Takako Inoue

Hepatitis B virus and its sexually transmitted infection – an update

Epidemiology: incidence and prevalence: About 5% of the world’s population has chronic hepatitis B virus (HBV) infection, and nearly 25% of carriers develop chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The prevalence of chronic HBV infection in human immunodeficiency virus (HIV)-infected individuals is 5%-15%; HIV/HBV coinfected individuals have a higher level of HBV replication, with higher rates of chronicity, reactivation, occult infection, and HCC than individuals with HBV only. The prevalence of HBV genotype A is significantly higher among men who have sex with men (MSM), compared with the rest of the population. Molecular mechanisms of infection, pathology, and symptomatology: HBV replication begins with entry into the hepatocyte. Sodium taurocholate cotransporting polypeptide was identified in 2012 as the entry receptor of HBV. Although chronic hepatitis B develops slowly, HIV/HBV coinfected individuals show more rapid progression to cirrhosis and HCC. Transmission and protection: The most common sources of HBV infection are body fluids. Hepatitis B (HB) vaccination is recommended for all children and adolescents, and all unvaccinated adults at risk for HBV infection (sexually active individuals such as MSM, individuals with occupational risk, and immunosuppressed individuals). Although HB vaccination can prevent clinical infections (hepatitis), it cannot prevent 100% of subclinical infections. Treatment and curability: The goal of treatment is reducing the risk of complications (cirrhosis and HCC). Pegylated interferon alfa and nucleos(t)ide analogues (NAs) are the current treatments for chronic HBV infection. NAs have improved the outcomes of patients with cirrhosis and HCC, and decreased the incidence of acute liver failure.

Gut Dysbiosis Associated With Hepatitis C Virus Infection

Background Little is known about the effect of hepatitis C virus (HCV) infection on gut microbiota and the relationship between alteration of gut microbiota and chronic hepatitis C (CHC) progression. We performed a comparative study of gut microbiota composition between CHC patients and healthy individuals. Methods Fecal samples from 166 CHC patients were compared with those from 23 healthy individuals; the gut microbiota community was analyzed using 16S ribosomal RNA gene sequencing. CHC patients were diagnosed with persistently normal serum alanine aminotransferase without evidence of liver cirrhosis (LC) (PNALT, n = 18), chronic hepatitis (CH, n = 84), LC (n = 40), and hepatocellular carcinoma in LC (n = 24). Results Compared with healthy individuals, bacterial diversity was lower in persons with HCV infection, with a decrease in the order Clostridiales and an increase in Streptococcus and Lactobacillus. Microbiota dysbiosis already appeared in the PNALT stage with the transient increase in Bacteroides and Enterobacteriaceae. Predicted metagenomics of microbial communities showed an increase in the urease gene mainly encoded by viridans streptococci during CHC progression, consistent with a significantly higher fecal pH in CH and LC patients than in healthy individuals or those in the PNALT stage. Conclusions HCV infection is associated with gut dysbiosis, even in patients with mild liver disease. Additionally, overgrowth of viridans streptococci can account for hyperammonemia in CH and LC. Further studies would help to propose a novel treatment strategy because the gut microbiome can be therapeutically altered, potentially reducing the complications of chronic liver disease.

Validation of Cross-Genotype Neutralization by Hepatitis B Virus-Specific Monoclonal Antibodies by In Vitro and In Vivo Infection

Vaccines based on hepatitis B virus (HBV) genotype A have been used worldwide for immunoprophylaxis and are thought to prevent infections by non-A HBV strains effectively, whereas, vaccines generated from genotype C have been used in several Asian countries, including Japan and Korea, where HBV genotype C is prevalent. However, acute hepatitis B caused by HBV genotype A infection has been increasing in Japan and little is known about the efficacy of immunization with genotype C-based vaccines against non-C infection. We have isolated human monoclonal antibodies (mAbs) from individuals who were immunized with the genotype C-based vaccine. In this study, the efficacies of these two mAbs, HB0116 and HB0478, were analyzed using in vivo and in vitro models of HBV infection. Intravenous inoculation of HBV genotype C into chimeric mice with human hepatocytes resulted in the establishment of HBV infection after five weeks, whereas preincubation of the inocula with HB0116 or HB0478 protected chimeric mice from genotype C infection completely. Interestingly, both HB0116 and HB0478 were found to block completely genotype A infection. Moreover, infection by a genotype C strain with an immune escape substitution of amino acid 145 in the hepatitis B surface protein was also completely inhibited by incubation with HB0478. Finally, in vitro analysis of dose dependency revealed that the amounts of HB0478 required for complete protection against genotype C and genotype A infection were 5.5 mIU and 55 mIU, respectively. These results suggested that genotype C-based vaccines have ability to induce cross-genotype immunity against HBV infection.

Hepatitis C Virus Genotype 2 May Not Be Detected by the Cobas AmpliPrep/Cobas TaqMan HCV Test, Version 1.0

Accurate hepatitis C virus (HCV) RNA quantification is essential for the management and efficacy of treatment of chronic hepatitis C. The HCV RNA level is assessed using real-time PCR-based assays. Two highly sensitive commercial assays for HCV RNA quantification are available in many countries: the

Changes in serum lipid profiles caused by three regimens of interferon‐free direct‐acting antivirals for patients infected with hepatitis C virus

Serum low‐density lipoprotein cholesterol (LDL‐C) increases during treatment of chronic hepatitis C (CHC) with interferon‐free direct‐acting antivirals (DAAs). We sought to compare the changes of serum lipid profiles caused by three regimens.

Clinical Significance of Two Real-Time PCR Assays for Chronic Hepatitis C Patients Receiving Protease Inhibitor-Based Therapy

The aim of this study was to determine the efficacy of two hepatitis C virus (HCV) real-time PCR assays, the COBAS AmpliPrep/COBAS TaqMan HCV test (CAP/CTM) and the Abbott RealTime HCV test (ART), for predicting the clinical outcomes of patients infected with HCV who received telaprevir (TVR)-based triple therapy or daclatasvir/asunaprevir (DCV/ASV) dual therapy. The rapid virological response rates in patients receiving TVR-based triple therapy were 92% (23/25) and 40% (10/25) for CAP/CTM and ART, respectively. The false omission rate (FOR) of ART was 93.3% (14/15), indicating that CAP/CTM could accurately predict clinical outcome in the early phase. In an independent examination of 20 patients receiving TVR-based triple therapy who developed viral breakthrough or relapse, the times to HCV disappearance by ART were longer than by CAP/CTM, whereas the times to HCV reappearance were similar. In an independent experiment of WHO standard HCV RNA serially diluted in serum containing TVR, the analytical sensitivities of CAP/CTM and ART were similar. However, cell cultures transfected with HCV and grown in medium containing TVR demonstrated that ART detected HCV RNA for a longer time than CAP/CTM. Similar results were found for 42 patients receiving DCV/ASV dual therapy. The FOR of ART was 73.3% (11/15) at week 8 after initiation of therapy, indicating that ART at week 8 could not accurately predict the clinical outcome. In conclusion, although CAP/CTM and ART detected HCV RNA with comparable analytical sensitivity, CAP/CTM might be preferable for predicting the clinical outcomes of patients receiving protease inhibitor-based therapy.

Metastatic site as a predictor of nivolumab efficacy in patients with advanced non-small cell lung cancer: A retrospective multicenter trial

Purpose To conduct a retrospective multicenter trial to determine the significance of metastatic site as a predictor of nivolumab efficacy in patients with advanced non-small cell lung cancer. Methods This study was conducted across three medical centers in Japan. We retrospectively reviewed all patients who commenced nivolumab treatment at these centers between December 17, 2015 and July 31, 2016. Clinical data were collected, including age, sex, smoking status, Eastern Cooperative Oncology Group performance status, and metastatic site (lymph nodes, liver, brain, bone, lungs [intrapulmonary metastasis], and malignant pleural effusion) at the time of commencing nivolumab treatment. Patients were followed-up until March 31, 2017. Results Two hundred and one patients were enrolled. The median age at the time of commencing nivolumab treatment was 68 (range, 27–87) years. One hundred and thirty-five patients were male, 157 patients had a history of smoking, 153 patients had a performance status of 0–1, and 42 patients had squamous cell carcinoma. The median progression-free survival of all patients was 2.5 months. In the univariate analysis, a performance status of ≥2 (hazard ratio [HR]: 1.89, 95.0% confidence interval [CI]: 1.33–2.69; p < 0.001) and liver (HR: 2.09, 95.0% CI: 1.35–3.25; p < 0.001) and lung (HR: 1.57, 95.0% CI: 1.14–2.16; p < 0.01) metastases correlated with a significantly shorter progression-free survival in nivolumab-treated patients. In the multivariate analysis, a performance status of ≥2 (HR: 1.54, 95.0% CI: 1.05–2.25; p < 0.05) and liver (HR: 1.90, 95.0% CI: 1.21–2.98; p < 0.01) and lung (HR: 1.41, 95.0% CI: 1.00–1.99; p < 0.05) metastases were independently correlated with a significantly shorter progression-free survival in nivolumab-treated patients. Conclusion Liver and lung metastases and a poor performance status are independent predictors of nivolumab efficacy in patients with advanced non-small cell lung cancer.

Does afatinib plus bevacizumab combination therapy induce positive conversion of T790M in previously-negative patients?

Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are markedly effective for T790M-positive patients. To confer their clinical benefit to more patients, a novel therapy to induce positive conversion in T790M-negative patients may be possible. We retrospectively reviewed medical records of patients who had received rebiopsy after completion of ABC-study: a prospective phase II study of Afatinib plus Bevacizumab Combination (ABC)-therapy after acquired resistance to EGFR-TKI. Between October 2014 and September 2016, 32 eligible patients were enrolled in ABC-study at our institutes. Eighteen patients were T790M-negative and 14 were T790M-positive before ABC-therapy. Rebiopsy was performed on 13 T790M-negative and 5 T790M-positive patients after progression of ABC-therapy. In 8 (62%) of 13 T790M-negative patients, T790M status changed from negative to positive after ABC-therapy. Seven of these 8 patients underwent osimertinib therapy. The response rate and median time to treatment failure were 86% and 12.2 months, respectively. There were no adverse events ≥grade 3, nor any treatment-related deaths. On the other hand, T790M remained positive after ABC-therapy in all 5 previous T790M-positive patients. ABC-therapy could induce positive conversion of T790M even in previously-negative patients. We hypothesize that ABC-therapy could provoke “clonal selection”, which purifies T790M-positive cancer cells in heterogeneous tumors. Further studies are warranted to confirm this phenomena.