Markers of epidemiological success of methicillin-resistant Staphylococcus aureus isolates in European populations.

OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) infections impose a considerable burden on health systems, yet there is remarkable variation in the global incidence and epidemiology of MRSA. The MACOTRA consortium aimed to identify bacterial markers of epidemic success of MRSA isolates in Europe using a representative MRSA collection originating from France, the Netherlands and the United Kingdom. METHODS: Operational definitions of success were defined in consortium meetings to compose a balanced strain collection of successful and sporadic MRSA isolates. Isolates were subjected to antimicrobial susceptibility testing and whole-genome sequencing; genes were identified and phylogenetic trees constructed. Markers of epidemiological success were identified using genome-based time-scaled haplotypic density analysis and linear regression. Antimicrobial usage data from ESAC-Net was compared with national MRSA incidence data. RESULTS: Heterogeneity of MRSA isolate collections across countries hampered the use of a unified operational definition of success; therefore, country-specific approaches were used to establish the MACOTRA strain collection. Phenotypic antimicrobial resistance varied within related MRSA populations and across countries. In time-scaled haplotypic density analysis, fluoroquinolone, macrolide and mupirocin resistance were associated with MRSA success, whereas gentamicin, rifampicin and trimethoprim resistance were associated with sporadicity. Usage of antimicrobials across 29 European countries varied substantially, and ß-lactam, fluoroquinolone, macrolide and aminoglycoside use correlated with MRSA incidence. DISCUSSION: Our results are the strongest yet to associate MRSA antibiotic resistance profiles and antibiotic usage with the incidence of infection and successful clonal spread, which varied by country. Harmonized isolate collection, typing, resistance profiling and alignment with antimicrobial usage over time will aid comparisons and further support country-specific interventions to reduce MRSA burden.

Understanding MRSA clonal competition within a UK hospital; the possible importance of density dependence.

BACKGROUND: Methicillin resistant Staphylococcus aureus (MRSA) bacteria cause serious, often healthcare-associated infections and are frequently highly resistant to diverse antibiotics. Multiple MRSA clonal complexes (CCs) have evolved independently and countries have different prevalent CCs. It is unclear when and why the dominant CC in a region may switch. METHODS: We developed a mathematical deterministic model of MRSA CC competing for limited resource. The model distinguishes 'standard MRSA' and multidrug resistant sub-populations within each CC, allowing for resistance loss and transfer between same CC bacteria. We first analysed how dynamics of this system depend on growth-rate and resistance-potential differences between CCs, and on their resistance gene accumulation. We then fit the model to capture the longitudinal CC dynamics observed at a single UK hospital, which exemplified the UK-wide switch from mainly CC30 to mainly CC22. RESULTS: We find that within a CC, gain and loss of resistance can allow for co-existence of sensitive and resistant sub-populations. Due to more efficient transfer of resistance at higher CC density, more drug resistance can accumulate in the population of a more prevalent CC. We show how this process of density dependent competition, together with prevalence disruption, could explain the relatively sudden switch from mainly CC30 to mainly CC22 in the UK hospital setting. Alternatively, the observed hospital dynamics could be reproduced by assuming that multidrug resistant CC22 evolved only around 2004. CONCLUSIONS: We showed how higher prevalence may advantage a CC by allowing it to acquire antimicrobial resistances more easily. Due to this density dependence in competition, dominance in an area can depend on historic contingencies; the MRSA CC that happened to be first could stay dominant because of its high prevalence advantage. This then could help explain the stability, despite frequent stochastic introductions across borders, of geographic differences in MRSA CC.

The impact of mass drug administration expansion to low onchocerciasis prevalence settings in case of connected villages.

BACKGROUND: The existence of locations with low but stable onchocerciasis prevalence is not well understood. An often suggested yet poorly investigated explanation is that the infection spills over from neighbouring locations with higher infection densities. METHODOLOGY: We adapted the stochastic individual based model ONCHOSIM to enable the simulation of multiple villages, with separate blackfly (intermediate host) and human populations, which are connected through the regular movement of the villagers and/or the flies. With this model we explore the impact of the type, direction and degree of connectedness, and of the impact of localized or full-area mass drug administration (MDA) over a range of connected village settings. PRINCIPAL FINDINGS: In settings with annual fly biting rates (ABR) below the threshold needed for stable local transmission, persistence of onchocerciasis prevalence can well be explained by regular human traffic and/or fly movement from locations with higher ABR. Elimination of onchocerciasis will then theoretically be reached by only implementing MDA in the higher prevalence area, although lingering infection in the low prevalence location can trigger resurgence of transmission in the total region when MDA is stopped too soon. Expanding MDA implementation to the lower ABR location can therefore shorten the duration of MDA needed. For example, when prevalence spill-over is due to human traffic, and both locations have about equal populations, then the MDA duration can be shortened by up to three years. If the lower ABR location has twice as many inhabitants, the reduction can even be up to six years, but if spill-over is due to fly movement, the expected reduction is less than a year. CONCLUSIONS/SIGNIFICANCE: Although MDA implementation might not always be necessary in locations with stable low onchocerciasis prevalence, in many circumstances it is recommended to accelerate achieving elimination in the wider area.

The effect of assortative mixing on stability of low helminth transmission levels and on the impact of mass drug administration: Model explorations for onchocerciasis.

BACKGROUND: Stable low pre-control prevalences of helminth infection are not uncommon in field settings, yet it is poorly understood how such low levels can be sustained, thereby challenging efforts to model them. Disentangling possible facilitating mechanisms is important, since these may differently affect intervention impact. Here we explore the role of assortative (i.e. non-homogenous) mixing and exposure heterogeneity in helminth transmission, using onchocerciasis as an example. METHODOLOGY/PRINCIPAL FINDINGS: We extended the established individual-based model ONCHOSIM to allow for assortative mixing, assuming that individuals who are relatively more exposed to fly bites are more connected to each other than other individuals in the population as a result of differential exposure to a sub-population of blackflies. We used the model to investigate how transmission stability, equilibrium microfilarial (mf) prevalence and intensity, and impact of mass drug administration depend on the assumed degree of assortative mixing and exposure heterogeneity, for a typical rural population of about 400 individuals. The model clearly demonstrated that with homogeneous mixing and moderate levels of exposure heterogeneity, onchocerciasis could not be sustained below 35% mf prevalence. In contrast, assortative mixing stabilised onchocerciasis prevalence at levels as low as 8% mf prevalence. Increasing levels of assortative mixing significantly reduced the probability of interrupting transmission, given the same duration and coverage of mass drug administration. CONCLUSIONS/SIGNIFICANCE: Assortative mixing patterns are an important factor to explain stable low prevalence situations and are highly relevant for prospects of elimination. Their effect on the pre-control distribution of mf intensities in human populations is only detectable in settings with mf prevalences <30%, where high skin mf density in mf-positive people may be an indication of assortative mixing. Local spatial variation in larval infection intensity in the blackfly intermediate host may also be an indicator of assortative mixing.

Impact of hepatitis E virus testing on the safety of blood components in Germany - results of a simulation study.

Hepatitis E virus (HEV) infections may be acquired through transfusion of blood components. As transfusion-transmitted infections mostly affect vulnerable individuals, measures to ensure the supply of safe blood components are under discussion. On the basis of the epidemiological situation in Germany, different testing strategy scenarios were investigated through simulation studies. Testing for HEV RNA by nucleic acid amplification technique (NAT) assays with a pool size of 96, and a 95% LoD of 20 IU/ml will result in an 80% reduction in expected HEV transmissions as well as of consequent chronic infections with subsequent severe complications.

Are Alternative Strategies Required to Accelerate the Global Elimination of Lymphatic Filariasis? Insights From Mathematical Models.

Background: With the 2020 target year for elimination of lymphatic filariasis (LF) approaching, there is an urgent need to assess how long mass drug administration (MDA) programs with annual ivermectin + albendazole (IA) or diethylcarbamazine + albendazole (DA) would still have to be continued, and how elimination can be accelerated. We addressed this using mathematical modeling. Methods: We used 3 structurally different mathematical models for LF transmission (EPIFIL, LYMFASIM, TRANSFIL) to simulate trends in microfilariae (mf) prevalence for a range of endemic settings, both for the current annual MDA strategy and alternative strategies, assessing the required duration to bring mf prevalence below the critical threshold of 1%. Results: Three annual MDA rounds with IA or DA and good coverage (≥65%) are sufficient to reach the threshold in settings that are currently at mf prevalence <4%, but the required duration increases with increasing mf prevalence. Switching to biannual MDA or employing triple-drug therapy (ivermectin, diethylcarbamazine, and albendazole [IDA]) could reduce program duration by about one-third. Optimization of coverage reduces the time to elimination and is particularly important for settings with a history of poorly implemented MDA (low coverage, high systematic noncompliance). Conclusions: Modeling suggests that, in several settings, current annual MDA strategies will be insufficient to achieve the 2020 LF elimination targets, and programs could consider policy adjustment to accelerate, guided by recent monitoring and evaluation data. Biannual treatment and IDA hold promise in reducing program duration, provided that coverage is good, but their efficacy remains to be confirmed by more extensive field studies.

Correction: Predicting anti-RhD titers in donors: Boostering response and decline rates are personal.

[This corrects the article DOI: 10.1371/journal.pone.0196382.].

Predicting anti-RhD titers in donors: Boostering response and decline rates are personal.

BACKGROUND: Anti-RhD immunised donors provide anti-RhD immunoglobulins used for the prevention of rhesus disease. These donors are periodically hyper-immunised (boostered) to retain a high titer level of anti-RhD. STUDY DESIGN AND METHODS: We analysed anti-RhD donor records from 1998 to 2016, consisting of 30,116 anti-RhD titers from 755 donors, encompassing 3,372 booster events. Various models were fit to these data to allow describing the anti-RhD titers over time. RESULTS: A random effects model with a log-linear anti-RhD titer decline over time and a saturating titer response to boostering is shown to fit the data well. This model contains two general model parameters, relating timing and maximum of the booster effect, as well as two parameters characterizing the individual donor, namely how fast the booster effect saturates with current titer and the anti-RhD decline rate. The average individual log2 decline is 0.55 per year, i.e. a 32% decline in absolute titer, with half of the donors declining between 13% and 41% per year. Their anti-RhD titer peaks around 26 days following a booster event. Boostering response reduces with higher titers at boostering; at median titer (log2 11) the mean increase per booster is log2 0.38, that is from an absolute titer of 2048 to 2665 (+30%), with half of all donors increasing between 16% and 65% in their titer. CONCLUSION: The model describes anti-RhD titer change per individual with only four parameters, two of which are donor specific. This information can be used to enhance the blood bank's immunisation programme, by deriving individualized immunization policies in which boostering is adjusted to the anticipated anti-RhD decline, effectiveness of boostering and titer levels required.

Cost-effectiveness of the screening of blood donations for hepatitis E virus in the Netherlands.

BACKGROUND: The incidence of hepatitis E virus (HEV) has increased substantially in Europe recently, thereby threatening blood safety. A cost-effectiveness analysis for HEV screening of blood donations in the Netherlands was performed. STUDY DESIGN AND METHODS: A simulation model was developed to mimic the process of donation, infections in the donor population, donation testing, and transmission to transfusion recipients. The variability of viral loads among donors was modeled using observed loads. The number of (incurable) chronic HEV infections among organ and stem cell transplant patients and the costs avoided by implementing blood screening were estimated. RESULTS: HEV screening of whole blood donations in pools of 24 would prevent 4.52 of the 4.94 transfusion-associated chronic HEV infections expected annually, at approximately €310,000 per prevented chronic case. Per case not curable by ribavirin prevention, costs are approximately 10 times higher. Selective screening, if logistically feasible, could reduce screening costs by 85%. Sensitivity analyses show that uncertainty in the HEV transmissibility and the frequency of HEV clearing greatly impact the estimated cost-effectiveness. Of all HEV infections nationwide one in 700 is estimated to be due to blood transfusion, while for chronic infections this is one in 3.5. CONCLUSION: Despite uncertainties in our estimates, preventing HEV transmission by screening of blood donations appears not excessively expensive compared to other blood-screening measures in the Netherlands. However, the impact on HEV disease burden may be relatively small as only a minority of all HEV cases is transmitted by blood transfusion.

Cost-Effectiveness of Hepatitis C Treatment for People Who Inject Drugs and the Impact of the Type of Epidemic; Extrapolating from Amsterdam, the Netherlands.

BACKGROUND: People who inject drugs (PWID) are disproportionally affected by the hepatitis C virus (HCV) infection. The efficacy of HCV treatment has significantly improved in recent years with the introduction of direct-acting antivirals (DAAs). However, DAAs are more costly than pegylated-interferon and ribavirin (PegIFN/RBV). We aimed to assess the cost-effectiveness of four HCV treatment strategies among PWID and treatment scale-up. METHODS: An individual-based model was used describing HIV and HCV transmission and disease progression among PWID. We considered two epidemiological situations. A declining epidemic, based on the situation in Amsterdam, the Netherlands, and a stable HCV epidemic, as observed in other settings. Data on HCV incidence, prevalence, treatment setting and uptake were derived from observed data among PWID in Amsterdam. We assessed the incremental cost-effectiveness ratio (ICER, costs in €/quality-adjusted life year (QALY)) of four treatment strategies: 1) PegIFN/RBV; 2) sofosbuvir/RBV for genotype 2-3 and dual DAA for genotype 1-4; 3) Dual DAA for all genotypes; 4) Dual DAA with 3x treatment uptake. RESULTS: In both types of epidemic, dual DAA therapy was most cost-effective strategy. In the declining epidemic, dual DAA yielded an ICER of 344 €/QALY while in the stable epidemic dual DAA led to cost-savings. Scaling-up treatment was also highly cost-effective. Our results were robust over a range of sensitivity analyses. CONCLUSION: HCV treatment with DAA-containing regimens is a highly cost-effective intervention among PWID. Based on the economic and population benefits of scaling-up treatment, stronger efforts are needed to achieve higher uptake rates among PWID.

Hepatitis C virus treatment as prevention among injecting drug users: who should we cure first?

BACKGROUND AND AIMS: Treatment of injecting drug users (IDU) for hepatitis C virus (HCV) infection may prevent onward transmission. Treating individuals who often share injecting equipment is most likely to prevent new infections. However, these high-risk IDU are also more likely to become re-infected than low-risk IDU. We investigated to which group treatment is best targeted. DESIGN: We modelled the expected benefits per treatment of one chronically HCV-infected IDU in a population of low- and high-risk IDU. The benefits of treating one low- or one high-risk IDU were compared. MEASUREMENTS: Benefits included the probability for the treated IDU to become and remain uninfected, as well as the expected number of prevented infections to others (i.e. we quantified the total expected decrease in chronic infections). FINDINGS: We found a threshold in HCV-RNA prevalence above which treating low-risk IDU, and below which treating high-risk IDU, resulted in the greatest benefits. This threshold was at 50% of exchanged syringes being HCV contaminated. When 42% of IDU engaged in high-risk behaviour (borrowing and lending out syringes 7.3 times more frequently than low-risk IDU), the corresponding threshold of HCV-RNA prevalence among IDU was at 32%. Larger-risk heterogeneity led to a lower corresponding threshold among IDU. A combination of HCV treatment and 50% risk reduction was best directed at high-risk IDU for prevalence among syringes up to 59%. The threshold was marginally sensitive to changes in disease and treatment variables. CONCLUSIONS: When more than half of all exchanged syringes in a population of injecting drug users (IDU) are contaminated by hepatitis C virus, it is most efficient to treat low-risk IDU first. Below this threshold, it is most efficient to treat high-risk IDU first.

Temporal trends in mortality among people who use drugs compared with the general Dutch population differ by hepatitis C virus and HIV infection status.

OBJECTIVES: We aimed to identify temporal trends in all-cause and cause-specific mortality rates among people who use drugs (PWUD) compared with the general Dutch population and to determine whether mortality trends differed by hepatitis C virus (HCV)/HIV (co) infection status. DESIGN: Longitudinal cohort study. METHODS: Using data from the Amsterdam Cohort Studies among 1254 PWUD (1985-2012), all-cause and cause-specific standardized mortality ratios (SMRs) were calculated; SMRs were stratified by serological group (HCV/HIV-uninfected, HCV-monoinfected, and HCV/HIV-coinfected) and calendar period. Temporal trends were estimated using Poisson regression. RESULTS: The overall all-cause SMR was 13.9 (95% confidence interval 12.6-15.3). The SMR significantly declined after 1996, especially due to a decline among women (P < 0.001). The highest SMR was observed among HCV/HIV-coinfected individuals during 1990-1996 (SMR 61.9, 95% confidence interval 50.4-76.0), which significantly declined after this period among women (P = 0.001). In contrast, SMR for HCV-monoinfected, and HCV/HIV-uninfected PWUD did not significantly change over time. The SMR for non-natural deaths significantly declined (P = 0.007), whereas the SMR for HIV-related deaths was the highest during all calendar periods. CONCLUSIONS: We found evidence for declining all-cause mortality among PWUD compared with the general population rates. Those with HCV/HIV-coinfection showed the highest SMR. The decline in the SMR seems to be attributable to the decline in mortality among women. Mortality rates due to non-natural deaths came closer to those of the general population over time. However, HIV-related deaths remain an important cause of mortality among PWUD when compared with the general Dutch population. This study reinforces the importance of harm-reduction interventions and HCV/HIV treatment to reduce mortality among PWUD.

Treatment as prevention among injecting drug users; extrapolating from the Amsterdam cohort study.

OBJECTIVE: To determine the potential of treatment as prevention for reducing HIV incidence among injecting drug users (IDU). METHODS: Transmission dynamics of HIV as influenced by cART uptake and demographic changes were studied using an individual-based model. Parameters were based on data of the Amsterdam Cohort Study, and counterfactual treatment scenarios were examined for this city. Demography of the modeled population was also varied to allow for more general conclusions. RESULTS: We estimated that over the complete HIV epidemic among IDU in Amsterdam the historic use of cART has led to only 2% less incidence. As individuals were treated from low CD4 cell counts, their decreased infectiousness was offset by increased infectious lifetime. Large reduction in incidence could result from a test and immediate treat strategy, with elimination of HIV occurring when the average time from infection to starting treatment was less than 2 months. However, substantial proportions of new infections were prevented only if the test and treat intervention was implemented within the first few years after HIV-epidemic onset, especially for a declining IDU population. Ignoring heterogeneity in risk-behavior led to overly optimistic expectations of the prevention effects of treatment. In general, treatment led to much greater reduction in incidence compared with stopping HIV-infected IDU from lending out syringes. CONCLUSION: A test and immediate treat strategy for HIV among IDU could lead to great reductions in incidence. To fully eliminate the spread of HIV, treatment as prevention should be combined with other interventions, with behavioral intervention directed at those not yet HIV infected.

The efficiency of targeted intervention in limiting the spread of HIV and Hepatitis C Virus among injecting drug users.

BACKGROUND: Interventions aimed at minimizing the spread of blood borne infections among Injecting Drug Users (IDU) are impeded by limitations in resources. To enhance their efficiency, it may be beneficial to target specific behavioural subpopulations, distinguished by syringe sharing tendencies. METHODS: We used mathematical modelling to explore the effects of two types of intervention: removal of individuals from the injecting population and risk decrease at group-level (e.g. distribution of syringes). We computed the direct effects of intervention on the probability of obtaining and spreading infection as a function of baseline risk behaviour. Population level effects of (targeted) intervention were explored using a differential equations model, which incorporated two levels of risk. RESULTS: Within most scenarios of risk distribution considered, HIV could be substantially reduced or eliminated by targeting high risk IDU only. Conversely, higher incidence reductions for HCV were reached in many scenarios when targeting low risk IDU. The potential for preventing infections by removal of uninfected IDU increases with baseline risk, but so does the probability that an IDU is already infected before being reached by intervention. Decreasing risk is likely to only delay rather than prevent infection for IDU borrowing many syringes, especially for a very infectious disease such as HCV. CONCLUSIONS: The efficiency of intervention on injecting drug users may be much enhanced by targeting specific risk subgroups. However, the optimal targeting policy depends strongly on the infection under consideration.

Decline in incidence of HIV and hepatitis C virus infection among injecting drug users in Amsterdam; evidence for harm reduction?

AIMS: In Amsterdam, HIV prevalence has nearly halved among injecting drug users (IDU) since 1990. Hepatitis C virus (HCV) prevalence also declined; HIV and HCV incidence dropped to nearly zero. We examined possible explanations for these time trends, among which the implementation of harm reduction measures aimed at reducing the risk behaviour of IDU. DESIGN: We used individual-based modelling of the spread of HIV and HCV. Information about demographic parameters was obtained from the Amsterdam Cohort Study (ACS) among drug users. The model included changes in inflow of new IDU and death rates over time, the latter dependent on age and time since HIV seroconversion. We considered different scenarios of risk behaviour. SETTING: IDU in Amsterdam. MEASUREMENTS: Simulated HIV and HCV incidence and prevalence were compared with ACS data. FINDINGS: Assuming that harm reduction measures had led to a strong decrease in risk behaviour over time improved the model fit (squared residuals decreased by 30%). However, substantial incidence and HIV prevalence decline were already reproduced by incorporating demographic changes into the model. In particular, lowered disease spread might be a result of depletion of high-risk IDU among those at risk for disease, and a decrease in the number of high-risk individuals in the population due to HIV-related mortality. CONCLUSIONS: Marked decreases in HIV and HCV in Amsterdam since 1990 could be due partly to harm reduction measures; however, they may also be attributable largely to changes in the IDU population. Future research aimed at quantifying the benefits of interventions should not neglect the impact of natural epidemic progression and demographic changes.

Determinants of persistent spread of HIV in HCV-infected populations of injecting drug users.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are both transmitted through populations of injecting drug users (IDU) by the sharing of contaminated syringes. Prevalence of HCV is high in most IDU populations, whereas HIV prevalence varies considerably across populations. Understanding the dynamics of these interacting infections may allow us to use HCV prevalence as an indicator for the risk of persistent spread of HIV. We developed a mathematical model that describes the spread of both HCV and HIV in an IDU population. The model allows for HCV-HIV co-infection and increased disease related mortality for both infections. Using this model we investigated how HIV and HCV prevalence both depend on level and heterogeneity of injecting risk behaviour, and how HIV and HCV prevalence are related. To gain knowledge of actual risk behaviour we analysed data from the Amsterdam Cohort Study (ACS) of drug users. We find that there is a threshold HCV prevalence at which HIV can invade into an IDU population; below threshold HIV cannot spread. This threshold depends strongly on heterogeneity of risk behaviour in the population, as well as on whether sharing is more likely to occur within or between risk behaviour groups. We find that our model agrees with the observed relationship between HCV and HIV prevalence as described by Vickerman et al. (2010), when in addition to risk heterogeneity as fitted from the ACS, we also assume that most contacts (>90%) occur amongst IDU of the same risk level (assortative mixing). We conclude that HCV prevalence can be used as an indicator of risk for successful HIV introduction into an IDU population. However, information on risk heterogeneity is required for determining this risk, and also for designing effective prevention strategies.

Reassessing the human immunodeficiency virus type 1 life cycle through age-structured modeling: life span of infected cells, viral generation time, and basic reproductive number, R0.

The rapid decay of the viral load after drug treatment in patients infected with human immunodeficiency virus type 1 (HIV-1) has been shown to result from the rapid loss of infected cells due to their high turnover, with a generation time of around 1 to 2 days. Traditionally, viral decay dynamics after drug treatment is investigated using models of differential equations in which both the death rate of infected cells and the viral production rate are assumed to be constant. Here, we describe age-structured models of the viral decay dynamics in which viral production rates and death rates depend on the age of the infected cells. In order to investigate the effects of age-dependent rates, we compared these models with earlier descriptions of the viral load decay and fitted them to previously published data. We have found no supporting evidence that infected-cell death rates increase, but cannot reject the possibility that viral production rates increase, with the age of the cells. In particular, we demonstrate that an exponential increase in viral production with infected-cell age is perfectly consistent with the data. Since an exponential increase in virus production can compensate for the exponential loss of infected cells, the death rates of HIV-1-infected cells may be higher than previously anticipated. We discuss the implications of these findings for the life span of infected cells, the viral generation time, and the basic reproductive number, R0.