Preclinical assessment of antiviral combination therapy in a genetically humanized mouse model for hepatitis delta virus infection.

Chronic delta hepatitis, caused by hepatitis delta virus (HDV), is the most severe form of viral hepatitis, affecting at least 20 million hepatitis B virus (HBV)-infected patients worldwide. HDV/HBV co- or superinfections are major drivers for hepatocarcinogenesis. Antiviral treatments exist only for HBV and can only suppress but not cure infection. Development of more effective therapies has been impeded by the scarcity of suitable small-animal models. We created a transgenic (tg) mouse model for HDV expressing the functional receptor for HBV and HDV, the human sodium taurocholate cotransporting peptide NTCP. Both HBV and HDV entered hepatocytes in these mice in a glycoprotein-dependent manner, but one or more postentry blocks prevented HBV replication. In contrast, HDV persistently infected hNTCP tg mice coexpressing the HBV envelope, consistent with HDV dependency on the HBV surface antigen (HBsAg) for packaging and spread. In immunocompromised mice lacking functional B, T, and natural killer cells, viremia lasted at least 80 days but resolved within 14 days in immunocompetent animals, demonstrating that lymphocytes are critical for controlling HDV infection. Although acute HDV infection did not cause overt liver damage in this model, cell-intrinsic and cellular innate immune responses were induced. We further demonstrated that single and dual treatment with myrcludex B and lonafarnib efficiently suppressed viremia but failed to cure HDV infection at the doses tested. This small-animal model with inheritable susceptibility to HDV opens opportunities for studying viral pathogenesis and immune responses and for testing novel HDV therapeutics.

Clinical and Economic Impact of Empirical Extended-Infusion Piperacillin-Tazobactam in a Community Medical Center.

BACKGROUND: Current medical center practice allows for the automatic conversion of all piperacillin/tazobactam orders from intermittent to extended infusion (EI). OBJECTIVE: To compare the clinical and cost impact of empirical extended-infusion piperacillin/tazobactam. METHODS: All consecutive patients treated with piperacillin/tazobactam for >48 hours were reviewed for inclusion. Patients were stratified into 2 groups: (1) traditional infusion (TI), preprotocol implementation, and (2) EI, postprotocol implementation. Patient demographics and primary and secondary diagnoses were extracted from the hospital discharge database. All patients were assessed for the primary end point of all cause 14-day in-hospital mortality. Secondary outcomes included length of hospital stay, duration of antibiotic therapy, cost per treatment course, and occurrence of Clostridium difficile infection. RESULTS: A total of 2150 patients were included (EI = 632; TI = 1518). After adjusting for comorbidity, length of stay, and age, 14-day in-hospital mortality was similar between groups (odds ratio = 1.16; 95% CI = 0.85-1.58; P = 0.37). Length of stay was similar between the EI group versus TI (mean ± SD: 12.5 ± 9.58 days vs 11.8 ± 9.58 days, respectively; P = 0.10) after adjusting for age and Chalson-Deyo comorbidity index. Total cost per treatment course was reduced in the EI group by 13% compared with the TI group ($565.90 ± $257.70 vs $648.30 ± $349.20, respectively; P < 0.0001). CONCLUSION: Automatic substitution of EI for TI piperacillin/tazobactam is safe and associated with significant cost savings. EI piperacillin/tazobactam was not associated with a reduction in mortality or length of stay.