Explore the vast range of titles available.

Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585. Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were −0·73 log IU/mL in group 1 (95% CI 0·17–1·31; p=0·03) and −1·54 log IU/mL in group 2 (1·21–1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change (r2=0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days [SE 0·24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 [SE 0·06] vs 0·739 [0·05], p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc.

Beef exports represent a substantial part of Paraguay’s agricultural sector. Cattle movements involve a high risk due to the possible spread of bovine diseases that can have a significant impact on the country’s economy. We analyzed cattle movements from 2014 to 2018 using the networks analysis methodology at the holding and district levels at different temporal scales. We built two types of networks to identify network characteristics that may contribute to the spread of two diseases with different epidemiological characteristics: i) a network including all cattle movements to consider the transmission of a disease of rapid spread like foot and mouth disease, and ii) a network including only cow movements to account for bovine brucellosis, a disease of slow spread that occurs mainly in adult females. Network indicators did not vary substantially among the cattle and cow only networks. The holdings/districts included in the largest strongly connected components were distributed throughout the country. Percolation analysis performed at the holding level showed that a large number of holdings should be removed to make the largest strongly connected component disappear. Higher values of the centrality indicators were found for markets than for farms, indicating that they may play an important role in the spread of an infectious disease. At the holding level (but not at the district level), the networks exhibited characteristics of small-world networks. This property may facilitate the spread of foot and mouth disease in case of re-emergence, or of bovine brucellosis in the country through cattle movements. They should be taken into account when implementing surveillance or control measures for these diseases.

Beef exports represent a substantial part of Paraguay’s agricultural sector. Cattle movements involve a high risk due to the possible spread of bovine diseases that can have a significant impact on the country’s economy. We analyzed cattle movements from 2014 to 2018 using the networks analysis methodology at the holding and district levels at different temporal scales. We built two types of networks to identify network characteristics that may contribute to the spread of two diseases with different epidemiological characteristics: i) a network including all cattle movements to consider the transmission of a disease of rapid spread like foot and mouth disease, and ii) a network including only cow movements to account for bovine brucellosis, a disease of slow spread that occurs mainly in adult females. Network indicators did not vary substantially among the cattle and cow only networks. The holdings/districts included in the largest strongly connected components were distributed throughout the country. Percolation analysis performed at the holding level showed that a large number of holdings should be removed to make the largest strongly connected component disappear. Higher values of the centrality indicators were found for markets than for farms, indicating that they may play an important role in the spread of an infectious disease. At the holding level (but not at the district level), the networks exhibited characteristics of small-world networks. This property may facilitate the spread of foot and mouth disease in case of re-emergence, or of bovine brucellosis in the country through cattle movements. They should be taken into account when implementing surveillance or control measures for these diseases.

In two “départements” in the South-West of France, bovine tuberculosis (bTB) outbreaks due to Mycobacterium bovis spoligotype SB0821 have been identified in cattle since 2002 and in wildlife since 2013. Using whole genome sequencing, the aim of our study was to clarify badger contribution to bTB transmission in this area. We used a Bayesian evolutionary model, to infer phylogenetic trees and migration rates between two pathogen populations defined by their host-species. In order to account for sampling bias, sub-population structure was inferred using the marginal approximation of the structured coalescent (Mascot) implemented in BEAST2. We included 167 SB0821 strains (21 isolated from badgers and 146 from cattle) and identified 171 single nucleotide polymorphisms. We selected a HKY model and a strict molecular clock. We estimated a badger-to-cattle transition rate (median: 2.2 transitions/lineage/year) 52 times superior to the cattle-to-badger rate (median: 0.042 transitions/lineage/year). Using the maximum clade credibility tree, we identified that over 75% of the lineages from 1989 to 2000 were present in badgers. In addition, we calculated a median of 64 transition events from badger-to-cattle (IQR: 10–91) and a median of zero transition event from cattle-to-badger (IQR: 0–3). Our model enabled us to infer inter-species transitions but not intra-population transmission as in previous epidemiological studies, where relevant units were farms and badger social groups. Thus, while we could not confirm badgers as possible intermediaries in farm-to-farm transmission, badger-to-cattle transition rate was high and we confirmed long-term presence of M. bovis in the badger population in the South-West of France.

In order to better understand transmission dynamics and appropriately target control and preventive measures, studies have aimed to identify who-infected-whom in actual outbreaks. Numerous reconstruction methods exist, each with their own assumptions, types of data, and inference strategy. Thus, selecting a method can be difficult. Following PRISMA guidelines, we systematically reviewed the literature for methods combing epidemiological and genomic data in transmission tree reconstruction. We identified 22 methods from the 41 selected articles. We defined three families according to how genomic data was handled: a non-phylogenetic family, a sequential phylogenetic family, and a simultaneous phylogenetic family. We discussed methods according to the data needed as well as the underlying sequence mutation, within-host evolution, transmission, and case observation. In the non-phylogenetic family consisting of eight methods, pairwise genetic distances were estimated. In the phylogenetic families, transmission trees were inferred from phylogenetic trees either simultaneously (nine methods) or sequentially (five methods). While a majority of methods (17/22) modeled the transmission process, few (8/22) took into account imperfect case detection. Within-host evolution was generally (7/8) modeled as a coalescent process. These practical and theoretical considerations were highlighted in order to help select the appropriate method for an outbreak.

Influenza is a major cause of mortality and morbidity worldwide. Despite numerous studies of the pathogenesis of influenza in humans and animal models the dynamics of infection and transmission in individual hosts remain poorly characterized. In this study, we experimentally modelled transmission using the H1N1pdm09 influenza A virus in pigs, which are considered a good model for influenza infection in humans. Using an experimental design that allowed us to observe individual transmission events occurring within an 18-hr period, we quantified the relationships between infectiousness, shed virus titre and antibody titre. Transmission event was observed on 60% of occasions when virus was detected in donor pig nasal swabs and transmission was more likely when donor pigs shed more virus. This led to the true infectious period (mean 3.9 days) being slightly shorter than that predicted by detection of virus (mean 4.5 days). The generation time of infection (which determines the rate of epidemic spread) was estimated for the first time in pigs at a mean of 4.6 days. We also found that the latent period of the contact pig was longer when they had been exposed to smaller amount of shed virus. Our study provides quantitative information on the time lines of infection and the dynamics of transmission that are key parts of the evidence base needed to understand the spread of influenza viruses though animal populations and, potentially, in humans.

High cure rates are achieved in HCV genotype-1b patients treated with daclatasvir and asunaprevir, DCV/ASV. Here we analyzed early HCV kinetics in genotype-1b infected Japanese subjects treated with DCV/ASV and retrospectively projected, using mathematical modeling, whether shorter treatment durations might be effective. HCV RNA levels were measured frequently during DCV/ASV therapy in 95 consecutively treated patients at a single center in Japan. Mathematical modeling was used to predict the time to cure, i.e, <1 virus copy in the extracellular body fluid. Patients with HCV<15 IU/ml at week 1 (n = 27) were excluded from modeling analysis due to insufficient HCV RNA data points. Eighty nine of the 95 included patients (94%) achieved cure, 3 (3%) relapsed due to treatment-emergent resistance, and 3 (3%) completed therapy but were lost during follow up. Model fits from 68 patients with sufficient data points indicate that after a short pharmacological delay (15.4 min [relative standard error, rse = 26%]), DCV/ASV effectiveness in blocking HCV production was 0.999 [rse~0%], HCV half-life in blood was t1/2 = 1.7 hr [rse = 21%], and HCV-infected cell loss rate was 0.391/d [rse = 5%]. Modeling predicted that 100% and 98.5% of patients who had HCV<15 IU/ml at days 14 and 28 might have been cured with 6 and 8 weeks of therapy, respectively. There was a trend (p = 0.058) between younger age and shorter time to cure. Modeling early HCV kinetics under DCV/ASV predicts that most patients would achieve cure with short treatment durations, suggesting that 24 weeks of DCV/ASV treatment can be significantly shortened.

Several studies have proven oseltamivir to be efficient in reducing influenza viral titer and symptom intensity. However, the usefulness of oseltamivir can be compromised by the emergence and spread of drug-resistant virus. The selective pressure exerted by different oseltamivir therapy regimens have received little attention. Combining models of drug pharmacokinetics, pharmacodynamics, viral kinetics and symptom dynamics, we explored the efficacy of oseltamivir in reducing both symptoms (symptom efficacy) and viral load (virological efficacy). We simulated samples of 1000 subjects using previously estimated between-subject variability in viral and symptom dynamic parameters to describe the observed heterogeneity in a patient population. We simulated random mutations conferring resistance to oseltamivir. We explored the effect of therapy initiation time, dose, intake frequency and therapy duration on influenza infection, illness dynamics, and emergence of viral resistance. Symptom and virological efficacies were strongly associated with therapy initiation time. The proportion of subjects shedding resistant virus was 27-fold higher when prophylaxis was initiated during the incubation period compared with no treatment. It fell to below 1% when treatment was initiated after symptom onset for twice-a-day intakes. Lower doses and prophylaxis regimens led to lower efficacies and increased risk of resistance emergence. We conclude that prophylaxis initiated during the incubation period is the main factor leading to resistance emergence.

Facemasks and respirators have been stockpiled during pandemic preparedness. However, data on their effectiveness for limiting transmission are scarce. We evaluated the effectiveness of facemask use by index cases for limiting influenza transmission by large droplets produced during coughing in households. A cluster randomized intervention trial was conducted in France during the 2008-2009 influenza season. Households were recruited during a medical visit of a household member with a positive rapid influenza A test and symptoms lasting less than 48 hours. Households were randomized either to the mask or control group for 7 days. In the intervention arm, the index case had to wear a surgical mask from the medical visit and for a period of 5 days. The trial was initially intended to include 372 households but was prematurely interrupted after the inclusion of 105 households (306 contacts) following the advice of an independent steering committee. We used generalized estimating equations to test the association between the intervention and the proportion of household contacts who developed an influenza-like illness during the 7 days following the inclusion. Influenza-like illness was reported in 24/148 (16.2%) of the contacts in the intervention arm and in 25/158 (15.8%) of the contacts in the control arm and the difference between arms was 0.40% (95%CI: -10% to 11%, P = 1.00). We observed a good adherence to the intervention. In various sensitivity analyses, we did not identify any trend in the results suggesting effectiveness of facemasks. This study should be interpreted with caution since the lack of statistical power prevents us to draw formal conclusion regarding effectiveness of facemasks in the context of a seasonal epidemic. clinicaltrials.gov NCT00774774.

Dog and cat rabies cases imported from rabies enzootic countries represent a major threat for areas that have acquired rabies-free status and quantitative risk analyses (QRAs) are developed in order to assess this risk of rabies reintroduction through dog and cat movements. Herein we describe a framework to evaluate dog and cat rabies incidence levels in exporting countries along with the associated uncertainty for such QRAs. For enzootic dog rabies areas (EDRAs), we extended and adapted a previously published method to specify the relationship between dog rabies vaccination coverage and canine rabies incidence; the relationship between dog and cat rabies incidences; and then to predict annual dog and cat rabies incidences. In non-enzootic dog rabies areas (nEDRAs), we provided annual incidence based on declared dog and cat rabies cases. For EDRAs, we predicted an annual incidence potentially greater than 1.5% in dogs and about ten times lower in cats with a high burden in Africa and Asia but much lower in Latin America. In nEDRAs, the occurrence of rabies was lower and of similar magnitude in dogs and cats. However, wildlife could still potentially infect dogs and cats through spillover events. This framework can directly be incorporated in QRAs of rabies reintroduction.