Importation of generic hepatitis C therapies: Bridging the price - access gap in high-income countries

The global burden of hepatitis C infection and the emergence of effective therapies An estimated 80-150 million people are infected with hepatitis C infection (HCV) worldwide, with the highest prevalence rates in low- and medium-income countries of Africa and Asia. HCV-related liver disease mortality is estimated to be half a million per annum.1,2 Chronic HCV treatment was interferon-based for two decades, with the addition of ribavirin (RBV),3 pegylated-interferon (PEG-IFN)4 and initial protease inhibitor direct acting antiviral (DAA) therapies (telaprevir, boceprevir)5,6 subsequently providing stepwise improvements in the rate of sustained virological response (SVR). Despite these improvements, interferon-containing HCV therapy uptake remained low in most countries, ranging from <1% to a maximum of 5% of people with chronic HCV initiating therapy each year.7 Fortunately, recent years have seen a revolution in HCV therapeutic development, with the advent of interferon-free DAA therapies, which disrupt replication through inhibition of HCV protease, polymerase and NS5A function.8 Simple (single daily dosing oral regimens), highly tolerable, short-duration (8-24 weeks) regimens with extremely high efficacy (cure rates above 95%) have been developed and registered internationally. Used in various combinations depending on HCV genotypes and previous treatment exposure, these include: sofosbuvir/ledipasvir ,9-11 paritaprevir/ritonavir/ombitasvir/dasabavir/+/-ribavirin ,12-14 sofosbuvir/daclatasvir,15,16 elbasvir/grazoprevir,17,18 and sofosbuvir/velpatasvir. There is clear evidence that HCV cure impacts HCV-related liver disease and hepatocellular carcinoma (HCC) risk.19 Early treatment may have greater benefit. Furthermore, as a result of the high efficacy and tolerance, and ease of delivery of these medications, HCV treatment as prevention is being explored in some countries, particularly treating high prevalence populations, such as people who inject drugs and incarcerated populations.20 The broad implementation of these therapeutic regimens has the potential to dramatically impact HCV-related disease burden globally. Indeed, new HCV treatments have been deemed so important that some (sofosbuvir, daclatasvir) were added to the 2015 WHO Essential Medicines List along with a number of their combinations.NHMRC project grant, App 108067

Numerical modelling of blue mussel (Mytilus edulis) bacterial contamination

Bivalve shellfish such as oysters and mussels can concentrate human pathogens when grown in areas impacted by municipal wastewater. Under EU regulation this risk to consumers is controlled by determining the sanitary quality of bivalve shellfish production areas based on the concentration of Escherichia coli present in shellfish flesh. The authors present a modelling approach to simulate an uptake of E. coli from seawater and subsequent depuration by Mytilus edulis. The model that dynamically predicts E. coli concentration in the mussel tissue is embedded within a 3-D numerical modelling system comprising hydrodynamic, biogeochemical, shellfish ecophysiological and the newly proposed microbial modules. The microbial module has two state variables, namely, the concentrations of E. coli in water and in the mussel tissue. Novel formulations to calculate the filtration rates by mussels and the resulting uptake of bacteria are proposed; these rates are updated at every computational time step. Concentrations of E. coli in seawater are also updated accordingly taking into account the amounts ingested by mussels. The model has been applied to Bantry Bay in the south-west of Ireland. The results indicate that the model is capable of reproducing the official classification of shellfish waters in the bay based on monthly sampling at several stations. The predicted filtration rates and ratios of E. coli in water and mussels also compare well with the literature. The model thus forms a tool that may be used to assist in the classification of shellfish waters at much greater spatial and temporal detail than that offered by a field monitoring programme. Moreover, it can also aid in designing an efficient monitoring programme. The model can also be utilised to determine the contribution of individual point sources of pollution on the microbial loading in mussels and, when incorporated into an operational framework, it can provide a short-term forecasting of microbial contamination in a shellfishery. Also, the model can be easily extended to include other shellfish and pathogen species.EU Interreg IVB Atlantic Area Programm

Factors associated with severity of hepatic fibrosis in people with chronic hepatitis C infection

The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.OBJECTIVE: To determine factors associated with hepatic fibrosis development in people with chronic hepatitis C virus (HCV) infection. METHODS: As a requirement for access to interferon therapy through the S100 scheme in Australia, individual pretreatment demographic and clinical information was collected on 2986 patients from 61 hospital-based liver clinics from 1 October 1994 through 31 December 1996. Patients with both a hepatic fibrosis score and an estimated duration of HCV infection (910) were divided into 540 with no or minimal hepatic fibrosis (stage 0–1) and 370 with moderate to severe hepatic fibrosis (stage 2–3). Seven factors were examined: age at HCV infection, sex, ethnicity, source of infection, duration of infection, alcohol intake, and mean ALT level. A further analysis was performed for all 1135 patients with a hepatic fibrosis score disregarding age at and duration of HCV infection. RESULTS: In multivariate analysis, four factors were significantly associated with moderate to severe hepatic fibrosis: age at infection (OR, 2.33 for age 31–40 years, 5.27 for age > 40 years, and 0.20 for age 30 years, compared with 3 times, compared with 1.5–2 times the upper limit of normal). In the analysis disregarding age at HCV infection and duration of HCV infection, older age was strongly associated with moderate to severe hepatic fibrosis (OR, 2.32 for age 36–40 years, 2.46 for age 41–50 years, 7.87 for age 51–60 years, and 7.15 for age > 60 years, compared with 16–30 years). There was no association in either analysis with sex or source of HCV infection. CONCLUSION: These factors may assist in targeting patients for both liver biopsy-based investigation and therapeutic intervention.Mark Danta, Gregory J Dore, Lisa Hennessy, Yueming Li, Chris R Vickers, Hugh Harley, Meng Ngu, William Reed, Paul V Desmond, William Sievert, Geoff C Farrell, John M Kaldor and Robert G Bate

Infrared absorption from Charge Density Waves in magnetic manganites

The infrared absorption of charge density waves coupled to a magnetic background is first observed in two manganites La{1-x}Ca{x}MnO{3} with x = 0.5 and x = 0.67. In both cases a BCS-like gap 2 Delta (T), which for x=0.5 follows the hysteretic ferro-antiferromagnetic transition, fully opens at a finite T{0} < T{Neel}, with 2 Delta(T{0})/kT{c} close to 5. These results may also explain the unusual coexistence of charge ordering and ferromagnetism in La{0.5}Ca{0.5}MnO{3}.Comment: File revtex + 3 figs. in epsf. To appear on Phys. Rev. Let

Small and large polarons in nickelates, manganites, and cuprates

By comparing the optical conductivities of La_{1.67}Sr_{0.33}NiO_{4} (LSNO), Sr_{1.5}La_{0.5}MnO_4 (SLMO), Nd_2CuO_{4-y} (NCO), and Nd_{1.96}Ce_{0.04}CuO_{4} (NCCO), we have identified a peculiar behavior of polarons in this cuprate family. While in LSNO and SLMO small polarons localize into ordered structures below a transition temperature, in those cuprates the polarons appear to be large, and at low T their binding energy decreases. This reflects into an increase of the polaron radius, which may trigger coherent transport.Comment: File latex, 15 p. incl. 4 Figs. epsf, to appear on the Journal of Superconductivity - Proc. "Stripes 1996" - Roma Dec 199

Infrared response of ordered polarons in layered perovskites

We report on the infrared absorption spectra of three oxides where charged superlattices have been recently observed in diffraction experiments. In La$_{1.67}$Sr$_{0.33}$NiO$_4$, polaron localization is found to suppress the low-energy conductivity through the opening of a gap and to split the $E_{2u}$-$A_{2u}$ vibrational manifold of the oxygen octahedra. Similar effects are detected in Sr$_{1.5}$La$_{0.5}$MnO$_4$ and in La$_2$NiO$_{4+y}$, with peculiar differences related to the type of charge ordering.Comment: File latex, 11 p. + 3 Figures, to appear on Phys. Rev. B (Rapid Commun.), 1 Oct. 1996. The figures will be faxed upon request. E-mail:[email protected] Fax: +39-6-446315

Carbon and water fluxes from ponderosa pine forests disturbed by wildfire and thinning

Disturbances alter ecosystem carbon dynamics, often by reducing carbon uptake and stocks. We compared the impact of two types of disturbances that represent the most likely future conditions of currently dense ponderosa pine forests of the southwestern United States: (1) high-intensity fire and (2) thinning, designed to reduce fire intensity. High- severity fire had a larger impact on ecosystem carbon uptake and storage than thinning. Total ecosystem carbon was 42% lower at the intensely burned site, 10 years after burning, than at the undisturbed site. Eddy covariance measurements over two years showed that the burned site was a net annual source of carbon to the atmosphere whereas the undisturbed site was a sink. Net primary production (NPP), evapotranspiration (ET), and water use efficiency were lower at the burned site than at the undisturbed site. In contrast, thinning decreased total ecosystem carbon by 18%, and changed the site from a carbon sink to a source in the first post- treatment year. Thinning also decreased ET, reduced the limitation of drought on carbon uptake during summer, and did not change water use efficiency. Both disturbances reduced ecosystem carbon uptake by decreasing gross primary production (55% by burning, 30% by thinning) more than total ecosystem respiration (TER; 33–47% by burning, 18% by thinning), and increased the contribution of soil carbon dioxide efflux to TER. The relationship between TER and temperature was not affected by either disturbance. Efforts to accurately estimate regional carbon budgets should consider impacts on carbon dynamics of both large disturbances, such as high-intensity fire, and the partial disturbance of thinning that is often used to prevent intense burning. Our results show that thinned forests of ponderosa pine in the southwestern United States are a desirable alternative to intensively burned forests to maintain carbon stocks and primary production

Molecular biological methods for studying the gut microbiota:the EU human gut flora project

Seven European laboratories co-operated in a joint project (FAIR CT97-3035) to develop, refine and apply molecular methods towards facilitating elucidation of the complex composition of the human intestinal microflora and to devise robust methodologies for monitoring the gut flora in response to diet. An extensive database of 16S rRNA sequences for tracking intestinal bacteria was generated by sequencing the 16S rRNA genes of new faecal isolates and of clones obtained by amplification with polymerase chain reaction (PCR) on faecal DNA from subjects belonging to different age groups. The analyses indicated that the number of different species (diversity) present in the human gut increased with age. The sequence information generated, provided the basis for design of 16S rRNA-directed oligonucleotide probes to specifically detect bacteria at various levels of phylogenetic hierarchy. The probes were tested for their specificity and used in whole-cell and dot-blot hybridisations. The applicability of the developed methods was demonstrated in several studies and the major outcomes are described

Dizajniranje i sinteza novih derivata tiofenkarbohidrazida, tienopirazola i tienopirimidina s antioksidativnim i antitumorskim djelovanjem

2-Amino-5-acetyl-4-methyl-thiophene-3-carboxylic acid ethyl ester (1) and 5-acetyl-2-amino-4-methylthiophene-3-carbohydrazide (2) were synthesized and used as starting materials for the synthesis of new series of 1-(5-amino-4-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-methylthiophen-2-yl) ethanone (3a), 1-(5-amino-4-(4-chloro-3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-methylthiophen-2-yl) ethanone (3b), 1-(4-methyl-2-amino-5-acetylthiophene-3-carbonyl) pyrazolidine-3,5-dione (4), (Z)-N\u27-(4-methyl-2-amino-5-acetylthiophene-3-carbonyl) formohydrazonic acid (5a), (Z)-ethyl-N\u27-(4-methyl-2-amino-5-acetylthiophene-3-carbonylformo hydrazonate (5b), 6-acetyl-3-amino-2,5-dimethylthieno2,3-dpyrimidin-4(3H)-one (8), 5-methyl-3-amino-2-mercapto-6-acetylthieno2,3-dpyrimidin-4(3H)-one (10) and 5-methyl-6-acetyl-2-thioxo-2,3-dihydrothieno2,3-dpyrimidin-4(1H)-one (12) as potential antioxidant and antitumor agents. Pharmacological results showed that compounds 6a, 6b, 8, 10 and 12 exhibited promising antitumor and antioxidant activity.Etilni ester 2-amino-5-acetil-4-metil-tiofen-3-karboksilne kiseline (1) i 5-acetil-2-amino-4-metiltiofen-3-karbohidrazid (2) sintetizirani su i upotrebljeni kao reaktanti u sintezi novih spojeva 1-(5-amino-4-(3,5-dimetil-1H-pirazol-1-karbonil)-3-metiltiofen-2-il) etanona (3a), 1-(5-amino-4-(4-klor-3,5-dimetil-1H-pirazol-1-karbonil)-3-metiltiofen-2-il) etanona (3b), 1-(4-metil-2-amino-5-acetiltiofen-3-karbonil) pirazolidin-3,5-diona (4), (Z)-N\u27-(4-metil-2-amino-5-acetiltiofen-3-karbonil) formohidrazonske kiseline (5a), (Z)-etil-N\u27-(4-metil-2-amino-5-acetiltiofen-3-karbonilformo hidrazonata (5b), 6-acetil-3-amino-2,5-dimetiltieno2,3-dpirimidin-4(3H)-one (8), 5-metil-3-amino-2-merkapto-6-acetiltieno2,3-dpirimidin-4(3H)-ona (10) i 5-metil-6-acetil-2-tiokso-2,3-dihidrotieno2,3-dpirimidin-4(1H)-ona (12) kao potencijalnih antioksidansa i citostatika. Farmakološka ispitivanja ukazuju na to da spojevi 6a, 6b, 8, 10 i 12 imaju značajno antitumorsko i antioksidativno djelovanje