Safety,tolerability and immunogenicity of GS-4774, a hepatitis B virus-specific therapeutic vaccine,in healthy subjects: A randomized study

Background

GS-4774 is a recombinant, heat-killed, yeast-based immunotherapy engineered to express hepatitis B virus (HBV)-specific antigens. GS-4774 is being developed as a therapeutic vaccine for chronic HBV infection. The aim of this study was to assess the safety, tolerability and immunogenicity of GS-4774 in healthy subjects.

Design

This was a randomized, open-label, dose-ascending study. Subjects were allocated to one of three dose groups (n = 20 per group) to receive 10, 40 or 80 yeast units (YU; 1 YU = 10⁷ yeast) of GS-4774 in two immunization regimens (five subcutaneous injections at weekly intervals with one monthly booster or three subcutaneous injections at monthly intervals). T-cell-mediated responses were determined by interferon (IFN)-γ enzyme-linked immunospot (ELISpot) assay and lymphocyte-proliferation assay (LPA).

Results

Adverse events were reported by 39 of 60 (65%) subjects; all were mild or moderate and none was serious. Adverse events occurred most frequently in the highest dose group, 80 YU, and the number of individual events was higher after weekly immunization than monthly. The most common adverse events were injection-site reactions. Most (88%) subjects responded to GS-4774 by at least one of the T-cell assays. Following immunization with GS-4774, IFN-γ-producing T-cells specific for HBV antigens were detectable in 30 (51%) subjects. The ELISpot response was observed at all doses, with the highest frequency of responders occurring at the highest dose (10 YU: 45%; 40 YU: 35%; 80 YU: 74%). Proliferative responses to HBV recombinant antigens were observed in 90% subjects; responses were mainly independent of GS-4774 dose and immunization regimen.

Conclusions

GS-4774 was safe and well-tolerated in healthy subjects with injection-site reactions being the most frequently reported adverse events. With both weekly and monthly regimens, GS-4774 provided HBV-specific immune responses at all doses evaluated. Further evaluation of GS-4774 is ongoing in patients with chronic HBV infection.Clinical trial registry: Clinicaltrials.gov (NCT01779505)     

Current therapy for hepatitis C: pegylated interferon and ribavirin

The combinations of peginterferon alfa-2a or peginterferon alfa-2b with ribavirin lead to significant improvement in sustained virological response when compared with standard interferon and ribavirin therapy. These newer agents represent the most effective treatments available for the initial therapy of patients with chronic hepatitis C. A review of the clinical trials to date suggests certain similarities and differences between the two preparations. For both regimens, however, it is apparent that information concerning the predictability of response and the importance of adherence to the treatment regimens will be of great value in the therapeutic management of chronic hepatitis C. Although viral load and genotype, gender, age, and absence of fibrosis have been shown consistently to be important predictors of response, identification of additional host immune and genetic factors involved in determining outcome of antiviral therapy are necessary.     

Factors influencing the participation of gastroenterologists and hepatologists in clinical research

Background  

Although clinical research is integral to the advancement of medical knowledge, physicians face a variety of obstacles to their participation as investigators in clinical trials. We examined factors that influence the participation of gastroenterologists and hepatologists in clinical research.     

Emphysema in the renal allograft

Two diabetic patients in whom emphysematous pyelonephritis developed after renal transplantation are described. Clinical recognition of this unusual and serious infection is masked by the effects of immunosuppression. Abdominal radiographic, ultrasound, and computed tomography findings are discussed. The clinical presentation includes urinary tract infection, sepsis, and acute tubular malfunction of the allograft in insulin-dependent diabetics.