Cost-Effectiveness Analysis of Rituximab for Chronic Lymphocytic Leukemia Using a Semi-Markovian Model Approach in R.

OBJECTIVES: This study aims to compare the strategies fludarabine, cyclophosphamide, and rituximab and fludarabine and cyclophosphamide for the treatment of chronic lymphocytic leukemia in Brazil. METHODS: A three-states clock-reset semi-Markovian model was constructed in R. The time horizon of the analysis was 15 years and monthly cycles were used. Transition probabilities were derived from the survival curves of the CLL-8 study. Other probabilities were also derived from the medical literature. Costs included in the model referred to the application of injectable drugs, prescription cost, cost of treating adverse events, and costs of supportive care. The model was evaluated by microsimulation. To determine the study result, multiple cost-effectiveness threshold values were used. RESULTS: In the main analysis, an incremental cost-effectiveness ratio of 19 029.38 PPP-US dollars (USD)/quality-adjusted life-year (QALY) (41 141.52 Brazilian real/QALY) was observed. In 1.8% of the iterations, fludarabine and cyclophosphamide was considered dominant over fludarabine, cyclophosphamide, and rituximab. It can be shown that at 1 gross domestic product (GDP) per capita/QALY, 36.1% of the iterations would consider the technology cost-effective. At 2 GDP per capita/QALY, this number rises to 82.1%. At 50 000 USD/QALY, 92.8% of the iterations would suggest the technology to be cost-effective. In terms of some threshold accepted or proposed around the world, the technology would be considered cost-effective at 50 000 USD/QALY, 3 GDP per capita/QALY, and 2 GDP per capita/QALY. It would not be cost-effective at 1 GDP per capita/QALY or the opportunity costs threshold. CONCLUSION: It can be considered that rituximab is cost-effective for the treatment of chronic lymphocytic leukemia in Brazil.

Protein secretion in Lactococcus lactis : an efficient way to increase the overall heterologous protein production.

Lactococcus lactis, the model lactic acid bacterium (LAB), is a food grade and well-characterized Gram positive bacterium. It is a good candidate for heterologous protein delivery in foodstuff or in the digestive tract. L. lactis can also be used as a protein producer in fermentor. Many heterologous proteins have already been produced in L. lactis but only few reports allow comparing production yields for a given protein either produced intracellularly or secreted in the medium. Here, we review several works evaluating the influence of the localization on the production yields of several heterologous proteins produced in L. lactis. The questions of size limits, conformation, and proteolysis are addressed and discussed with regard to protein yields. These data show that i) secretion is preferable to cytoplasmic production; ii) secretion enhancement (by signal peptide and propeptide optimization) results in increased production yield; iii) protein conformation rather than protein size can impair secretion and thus alter production yields; and iv) fusion of a stable protein can stabilize labile proteins. The role of intracellular proteolysis on heterologous cytoplasmic proteins and precursors is discussed. The new challenges now are the development of food grade systems and the identification and optimization of host factors affecting heterologous protein production not only in L. lactis, but also in other LAB species.

Identification and characterization of a Brucella abortus ATP-binding cassette transporter homolog to Rhizobium meliloti ExsA and its role in virulence and protection in mice.

Brucella abortus is a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. The mechanism of virulence of Brucella spp. is not fully understood yet. Furthermore, genes that allow Brucella to reach the intracellular niche and to interact with host cells need to be identified. Using the genomic survey sequence (GSS) approach, we identified the gene encoding an ATP-binding cassette (ABC) transporter of B. abortus strain S2308. The deduced amino acid sequence encoded by this gene exhibited 69 and 67% identity with the sequences of the ABC transporters encoded by the exsA genes of Rhizobium meliloti and Mesorhizobium loti, respectively. Additionally, B. abortus ExsA, like R. meliloti and M. loti ExsA, possesses ATP-binding motifs and the ABC signature domain features of a typical ABC transporter. Furthermore, ortholog group analysis placed B. abortus ExsA in ortholog group 6 of ABC transporters more likely to be involved in bacterial pathogenesis. In R. meliloti, ExsA is an exopolysaccharide transporter essential for alfalfa root nodule invasion and establishment of infection. To test the role of ExsA in Brucella pathogenesis, an exsA deletion mutant was constructed. Replacement of the wild-type exsA by recombination was demonstrated by Southern blot analysis of Brucella genomic DNA. Decreased survival in mice of the Brucella DeltaexsA mutant compared to the survival of parental strain S2308 demonstrated that ExsA is critical for full bacterial virulence. Additionally, the B. abortus exsA deletion mutant was used as a live vaccine. Challenge experiments revealed that the exsA mutant strain induced superior protective immunity in BALB/c mice compared to the protective immunity induced by strain S19 or RB51.