Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals

Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses

Explaining IMF lending decisions after the Cold War

This paper empirically investigates the economic and political factors that affect a country's likelihood to sign an arrangement with the IMF and the determinants of the financial size of such a program. Arguably the world and the global financial architecture underwent structural changes after the ending of Cold War and so did the role of the IMF. Hence, we update and extend the work of Sturm et al. (2005) by employing a panel model for 165 countries that focuses on the post-Cold War era, i.e., 1990-2009. Our results, based on extreme bounds analysis, suggest that some economic and political variables are robustly related to these two dimensions of IMF program decisions. Furthermore, we show that it is important to distinguish between concessional and non-concessional IMF loans

Internet-based channel orientation for domesticated services firm: Some drivers and consequences

Undeniably, several studies have reported on both antecedents and the consequents of infusing internet-based channel orientation into the operations of small or micro domesticated firms. However, in the developing and to be precise the African context, such studies are somewhat scant. To address this yearlong theoretical and practical gap, this study takes inspirations from the theoretical underpinnings of both micro-institutional view of the firm as well as resource strategic action. Henceforth, this study supplements the existing internet orientation literature and adds to the on-going debate why internet channel orientation stands as the focal point and engine of survival in small and midsized enterprises. In light of this, this study proposes that entrepreneurial capability of the firm and industry competition predict Internet-based channel orientation (IORIENT) of the firm. Furthermore, the study tests the assumption that the utilisation IORIENT not only potentially contributes to greater market-sensing capability but that it can also indirectly lead to firm competitiveness. Survey data from 198 firms offer initial support for the research propositions. Overall, the research study encourages firms not to only invest in Internet marketing tools but also to effectively use these tools as this is critical to their long-term competitiveness. © 2019, IFIP International Federation for Information Processing