BackgroundThe evidence evaluating the benefits of programmatic nutrition interventions to HIV-infected individuals in developing countries, where there is a large overlap between HIV prevalence and malnutrition, is limited. This study evaluates the impact of food assistance (FA) on change in weight and disease progression as measured by WHO staging.MethodsWe utilize program data from The AIDS Support Organization (TASO) in Uganda to compare outcomes among FA recipients to a control group, using propensity score matching (PSM) methods among 14,481 HIV-infected TASO clients.ResultsFA resulted in a significant mean weight gain of 0.36 kg over one year period. This impact was conditional on anti-retroviral therapy (ART) receipt and disease stage at baseline. FA resulted in mean weight gain of 0.36 kg among individuals not receiving ART compared to their matched controls. HIV-infected individuals receiving FA with baseline WHO stage II and III had a significant weight gain (0.26 kg and 0.2 kg respectively) compared to their matched controls. Individuals with the most advanced disease at baseline (WHO stage IV) had the highest weight gain of 1.9 kg. The impact on disease progression was minimal. Individuals receiving FA were 2 percentage points less likely to progress by one or more WHO stage compared to their matched controls. There were no significant impacts on either outcome among individuals receiving ART.ConclusionsGiven the widespread overlap of HIV and malnutrition in sub-Saharan Africa, FA programs have the potential to improve weight and delay disease progression, especially among HIV-infected individuals not yet on ART. Additional well designed prospective studies evaluating the impact of FA are urgently needed.

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Salmonellosis in humans is a costly disease traditionally assumed to be associated with exposure to contaminated food. We have developed a farm-to-fork model that allows estimation of the human health costs and risks associated with Salmonella in pork. This analysis focuses on the stages of the pork production chain up to the point of producing a chilled pork carcass. The model predicts the number of human cases of salmonellosis associated with pork (mean, 99,430; 90% confidence interval, 20,970 to 245,560) and the corresponding social costs (mean, $81.53 million; 90% confidence interval, $18.75 million to $197.44 million). Sensitivity and scenario analyses suggest that changes in Salmonella status during processing are more important for human health risk and have a higher benefit:cost ratio when compared with on-farm strategies for Salmonella control. Specifically, benefit:cost ratios are less than 1 (indicating they are not likely to be profitable from a social economic perspective) for the on-farm strategies of vaccination and meal feeding, whereas rinsing carcasses at various temperatures with and without sanitizer all have benefit:cost ratios greater than 1 (indicating they are profitable from a social economic perspective). This type of modeling is useful for evaluation of the relative cost effectiveness of interventions at different points in the food chain when allocating limited food safety dollars and is best used for examining trends and alternative strategies rather than for providing definitive dollar value estimates of risk. The dollar value estimates must be considered in the context of the wide confidence intervals.

Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (∼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.KEYWORDS Hepatitis C virus NS3 serine protease inhibitor, R-ketoamide, narlaprevir, SCH 900518 H epatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma and liver failure in humans. 1 An estimated 3% of the human population worldwide is chronically infected with HCV. 2 Currently the only available treatment regimens are subcutaneous R-interferon or long-acting pegylated-interferon, alone or in combination with oral antiviral agent ribavirin. 3 The approved therapy is still far from ideal for the hard to treat genotype-1 patients 4 and is frequently accompanied by adverse side effects. There is an unmet medical need to discover new, more effective and tolerable regimens for the treatment of HCV infection. Advances in the understanding of molecular pathways of HCV replication have resulted in several small molecule direct-acting antivirals entering clinical trials in the past few years.Since identification of this virus, the NS3 serine protease contained within the N-terminal region of the NS3 protein has been studied extensively. 5 This chymotrypsin-like serine protease plays a pivotal role in viral replication and, therefore, is an attractive target for HCV antiviral therapeutics. 6,7 Intense efforts were focused in the past decade to discover novel small molecule agents that inhibit NS3 serine protease. 8 Proof of concept studies in humans with BILN 2061, a noncovalent P1-P3 macrocyclic inhibitor, validated this hypothesis. 9 Since then, several NS3 protease inhibitors have progressed to human clinical trials. Currently the most advanced among those are boceprevir (SCH 503034), 1, 10,11 and telaprevir (VX950), 12,13 from the slow-binding reversible R-ketoamide class, in phase III human evaluation. Inhibitors in phase II studies, from the structurally distinct noncovalent macrocyclic class, include 14 15 and MK-7009 (P2-P4 macrocycle). 16 Other NS3 protease inhibitors currently in clinical evaluation (structure not yet disclosed) include BI-201335, ABT-450, PHX-1766, ACH-1625 and VX-813. 8 Inhibitor 1 exhibited K i * = 14 nM in the enzyme binding assay, 17 EC 90 = 350 nM in the cell-based replicon assay, 18 and acceptable pharmacokinetic profile in rats and dogs (Figure 1). In our efforts to discover a second generation HCV protease inhibitor, we focused mainly on improving the in vitro potency and preclinical pharmacokinetic profile of the inhibitor, specifically exposure in monkeys. Further...

Antimicrobial resistance is an issue of increasing global concern. Several investigators have suggested that antibiotic use in food-producing animals is a major contributor to the increasing incidence of antimicrobial-resistant organisms causing illness in humans (F. J. Angulo, K. R. Johnson, R. V. Tauxe, and M. L. Cohen, Microb. Drug Res. 6:77-83, 2000; P. D. Fey, T. J. Safranek, M. E. Rupp, E. F. Dunne, R. Efrain, P. C. Iwen, P. A. Bradford, F. J. Angulo, and S. H. Hinrichs, N. Engl. J. Med. 342:1242-1249, 2000; S. A. McEwen and P. J. Fedorka-Cray, Commun. Infect. Dis. 34(Suppl. 3):S93-S106, 2002; D. L. Smith, A. D. Harris, J. A. Johnson, E. K. Silbergeld, and J. G. Morris, Jr., Proc. Natl. Acad. Sci. USA 99:6434-6439, 2002; D. G. White, S. Zhao, R. Sudler, S. Ayers, S. Friedman, S. Chen, P. F. McDermott, D. D. Wagner, and J. Meng, N. Engl. J. Med. 345:1147-1154, 2001; W. Witte, Science 279:996, 1998). In this paper, we discuss this and other assumptions relevant to a quantitative risk assessment model for salmonellosis in humans. We also discuss other important aspects of modeling food safety and food-associated antimicrobial resistance risk to humans. We suggest that the role of food-producing animals in the origin and transmission of antimicrobial resistance and "foodborne" pathogens has been overestimated and overemphasized in the scientific literature; consequently, nonfoodborne transmission, including pet-associated human cases, has been underemphasized. Much evidence exists for the potential contribution to infectious disease that may be of human or pet origin (that may contact humans through food but not be of a food origin). Risk analyses that do not acknowledge the potential for these sources of cross-contamination will understate the contribution that origin has in the realm of foodborne and food-associated diseases (e.g., Salmonella) and the resulting uncertainty levels in the food system, thus leading to biased inferences. We emphasize the importance of evaluating both the foodborne and nonfoodborne transmission risk for salmonellosis and outline the basics of an analytical modeling approach in food safety with examples to illustrate strengths and limitations in the modeling. Examples illustrate, on a simplistic level, how varying assumptions and other inputs can influence the output of food-associated quantitative risk models.

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