day 67 to 220. Immunoglobulin G class antibody to HEV (anti-HEV IgG) was below the cut-off value until day 37 and exceeded the cut-off value to positive on day 67, accompanied by normalization of liver function and negative conversion of HEV RNA. Thereafter, the titer decreased gradually, falling below the cut-off value on day 163, and continuing negative until day 220. Although the persistent duration of anti-HEV IgG positive is believed to be generally long, it was within only 126 days for this subclinical case. Further investigation is needed to determine whether short-term positivity for anti-HEV IgG is typical in subclinical HEV infection.

Malignant gastrointestinal neuroectodermal tumor presenting with small intestinal obstruction: A case report.

Malignant gastrointestinal neuroectodermal tumors (GNETs) are rare malignant mesenchymal neoplasms. To our knowledge, only 99 cases have been reported worldwide. The tumor has an aggressive malignancy, with a rapid progression. The histological features of GNET overlap with those of clear cell sarcoma, which contain Ewing sarcoma breakpoint region 1 mutation. GNETs lack melanocyte-specific markers, while clear cell sarcoma exhibits melanocytic differentiation. Various symptoms have been reported previously, and the most reported lesion is in the small bowel. The patient was a 69-year-old man who presented with abdominal pain and vomiting. Computed tomography revealed a nodule in the small bowel, which induced small intestinal obstruction. Enteroscopic images revealed a submucosal tumor. Surgery was performed, and the patient was diagnosed with GNET. Only two patients whose primary lesions were in the small intestine, including the patient in this report, have undergone enteroscopy before surgery. This is a rare case of GNET in which a patient underwent enteroscopy before surgical treatment.

Phase II Prospective Study of Trastuzumab in Combination with S-1 and Oxaliplatin (SOX100) Therapy for HER2-Positive Advanced Gastric Cancer.

PURPOSE: The standard first-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive advanced gastric cancer (AGC) is trastuzumab in combination with cisplatin and fluoropyrimidines. We evaluated the efficacy and safety of S-1 and oxaliplatin (100 mg/m2) (SOX100) combined with trastuzumab, a monoclonal antibody against HER2 for HER2-positive AGC. METHODS: In this single-arm, multicenter phase II study, patients with HER2-positive AGC received S-1 (80-120 mg per day) orally on days 1-14, oxaliplatin (100 mg/m2) intravenously on day 1, and trastuzumab (8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks) intravenously. The primary end point was 1-year survival rate. The secondary end points included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. RESULTS: A total of 25 patients from six centers were enrolled from December 2015 to March 2020. In the 25 patients evaluable for analysis, the 1-year survival rate was 70.8% [90% confidence interval (CI) = 55.5-86.1%], whereas the median OS, PFS, and ORR were 17.8 (95% CI 10.5-22.9) months, 7.6 (95% CI 5.0-10.9) months, and 75.0% (95% CI 53.3-90.2), respectively. Major grade 3/4 adverse events included anorexia (20%), anemia (16%), peripheral sensory neuropathy (16%), and diarrhea (15%). CONCLUSION: SOX100 combined with trastuzumab was effective with a favorable safety profile in patients with HER2-positive AGC.

Positive selection of core 70Q variant genotype 1b hepatitis C virus strains induced by pegylated interferon and ribavirin.

BACKGROUND: Approximately 20% of patients with hepatitis C virus (HCV) genotype 1b infection have nonresponse to the most current treatment, pegylated interferon with ribavirin. Mutations in the HCV core region were recently proposed to be associated with nonresponse. Our aim was to evaluate the viral factors associated with treatment failure. METHODS: HCV variants were determined directly and after cloning in 66 HCV-1b-infected Japanese patients and in 5 urokinase-type plasminogen activator transgenic severe combined immunodeficiency mice with human hepatocytes (chimeric mice), at baseline, during treatment, and after treatment. RESULTS: At baseline, glutamine at position 70 of the HCV core protein (70Q) was detected by direct sequencing in 20% of patients with virologic response and in 43.8% of patients with nonresponse. Among patients with nonresponse, who were examined during and after treatment, the prevalence of the 70Q substitution increased to 56.3%, which indicates that treatment-induced selection occurred in all patients with nonresponse who had 70Q quasispecies detectable by cloning. This observation was reinforced by the results from experimentally infected chimeric mice. Logistic regression analysis indicated that detection of 70Q quasispecies was associated with a statistically significantly increased risk of nonresponse (odds ratio, 15.1; P = .004) in the studied cohort. CONCLUSION: Presence of the 70Q quasispecies at baseline was associated with an increased risk of treatment failure, as indicated by the positive selection of the 70Q clones induced by treatment with pegylated interferon with ribavirin. These results urge further investigation of the mechanisms of this association.

Novel adsorptive type apheresis device Immunopure for ulcerative colitis from clinical perspectives based on clinical trials: Japan and Europe.

Several adsorptive type devices for ulcerative colitis are used for the induction of remission in patients with active severe disease worldwide. In 2020, the novel apheresis device Immunopure for ulcerative colitis was launched in Japan. Immunopure, like the polyethylene terephthalate column, uses polyarylate, a type of polyester resin, as the adsorbent. Similar to the cellulose acetate column, Immunopure is filled with adsorbent beads and expected to provide ease of use, with minimal risk of column clogging. Immunopure adsorbs leukocytes and platelets, especially activated platelets and platelet-leukocyte aggregates. In this article, the capability of Immunopure is evaluated from clinical perspective based on a clinical trial in Japan/Europe. As a result, Immunopure is comparable to other products in clinical effectiveness and indicated for the treatment of patients with refractory moderate ulcerative colitis, making it highly useful in clinical practice.

[Bi-weekly docetaxel and doxifluridine combination therapy in pretreated patients with unresectable and/or advanced gastric cancer].

We report an investigation of the therapeutic efficacy and safety of combination chemotherapy with docetaxel (DOC) and doxifluridine (5'-DFUR) administered as second-line or third-line chemotherapy in 23 cases of unresectable and/or advanced gastric cancer. Treatment consisted of intravenous DOC (40mg/m/2) on day 1 and 15, and oral 5'-DFUR (600mg/body) on days 1 to 28 every 4 weeks. The response rate for its antitumor efficacy was 17.4 %, with partial response in 4 cases, no change in 6 cases, progressive disease in 12 cases, and one case not evaluable. By site, the response rate was 11. 8% for primary tumors (2/17), 33.3% for lymph nodes (3/9) , and 26.9% for liver metastasis (1/7). Median time to treatment failure was 2.6 months, median overall survival was 4.6 months. The one-year survival rate was 26.1 %, and the two-year survival rate was 13.0%. The most common grade 3 to 4 toxicities were neutropenia( 4.3%), fatigue (8.7%), stomatitis (8.7%), anorexia(4.3% ), and rash (4.3%). Our data suggest that the combination of docetaxel and 5'-DFUR has a promising therapeutic index in patients with unresectable advanced gastric cancer as second-line or third-line chemotherapy.

Abbott RealTime hepatitis C virus (HCV) and Roche Cobas AmpliPrep/Cobas TaqMan HCV assays for prediction of sustained virological response to pegylated interferon and ribavirin in chronic hepatitis C patients.

Two commercial real-time PCR assays are currently available for sensitive hepatitis C virus (HCV) RNA quantification: the Abbott RealTime HCV assay (ART) and Roche Cobas AmpliPrep/Cobas TaqMan HCV assay (CAP/CTM). We assessed whether the two real-time PCR assays were more effective than Roche Cobas Amplicor HCV Monitor test, v.2.0 (CAM) for prediction of the sustained virological response (SVR) to pegylated interferon (PEG-IFN) plus ribavirin (RBV) in chronic hepatitis C. Sixty patients chronically infected with HCV genotype 1b (37 males and 23 females, 53 +/- 12 years of age) were treated with PEG-IFNalpha2b plus RBV for 48 weeks. Stored specimens at nine time points for each patient (at baseline, on treatment, and 24 weeks after treatment) were tested by the two real-time PCR assays and CAM. Twenty-six (43.3%) patients reached SVR. The positive predictive values (PPVs) for SVR of undetectable HCV RNA at week 12 by CAM, ART, and CAP/CTM were 74.3%, 88.0%, and 95.2%, respectively. An undetectable HCV RNA level by CAM, ART, and CAP/CTM correctly predicted SVR at week 4 in 100%, 100%, and 100% of patients, at weeks 5 to 8 in 91.7%, 100%, and 100% of patients, at weeks 9 to 12 in 55.6%, 75%, and 87.5% of patients, and at weeks 13 to 24 in 0%, 26.7%, and 40% of patients, respectively. Of 16 patients who relapsed after treatment, HCV RNA was detectable in 2 patients at the end of treatment by CAP/CTM but undetectable by ART and CAM. HCV RNA tests using ART and CAP/CTM are considered to be more effective at predicting SVR than CAM, and the PPV for SVR was slightly higher in CAP/CTM than in ART.

[A case of advanced ampullary carcinoma successfully resected after primary chemotherapy with s-1 and gemcitabine].

The patient was a 53-year-old male who was admitted on an emergency basis with obstructive jaundice. He was diagnosed as having advanced ampullary carcinoma(T4 N0 H1, Stage IV b). To reduce the degree of obstructive jaundice, a self-expandable metallic stent was placed in the area of the biliary obstruction. Immediately after relief from obstructive jaundice, combination chemotherapy of S-1 and gemcitabine was given. Subsequently, CA19-9, the tumormarker level was reduced, the metastatic liver tumor disappeared, and the size of the primary lesion was remarkably reduced. Therefore, a curative surgical resection was done. This is a very instructive case for developing effective chemotherapy options to treat biliary tract cancers involving ampullary carcinoma.

Suppressive effect of oral administration of branched-chain amino acid granules on oxidative stress and inflammation in HCV-positive patients with liver cirrhosis.

AIM: In chronic hepatitis C virus (HCV) infection, it is thought that both chronic persistent inflammation and oxidative stress contribute to the development of hepatocellular carcinoma (HCC), and it has been reported that long-term oral supplementation with branched-chain amino acid (BCAA) granules could inhibit liver carcinogenesis. However, the extent of the involvement of these factors remains obscure. METHODS: To clarify the involvement of inflammation and oxidative stress in the inhibition of liver carcinogenesis, we evaluated the effect of oral administration of BCAA granules on oxidative stress and inflammation in HCV-positive patients with liver cirrhosis. RESULTS: Twenty-seven patients were enrolled in the study: 18 of the patients were treated with BCAA granules (administered group) and nine were observed without BCAA granules (non-administered group). In the non-administered group, the production of oxidative stress, as indicated by urine 8-hydroxydeoxyguanosine (8-OHdG) and 15-F2t-Isoprostane (8-IsoPs), significantly increased with time, while in the administered group the levels of ferritin and 8-OHdG decreased significantly. Comparison of the two groups demonstrated that highly sensitive CRP, ferritin, 8-OHdG and 8-IsoPs were significantly reduced by taking BCAA granules. The time-course analysis showed that ferritin and highly sensitive CRP seemed to decrease first, followed by a decrease of 8-OHdG and 8-IsoPs. CONCLUSION: These findings indicated that the administration of BCAA granules influenced microinflammation and the metabolism of iron in HCV-positive patients with liver cirrhosis, and subsequently seemed to reduce the production of oxidative stress, possibly leading to a decrease in the occurrence of HCC.

A weak association between occult HBV infection and non-B non-C hepatocellular carcinoma in Japan.

BACKGROUND: In Japan, approximately 10% of hepatocellular carcinoma (HCC) patients are negative for both hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV), i.e., they constitute the so-called category of non-B non-C (NBNC) HCC. Little is known about the characteristics of NBNC-HCC. METHODS: Potential risk factors for carcinogenesis (including occult HBV infection [HBsAg is negative but HBV DNA is positive by polymerase chain reaction (PCR)], obesity, and diabetes) were assessed in 233 HCC patients grouped according to hepatitis virus serological status (152 with HCV-HCC, 36 with HBV-HCC, and 45 with NBNC-HCC). RESULTS: The prevalence of patients with obesity or diabetes was significantly higher in the NBNC-HCC group than in the HBV-HCC group. The same trend was observed even when patients with massive alcohol intake were excluded from the analysis. Only 8 patients (18%) in the NBNC-HCC group had detectable serum HBV DNA, and this was at very low levels (HBV/Ce/C2 and HBV/D were determined in 7 and 1 patients, respectively). In the NBNC-HCC group, the determined nucleotide sequences of the enhancer II/core promoter/precore/core region did not contain any HCC-associated mutations, whereas 25 of 30 patients in the HBV-HCC group carried strains with C1653T, T1753V, and/or A1762T/G1764A mutations. CONCLUSIONS: A weak association between occult HBV infection and HCC development was observed in the NBNC patients. This study indicates that nonalcoholic steato-hepatitis should be further investigated to assess its contribution to HCC development in this category of patients.

Accidental exposure to HCV antibody-positive blood in hospital and pre-emptive one-shot interferon alpha-2b treatment.

AIMS: Infection with hepatitis viruses following blood exposure accidents, such as needle stick injuries, is a serious issue for medical staff. In particular, although accidental exposure to hepatitis C virus (HCV) occurs frequently, postexposure prophylactic measures have not been established yet. In this study we investigate the efficacy of recombinant alpha-2b interferon (IFN) as a single, 10 MU intramuscular injection for preventing transmission. METHODS: 264 incidents of accidental blood to HCV antibody-positive blood, occurring between 1993 and 2003 in the Social Insurance Chukyo Hospital, were surveyed. Accident reports, which described in detail the circumstances and the presence or absence of infectious disease in the blood, and accidental exposure to HCV antibody-positive blood was investigated. RESULTS: Pre-emptive IFN treatment was given in 115 out of 157 cases occurring between 1993 and 1998. One case developed acute HCV. Phylogenetic analysis provided evidence that the accident caused the infection and the patient was cured by immediate IFN therapy. Between 1999 and 2003, the exposed were in principle followed-up without IFN treatment; IFN treatment was only given when requested. As a result, IFN was given in 14 of 107 cases. During this period, no transmission was observed. CONCLUSION: Taken together, the benefits of pre-emptive IFN treatment were considered unremarkable and a follow-up without treatment, or immediate IFN therapy after confirmation of the onset, was recommended.

Impaired cytotoxic T lymphocyte inductivity by dendritic cells derived from patients with hepatitis C virus-positive hepatocellular carcinoma.

AIM: Peptide-based therapeutic vaccines are being developed. The aim of this study was to determine the feasibility of immunotherapy to hepatitis C virus (HCV)-positive hepatocellular carcinoma (HCC) by assessing the inductivity of peptide-specific cytotoxic T lymphocyte (CTL) by dendritic cells. METHODS: The inductivity of CTL was characterized in six patients with HCV-positive HCC, and compared to seven healthy volunteers and six patients with chronic HCV hepatitis (control). RESULTS: Peptide-specific CTL was comparably induced in controls, but not induced in any patients with HCC. To characterize this, the cytokine profile and the expression of surface molecules interacting between dendritic and T cells were evaluated. Among the cytokines, production of interferon (IFN)-gamma was found to be impaired and closely related to the results of CTL assays, while the expression of surface molecules showed no significant changes. CONCLUSIONS: In HCV-positive HCC patients, CTL inductivity by dendritic cells is impaired. This may be related to the impaired production of IFN-gamma.

Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1.

BACKGROUND: The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region. METHODS: Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing. RESULTS: Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently. CONCLUSIONS: History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.

Measurement of hepatitis B virus core-related antigen as predicting factor for relapse after cessation of lamivudine therapy for chronic hepatitis B virus infection.

BACKGROUND: Prolonged lamivudine therapy has two major problems: breakthrough hepatitis during treatment and relapse of aminotransferase (ALT) after cessation of the therapy. The aim of this study was to examine factors that could predict ALT flare after stopping lamivudine therapy. METHODS: We analyzed 22 Japanese patients with chronic hepatitis B infection, in whom lamivudine therapy was stopped after HBV DNA level had been gone undetectable (<3.7LGE/ml) during at least six consecutive months. The post-treatment followed up was carried for 28 months in median (range 9-41). HBV core-related antigen (HBcrAg) assay was assessed using newly developed assay. RESULTS: After cessation of lamivudine therapy, 11 patients (50%) had relapsed (reactivation of serum ALT >80IU/l, relapsers) and remaining 11 (50%) did not relapse (non-relapsers). In the univariate comparison of relapsers versus non-relapsers, HBcrAg level at lamivudine cessation point (4.5+/-1.0 versus 3.4+/-0.9; p=0.0145) has been shown as a significant predictive factor for non-relapse. All patients with HBcrAg <3.0logU/ml at the cessation point had no ALT flares. Multivariate analysis on effects of 10 factors (age, sex, cirrhosis, pretreatment ALT level, HBV DNA level, HBcrAg level, mean months till undetectable HBV DNA, duration of undetectable HBV DNA and HBcrAg level at lamivudine cessation point), indicated that HBcrAg level at lamivudine cessation point <3.4log U/ml was the only independent predictive factor for absence of the post-treatment relapse. CONCLUSIONS: HBcrAg level at lamivudine cessation point might be useful as a prognostic predictor of response to lamivudine therapy cessation. The measurement of HBcrAg is a useful additional test for monitoring chronic HBV infection.

A case-control study of response to lamivudine therapy for 2 years in Japanese and Chinese patients chronically infected with hepatitis B virus of genotypes Bj, Ba and C.

BACKGROUND/AIMS: In eastern Asian countries, hepatitis B virus (HBV) genotype Ba (HBV/Ba), HBV/Bj and HBV/C are prevalent. The aim was to investigate the response or resistance to lamivudine therapy among patients with different HBV genotypes. METHODS: Of 67 Japanese and Chinese patients with chronic hepatitis B, 18 patients with HBV/Bj, 15 with HBV/Ba and 34 with HBV/C were selected for a case-control study matched according to gender and age. All the patients were treated with lamivudine for 2 years and evaluated the response or emergence of the YMDD mutation at year 2 during the treatment. HBV genotypes were detected by the restriction fragment length polymorphism. The YMDD mutation was detected by the direct sequencing after amplification by PCR. RESULTS: At year 2 during therapy, 44.8% of the patients showed normalization of ALT and undetectable HBV DNA (favorable response), 35.8% developed the YMDD mutation. There was no significant difference of response to the therapy among the three genotype groups. The emergence of the YMDD mutation was associated with HBV/C. By the multiple logistic regression analysis, however, the significant factor of a favorable response was a higher pretreatment ALT level and negative HBeAg status and the significant factor of the emergence of the YMDD mutation was HBV/C. CONCLUSIONS: Higher pretreatment ALT level, HBeAg status or HBV genotype may affect the response or resistance to lamivudine therapy.