BMS-790052, a first-in-class hepatitis C virus (HCV) replication complex inhibitor, targeting nonstructural protein 5A (NS5A), displays picomolar to nanomolar potency against genotypes 1 to 5. This exceptional potency translated into robust anti-HCV activity in clinical studies with HCV genotype 1-infected subjects. To date, all BMS-790052-associated resistance mutations have mapped to the N-terminal region of NS5A. To further characterize the antiviral activity of BMS-790052, HCV replicon elimination and colony formation assays were performed. Replicon was cleared from genotype 1a and 1b replicon cells in a time-and dose-dependent manner. Elimination of the genotype 1a replicon required longer treatment durations and higher concentrations of BMS-790052 than those for the genotype1b replicon. Single amino acid substitutions that conferred relatively low levels of resistance were observed at early time points and at low doses. Higher doses and longer treatment durations yielded mutations that conferred greater levels of resistance, including linked amino acid substitutions. Replicon cells that survived inhibitor treatment remained fully sensitivity to pegylated alpha interferon (pegIFN-␣) and other HCV inhibitors. Moreover, genotype 1a replicon elimination was markedly enhanced when pegIFN-␣ and BMS-790052 were combined. Resistant variants observed in this study were very similar to those observed in a multiple ascending dose (MAD) monotherapy trial of BMS-790052, validating replicon elimination studies as a model to predict clinical resistance. Insights gained from the in vitro anti-HCV activity and resistance profiles of BMS-790052 will be used to help guide the clinical development of this novel HCV inhibitor. H epatitis C virus (HCV), a member of the Flaviviridae family of RNA viruses, is a major cause of liver disease worldwide (1). The ϳ9.6-kb HCV genome encodes a polyprotein that is processed into structural proteins (core, E1, and E2), a small ion channel protein (p7), and nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) required for polyprotein processing and RNA replication (2). Until very recently, standard-of-care therapy for HCV-infected individuals consisted of a combination of pegylated interferon (pegIFN) and ribavirin (RBV) (18). Because of complications with side effects and incomplete antiviral efficacy, only ϳ50% of individuals infected with HCV genotype 1 achieved a sustained viral response upon treatment (18). Today, an increasing number of small-molecule inhibitors targeting specific viral proteins are in various stages of development, and two drugs that target the HCV NS3 protease, telaprevir and boceprevir, have been approved for clinical use for HCV genotype 1-infected patient treatment in combination with pegIFN and RBV. Collectively referred to as directly acting antiviral agents (DAA), these virus-specific inhibitors hold the promise of improving or even replacing IFN-based HCV therapy (9). Many of the DAA in development are directed against the viral enzymatic activities...

The antiviral profile of BMS-790052, a potent hepatitis C virus (HCV) replication complex inhibitor targeting nonstructural protein NS5A, is well characterized for HCV genotype-1. Here, we report that BMS-790052 inhibits hybrid replicons containing HCV genotype-4 NS5A genes with 50% effective concentrations (EC 50 s) ranging from 7 to 13 pM. NS5A residue 30 was an important site for BMS-790052-selected resistance in the hybrid replicons. Our results support the potential of BMS-790052 as a valuable component of combination therapy for HCV genotype-4 chronic infection.

The activities defined in the BRACE heuristic contribute to the optimization of the benefit-risk profile of therapeutic products in the clinical world at both the patient and population health level. With interdisciplinary collaboration, pharmacoepidemiologists are well suited for bringing in methodology expertise, relevant research, and public health perspectives into the BRACE process.

In recent years, comparative effectiveness research has been more aggressively pursued as a means to improve health care, including systematic reviews and meta-analyses to inform health policy decision making. Because most clinical trials have pre-specified approaches to collecting data on efficacy, the value of systematic reviews and meta-analyses in assessing efficacy outcomes is generally accepted. In contrast, collection of data on adverse events is seldom well structured. Hence, the methodological considerations for comparing adverse events from such non-aligned sources differ substantially from those for comparing efficacy endpoints. We address several important pitfalls in performing systematic reviews and meta-analyses on adverse events in clinical trials, and we offer recommendations for remedies. Some pitfalls arise from the fact that adverse events often are not the primary endpoints in clinical trials, hence incomplete reporting, inconsistent event definitions, various level of effort in reporting unexpected adverse events, and inappropriate use of statistical testing. Others are posed by certain important characteristics of adverse events data. The very concept of "adverse events" may skew the ascertainment, attribution, and reporting of the events. In addition, problems for meta-analysis methods arise in situations involving zero or rare events and withdrawal or loss to follow-up because of adverse events. We highlight recent initiatives that may improve the assessment and cross-study summary of adverse events. We anticipate that future guidance for conducting systematic reviews and meta-analyses will evolve to address the important methodological pitfalls we highlight here, and the practice of assessing the totality of evidence on drug safety will be improved.

Summary.  Background: Data on clinical outcomes of patients in the general population undergoing knee replacement or hip replacement surgery are sparse. Objectives: To conduct an observational study using insurance claims data to assess the incidence of selected clinical events following knee replacement or hip replacement surgery in the USA. Patients/Methods: A total of 97 469 knee replacement patients and a total of 45 203 hip replacement patients were included during the period 2004–2008; the median age was 64 years, and 63% of knee replacement patients and 55% of hip replacement patients were women. Results: During a median follow‐up of 70–71 days, the incidence rates in knee replacement patients and hip replacement patients were, respectively: ischemic stroke, 15 and 19 per 1000 person‐years; acute coronary syndrome (ACS), 15 and 18 per 1000 person‐years; bleeding events, 46 and 47 per 1000 person‐years; venous thromboembolism (VTE), 64 and 45 per 1000 person‐years; and hepatic events, one and one per 1000 person‐years. Approximately 45% of knee replacement and hip replacement patients had no claims for outpatient anticoagulant therapy within 1 week after discharge from hospital. Conclusions: Ischemic events such as stroke, ACS and VTE are important adverse events following knee replacement and hip replacement surgery. The results reported here can help in making challenging decisions regarding the clinical management of risks attributable to bleeding events and clotting events.