Impact of HBeAg on Hepatocellular Carcinoma Risk During Oral Antiviral Treatment in Patients With Chronic Hepatitis B.

BACKGROUND & AIMS: Antiviral treatment from hepatitis B envelope antigen (HBeAg)-positive status may attenuate the integration of hepatitis B virus DNA into the host genome causing hepatocellular carcinoma (HCC). We investigated the impact of HBeAg status at the onset of antiviral treatment on the risk of HCC. METHODS: The incidence of HCC was evaluated in Korean patients with chronic hepatitis B who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative phase. The results in the Korean cohort were validated in a Caucasian PAGE-B cohort. RESULTS: A total of 9143 Korean patients (mean age, 49.2 years) were included: 49.1% were HBeAg-positive and 49.2% had cirrhosis. During follow-up (median, 5.1 years), 916 patients (10.0%) developed HCC. Baseline HBeAg positivity was not associated with the risk of HCC in the entire cohort or cirrhotic subcohort. However, in the non-cirrhotic subcohort, HBeAg positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.26-0.66), propensity score-matching (aHR, 0.46; 95% CI, 0.28-0.76), and inverse probability weighting analyses (aHR, 0.44; 95% CI, 0.28-0.70). In the Caucasian cohort (n = 719; mean age, 51.8 years; HBeAg-positive, 20.3%; cirrhosis, 34.8%), HBeAg-positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the non-cirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR, 0.21; 95% CI, 0.00-1.67). CONCLUSIONS: This multinational cohort study implies that HBeAg positivity at the onset of antiviral treatment seems to be an independent factor associated with a lower risk of HCC in patients with chronic hepatitis B without cirrhosis, but not in those with cirrhosis.

Unmet Needs in Clinical and Basic Hepatitis B Virus Research.

Chronic hepatitis B (CHB) has become a treatable and controllable disease. The current nucleos(t)ide analogue (NUC) and pegylated interferon therapies effectively help slow disease progression and reduce the risk of cirrhosis, hepatocellular carcinoma (HCC), and CHB-associated mortality. Long-term viral suppression is easily achievable by NUC therapy, with limited adverse reactions. However, several unmet requirements still exist, including safety and risk-stratified HCC surveillance among patients who received long-term NUC therapy. Criteria for determining which patients should receive finite-duration NUC therapy and which should receive combination therapy with both NUC and pegylated interferon remain unsettled. The management of hepatitis B virus (HBV) e antigen-positive viremic patients with normal liver function and the incorporation of new biomarkers to help manage CHB require further exploration. To achieve functional cure (ie, HBV surface antigen seroclearance) and complete cure (ie, eradication of covalently closed circular DNA) of CHB, several challenges in basic research must be addressed, including the development of an efficient cell culture system and animal models for HBV investigation, development of treatment to eradicate covalently closed circular HBV DNA, and development of immunotherapy for CHB. This brief review focuses on unmet needs in both clinical and basic HBV research.

The twenty-year story of a plant-based vaccine against hepatitis B: stagnation or promising prospects?

Hepatitis B persists as a common human disease despite effective vaccines having been employed for almost 30 years. Plants were considered as alternative sources of vaccines, to be mainly orally administered. Despite 20-year attempts, no real anti-HBV plant-based vaccine has been developed. Immunization trials, based on ingestion of raw plant tissue and conjugated with injection or exclusively oral administration of lyophilized tissue, were either impractical or insufficient due to oral tolerance acquisition. Plant-produced purified HBV antigens were highly immunogenic when injected, but their yields were initially insufficient for practical purposes. However, knowledge and technology have progressed, hence new plant-derived anti-HBV vaccines can be proposed today. All HBV antigens can be efficiently produced in stable or transient expression systems. Processing of injection vaccines has been developed and needs only to be successfully completed. Purified antigens can be used for injection in an equivalent manner to the present commercial vaccines. Although oral vaccines require improvement, plant tissue, lyophilized or extracted and converted into tablets, etc., may serve as a boosting vaccine. Preliminary data indicate also that both vaccines can be combined in an effective parenteral-oral immunization procedure. A partial substitution of injection vaccines with oral formulations still offers good prospects for economically viable and efficacious anti-HBV plant-based vaccines.

Anti-HBs cellular immune response in kidney recipients before and 4 months after transplantation.

Patients with renal failure represent a population at risk for hepatitis B, since only 50 to 60% of them develop protective humoral responses after vaccination. As this could be due to an altered regulation of cellular immune responses, the objectives of the present study were to evaluate the proliferative abilities of lymphocytes from patients with chronic renal failure after stimulation in vitro with a mitogen (pokeweed mitogen [PWM]) or HBsAg. In order to differentiate between the immunodeficiency associated with renal failure and that due to immunosuppression posttransplantation, the same subjects were tested before and 4 months after kidney transplantation. The lymphoproliferation assay used was performed by flow cytometry, which is based on sequential analysis of the cell cycle and which allows analysis of cytokine production. Serologically, the group of 36 patients tested comprised 22% nonresponders, 30% poor responders, and 48% responders. Lymphocyte growth was observed for all patients after stimulation with PWM, indicating that these cells had the capacity to proliferate in vitro. The level of lymphoproliferation in response to PWM was significantly reduced after transplantation, yet both before and after transplantation, all serologic nonresponders developed cellular responses to at least two vaccines. No correlation between humoral and cellular responses was shown. Proliferating cells were lymphocytes, which mostly secreted interleukin 4 (IL-4) and IL-10 for the three serologic groups. This study suggests that even when repeated vaccination fails to induce significant antibody levels in patients with renal failure, specific HBs cellular responses develop, and these may prove to be efficient in protecting these patients against hepatitis B.

Seguimiento longitudinal de 64 niños crónicamente infectados por virus B, tratados y no tratados con interferon / Longitudinal follow up of 64 children chronically infected with hepatitis B virus; treated and not treated with interferon

Con la finalidad de contribuir a conocer el espectro de la enfermedad se presentan las características evolutivas de un grupo de niños crónicamente infectados con virus de hepatitis B (VHB), 38 de ellos recibieron tratamiento con interferon y 26 no lo recbieron. El tiempo mínimo de infección fue de 8 meses, la edad promedio fue de 4,7 años con ligero predominio del sexo masculino (39/25) y el tiempo promedio de observación fue de 5 años 3 meses (rango 6 meses-14 años). La muestra se dividió en dos grandes grupos: a) 40 pacientes AgeHB positivos, de los cuales 26 recibieron tratamiento y 14 no. b) 24 pacientes AgeHB negativos, 12 tratados y 12 sin tratamiento. La dosis fue de 5.000.000 unidades por metro cuadrado de superficie corporal 3 veces por semana durante 16 semanas. Los resultados no mostraron diferencias estadísticamente significativas que sugieran efectos favorables del INF en el logro de la seroconversión del Age ni del Ags, mientras que la edad si incluye significativamente en la seroconversión del Ags, por lo que se plantea si la seroconversión obtenida puede deberse más a la tendencia natural de la enfermedad a eliminar el virus que al efecto del inteferon. En el lapso de estudio solo un caso evolucionó a cirrosis (1,7 por ciento) y en ninguno se ha detectado hepatocarcinoma