Lead clinical and preclinical antimalarial drugs can significantly reduce sporozoite transmission to vertebrate populations.

To achieve malarial elimination, we must employ interventions that reduce the exposure of human populations to infectious mosquitoes. To this end, numerous antimalarial drugs are under assessment in a variety of transmission-blocking assays which fail to measure the single crucial criteria of a successful intervention, namely impact on case incidence within a vertebrate population (reduction in reproductive number/effect size). Consequently, any reduction in new infections due to drug treatment (and how this may be influenced by differing transmission settings) is not currently examined, limiting the translation of any findings. We describe the use of a laboratory population model to assess how individual antimalarial drugs can impact the number of secondary Plasmodium berghei infections over a cycle of transmission. We examine the impact of multiple clinical and preclinical drugs on both insect and vertebrate populations at multiple transmission settings. Both primaquine (>6 mg/kg of body weight) and NITD609 (8.1 mg/kg) have significant impacts across multiple transmission settings, but artemether and lumefantrine (57 and 11.8 mg/kg), OZ439 (6.5 mg/kg), and primaquine (<1.25 mg/kg) demonstrated potent efficacy only at lower-transmission settings. While directly demonstrating the impact of antimalarial drug treatment on vertebrate populations, we additionally calculate effect size for each treatment, allowing for head-to-head comparison of the potential impact of individual drugs within epidemiologically relevant settings, supporting their usage within elimination campaigns.

Estimating the transmissibility of H5N1 and the effect of vaccination in Indonesia.

The spread of H5N1 avian influenza continues to pose an economic burden and a public health risk worldwide. Despite this, estimates of the transmissibility of infection exist in only a handful of settings and vary considerably. Using final size methods and flock-level infection data from a field trial of mass vaccination, we obtained the first estimates of the transmissibility of infection between and within flocks in Indonesia. We also found that outbreaks in areas designated as vaccination zones were less transmissible than in non-vaccination zones. However, this reduction is only comparable with a limited degree of protective vaccination coverage. Quantifying the overall effect of vaccination in these zones remains challenging. However, this result would appear to imply that, although the interventions applied in vaccination zones were not sufficient to completely prevent transmission in all areas, when outbreaks occur, they are less transmissible than those in areas where vaccination was not applied. This could be either a direct or an indirect effect of vaccination. Given the dynamism of small-scale poultry production in Indonesia, more regular vaccination may be required to ensure that infection is fully controlled in vaccination zones.

Transmission-blocking interventions eliminate malaria from laboratory populations.

Transmission-blocking interventions aim to reduce the prevalence of infection in endemic communities by targeting Plasmodium within the insect host. Although many studies have reported the successful reduction of infection in the mosquito vector, direct evidence that there is an onward reduction in infection in the vertebrate host is lacking. Here we report the first experiments using a population, transmission-based study of Plasmodium berghei in Anopheles stephensi to assess the impact of a transmission-blocking drug upon both insect and host populations over multiple transmission cycles. We demonstrate that the selected transmission-blocking intervention, which inhibits transmission from vertebrate to insect by only 32%, reduces the basic reproduction number of the parasite by 20%, and in our model system can eliminate Plasmodium from mosquito and mouse populations at low transmission intensities. These findings clearly demonstrate that use of transmission-blocking interventions alone can eliminate Plasmodium from a vertebrate population, and have significant implications for the future design and implementation of transmission-blocking interventions within the field.

Impact of the implementation of rest days in live bird markets on the dynamics of H5N1 highly pathogenic avian influenza.

Live bird markets (LBMs) act as a network 'hub' and potential reservoir of infection for domestic poultry. They may therefore be responsible for sustaining H5N1 highly pathogenic avian influenza (HPAI) virus circulation within the poultry sector, and thus a suitable target for implementing control strategies. We developed a stochastic transmission model to understand how market functioning impacts on the transmission dynamics. We then investigated the potential for rest days-periods during which markets are emptied and disinfected-to modulate the dynamics of H5N1 HPAI within the poultry sector using a stochastic meta-population model. Our results suggest that under plausible parameter scenarios, HPAI H5N1 could be sustained silently within LBMs with the time spent by poultry in markets and the frequency of introduction of new susceptible birds' dominant factors determining sustained silent spread. Compared with interventions applied in farms (i.e. stamping out, vaccination), our model shows that frequent rest days are an effective means to reduce HPAI transmission. Furthermore, our model predicts that full market closure would be only slightly more effective than rest days to reduce transmission. Strategies applied within markets could thus help to control transmission of the disease.

Modelling heterogeneity and the impact of chemotherapy and vaccination against human hookworm.

There is a growing emphasis on the development of vaccines against helminths (worms), and mathematical models provide a useful tool to assess the impact of new vaccines under a range of scenarios. The present study describes a stochastic individual-based model to assess the relative impact of chemotherapy and vaccination against human hookworm infection and investigates the implications of potential correlations between risk of infection and vaccine efficacy. Vaccination is simulated as a reduction in susceptibility to infection and the model includes population heterogeneities and dynamical waning of protection. To help identify appropriate measures of vaccine impact, we present a novel framework to quantify the vaccine impact on the infection-associated morbidity and introduce a measure of symmetry to study the correspondence between reduction in intensity and reduction in morbidity. Our modelling shows that, in high-transmission settings, the greatest impact of vaccination will be attained when vaccine efficacy is the greatest among individuals harbouring the heaviest worm burdens, and that the decline of morbidity primarily depends on the level of protection attained in the most at risk 8-12% of the population. We also demonstrate that if risk of infection and vaccine protection are correlated, there is not always a direct correspondence between the reduction in worm burden and in morbidity, with the precise relationship varying according to transmission setting.

HIV, sexually transmitted infections, and risk behaviours in male sex workers in London over a 10 year period.

OBJECTIVES: To describe changing characteristics of men who sold sex in London between 1994 and 2003. METHODS: A baseline survey of 823 male sex workers attending a specialist clinic, plus follow up of 628 men for 1379 person years. RESULTS: Men recruited earlier (1994 to 1996) were more likely than those recruited later (2000 to 2003) to be UK born and to self define as homosexual. Later recruits included more men from South/Central America and eastern Europe and a higher proportion reported regular female partners. Baseline prevalence of HIV was 9% (59/636), and multivariate analysis showed an associated with injecting drug use and unprotected sex with a casual partner. During follow up there were 49 incident cases of HIV. Survival analysis showed earlier recruitment (1994-6) to be associated with a higher incidence of HIV. The prevalence of gonorrhoea increased over time. CONCLUSIONS: Men who sell sex are at risk of HIV and other STIs, but these risks do not appear to be directly linked to sex work. The changing demographics of these men is associated with different patterns of infection and poses challenges for service delivery.

Seroprevalence of IgG antibodies to SARS-coronavirus in asymptomatic or subclinical population groups.

We systematically reviewed the current understanding of human population immunity against SARS-CoV in different groups, settings and geography. Our meta-analysis, which included all identified studies except those on wild animal handlers, yielded an overall seroprevalence of 0.10% [95% confidence interval (CI) 0.02-0.18]. Health-care workers and others who had close contact with SARS patients had a slightly higher degree of seroconversion (0.23%, 95% CI 0.02-0.45) compared to healthy blood donors, others from the general community or non-SARS patients recruited from the health-care setting (0.16%, 95% CI 0-0.37). When analysed by the two broad classes of testing procedures, it is clear that serial confirmatory test protocols resulted in a much lower estimate (0.050%, 95% CI 0-0.15) than single test protocols (0.20%, 95% CI 0.06-0.34). Potential epidemiological and laboratory pitfalls are also discussed as they may give rise to false or inconsistent results in measuring the seroprevalence of IgG antibodies to SARS-CoV.

Methods for estimating the case fatality ratio for a novel, emerging infectious disease.

During the course of an epidemic of a potentially fatal disease, it is important that the case fatality ratio be well estimated. The authors propose a novel method for doing so based on the Kaplan-Meier survival procedure, jointly considering two outcomes (death and recovery), and evaluate its performance by using data from the 2003 epidemic of severe acute respiratory syndrome in Hong Kong, People's Republic of China. They compare this estimate obtained at various points in the epidemic with the case fatality ratio eventually observed; with two commonly quoted, naïve estimates derived from cumulative incidence and mortality statistics at single time points; and with estimates in which a parametric mixture model is used. They demonstrate the importance of patient characteristics regarding outcome by analyzing subgroups defined by age at admission to the hospital.

Gender difference in HIV-1 RNA viral loads.

OBJECTIVES: To test and characterize the dependence of viral load on gender in different countries and racial groups as a function of CD4 T-cell count. METHODS: Plasma viral load data were analysed for > 30,000 HIV-infected patients attending clinics in the USA [HIV Insight (Cerner Corporation, Vienna, VA, USA) and Plum Data Mining LLC (East Meadow, NY, USA) databases] and the Netherlands (Athena database; HIV Monitoring Foundation, Amsterdam, Netherlands). Log-normal regression models were used to test for an effect of gender on viral load while adjusting for covariates and allowing the effect to depend on CD4 T-cell count. Sensitivity analyses were performed to test the robustness of conclusions to assumptions regarding viral loads below the lower limit of quantification (LLOQ). RESULTS: After adjusting for covariates, women had (nonsignificantly) lower viral loads than men (HIV Insight: -0.053 log(10) HIV-1 RNA copies/mL, P = 0.202; Athena: -0.005 log(10) copies/mL, P = 0.667; Plum: -0.072 log(10) copies/mL, P = 0.273). However, further investigation revealed that the gender effect depended on CD4 T-cell count. Women had consistently higher viral loads than men when CD4 T-cell counts were at most 50 cells/microL, and consistently lower viral loads than men when CD4 T-cell counts were greater than 350 cells/microL. These effects were remarkably consistent when estimated independently for the racial groups with sufficient data available in the HIV Insight and Plum databases. CONCLUSIONS: The consistent relationship between gender-related differences in viral load and CD4 T-cell count demonstrated here explains the diverse findings previously published.

Adherence to antiretroviral therapy and its impact on clinical outcome in HIV-infected patients.

We analyse data on patient adherence to prescribed regimens and surrogate markers of clinical outcome for 168 human immunodeficiency virus infected patients treated with antiretroviral therapy. Data on patient adherence consisted of dose-timing measurements collected for an average of 12 months per patient via electronic monitoring of bottle opening events. We first discuss how such data can be presented to highlight suboptimal adherence patterns and between-patient differences, before introducing two novel methods by which such data can be statistically modelled. Correlations between adherence and subsequent measures of viral load and CD4+T-cell counts are then evaluated. We show that summary measures of short-term adherence, which incorporate pharmacokinetic and pharmacodynamic data on the monitored regimen, predict suboptimal trends in viral load and CD4+T-cell counts better than measures based on adherence data alone.

Investigating ethnic inequalities in the incidence of sexually transmitted infections: mathematical modelling study.

OBJECTIVES: To investigate ethnic differences in rates of gonorrhoea using empirical sexual behaviour data in a simple mathematical model. To explore the impact of different intervention strategies in this simulated population. METHODS: The findings from cross sectional studies of gonorrhoea rates and sexual behaviour in three ethnic groups in south east London were used to determine the parameters for a deterministic, mathematical model of gonorrhoea transmission dynamics, in a population stratified by sex, sexual activity (rate of partner change), and ethnic group (white, black African, and black Caribbean). We compared predicted and observed rates of infection and simulated the effects of targeted and population-wide intervention strategies. RESULTS: In model simulations the reported sexual behaviours and mixing patterns generated major differences in the rates of gonorrhoea experienced by each subpopulation. The fit of the model to observed data was sensitive to assumptions about the degree of mixing by level of sexual activity, the numbers of sexual partnerships reported by men and women, and the degree to which observed data underestimate female infection rates. Interventions to reduce duration of infection were most effective when targeted at black Caribbeans. CONCLUSIONS: Average measures of sexual behaviour in large populations are inadequate descriptors for the epidemiology of gonorrhoea. The consistency between the model results and empirical data shows that profound differences in gonorrhoea rates between ethnic groups can be explained by modest differences in a limited number of sexual behaviours and mixing patterns. Targeting effective services to particular ethnic groups can have a disproportionate influence on disease reduction in the whole community.

Extending backcalculation to analyse BSE data.

We review the origins of backcalculation (or back projection) methods developed for the analysis of AIDS (acquired immunodeficiency syndrome) incidence data. These techniques have been used extensively for >15 years to deconvolute clinical case incidence, given knowledge of the incubation period distribution, to obtain estimates of past HIV (human immunodeficiency virus) infection incidence and short-term predictions of future AIDS incidence. Adaptations required for the analysis of bovine spongiform encephalopathy (BSE) incidence included: stratification of BSE incidence by age as well as birth cohort; allowance for incomplete survival between infection and the onset of clinical signs of disease; and decomposition of the age- and time-related infection incidence into a time-dependent feed risk component and an age-dependent exposure/susceptibility function. The most recent methodological developments focus on the incorporation of data from clinically unaffected cattle screened using recently developed tests for preclinical BSE infection. Backcalculation-based predictions of future BSE incidence obtained since 1996 are examined. Finally, future directions of epidemiological analysis of BSE epidemics are discussed taking into account ongoing developments in the science of BSE and possible changes in BSE-related policies.

Patterns of antiretroviral use in the United States of America: analysis of three observational databases.

OBJECTIVE: To characterize patterns of antiretroviral use in HIV-infected patients and explore variation by patient characteristics and disease stage. METHODS: Three large patient databases recording information derived from routine clinical attendance were analyzed: HIV Insight (n = 10 873), Target Management Services (n = 2226) and Clinical Partners (n = 1505). Each database records the dates of starting and stopping individual antiretroviral agents over time, measurements of CD4 T-cell counts and HIV-RNA levels at approximately 6-monthly intervals, and the demographic characteristics of patients. The number, frequency and duration of different antiretroviral combinations over time and their relationship to stage of HIV-disease and demographic characteristics were explored. RESULTS: Over 2000 different combinations of antiretroviral agents are recorded. From 1987 onwards, the use of zidovudine increased, with 23% of patients receiving monotherapy by 1990. The majority of treated patients remained on monotherapy until the introduction of highly active antiretroviral therapy (HAART) in 1996. By 1999, the standard of care was HAART, with 84% of patients beginning antiretroviral therapy with HAART. Those of African American race (odds ratio 0.59) and funded by Medicaid (odds ratio 0.72) were significantly less likely to begin antiretroviral therapy on HAART. Until 1995, there was a significant decrease in CD4 T-cell count when starting antiretroviral therapy. No significant trend was observed in either CD4 T-cell count or viral load after this time. Those starting on HAART therapies were significantly less likely to stop or switch regimens than those on nucleoside reverse transcriptase inhibitor (NRTI)-only therapies (P < 0.001). CONCLUSIONS: Complex patterns of antiretroviral treatment are observed in this large population. Changes over time mirror the introduction of the new antiretroviral agents.

Estimating the human health risk from possible BSE infection of the British sheep flock.

Following the controversial failure of a recent study and the small numbers of animals yet screened for infection, it remains uncertain whether bovine spongiform encephalopathy (BSE) was transmitted to sheep in the past via feed supplements and whether it is still present. Well grounded mathematical and statistical models are therefore essential to integrate the limited and disparate data, to explore uncertainty, and to define data-collection priorities. We analysed the implications of different scenarios of BSE spread in sheep for relative human exposure levels and variant Creutzfeldt-Jakob disease (vCJD) incidence. Here we show that, if BSE entered the sheep population and a degree of transmission occurred, then ongoing public health risks from ovine BSE are likely to be greater than those from cattle, but that any such risk could be reduced by up to 90% through additional restrictions on sheep products entering the food supply. Extending the analysis to consider absolute risk, we estimate the 95% confidence interval for future vCJD mortality to be 50 to 50,000 human deaths considering exposure to bovine BSE alone, with the upper bound increasing to 150,000 once we include exposure from the worst-case ovine BSE scenario examined.

Surrogate markers for disease progression in treated HIV infection.

OBJECTIVE: To characterize the relationships among highly active antiretroviral therapy (HAART), HIV-1 RNA levels, immune system markers, and clinical outcome in a cohort of HIV-1-infected homosexual men. PATIENTS: A total of 123 men enrolled in the Amsterdam cohort study of HIV-1 infection and AIDS with a documented seroconversion for HIV-1 antibodies and known date of seroconversion were included in this study. METHODS: CD4 + /CD8 + T-cell counts and HIV-1 RNA levels in plasma were measured approximately every 6 months. Dates of starting and stopping antiretroviral therapy were also recorded. The relationship between HIV-1 RNA in plasma, CD4 + /CD8 + T-cell counts and HAART and their influence on clinical outcome were examined using a graphical chain modeling approach. Generalized estimating equations were used to examine correlations among the three disease markers. Hazards models with time-dependent covariates were used to examine the influence of HAART and the disease markers on progression to AIDS. RESULTS: HAART was significantly associated with reduced disease progression (relative hazard [RH] of AIDS, 0.20;, 95% confidence interval [CI], 0.05-0.85). The most recent HIV-1 RNA measurement and CD4 + T-cell count are independently associated with disease progression (adjusted RH for HIV-1 RNA 1.8 per log 10 increase; 95% CI, 1.2-2.6, p =.002; adjusted RH for CD4 + 0.48 per 100 x 10(6)/L increase; 95% CI, 0.40-0.58; p <.001). Depending on these measurements, HAART was no longer significantly associated with AIDS (adjusted RH, 0.81; 95% CI, 0.18-3.6; p =.78). CONCLUSIONS: HIV-1 RNA levels in plasma and CD4 + T-cell counts are currently considered as effective surrogate markers for the effect of HAART on disease progression in this cohort.

Comparison of the effectiveness of non-nucleoside reverse transcriptase inhibitor-containing and protease inhibitor-containing regimens using observational databases.

OBJECTIVES: To compare the effectiveness of first protease inhibitor (PI)-containing and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens. METHODS: Data were analysed from three large HIV patient databases: Apache HIV Insight (APACHE), Target Management Services (TMS) and Clinical Partners (CP). The effectiveness of therapy was the time taken for HIV-1 RNA to fall below detectable levels on first highly active antiretroviral therapy regimen (PI- or NNRTI-containing) and the subsequent time to failure (two consecutive detectable measurements). Comparisons were made using proportional hazards models, adjusting for differences in age, sex, previous reverse transcriptase inhibitor use, calendar year and baseline viral load and CD4 T-cell count. RESULTS: The type of regimen was not associated with time to undetectable viral load in any of the three databases, all of which had high power to detect a difference. PI-containing regimens were significantly less likely to fail after reaching undetectable viral loads for APACHE and CP patients (relative hazard, 1.7; 95% confidence interval, 1.3--2.1 and relative hazard, 1.6; 95% confidence interval, 1.0--2.5 respectively). These results remained significant after allowing for an unmeasured confounder with moderate effect on risk. No significant association between time to failure and regimen was found for TMS patients, possibly due to low power (67% to detect a relative hazard of 1.5). No difference was found between regimens in the time taken for an increase of > 100 x 10(9)cells/l in CD4 T-cell count. In the APACHE database, those on NNRTI-containing regimens were more likely to have a failing CD4 T-cell response. CONCLUSIONS: PI-containing regimens have a lower risk of treatment failure than NNRTI-containing regimens.

A prospective social and molecular investigation of gonococcal transmission.

BACKGROUND: Gonorrhoea is a common infectious disease, poorly controlled despite effective treatments. Tracing chains of transmission is difficult, because sexual partners are commonly difficult or impossible to identify. We assess the use of gonococcal opa-typing in identifying transmission links not revealed through interview. METHODS: Epidemiological data and gonococcal isolates were collected prospectively from patients at two UK clinics in London and Sheffield. Social and epidemiological data were combined with molecular typing of gonococcal isolates by a new methodology based on the polymorphisms of the opa gene. FINDINGS: In London, interview data and opa-typing on samples from 215 cases showed a diverse population with few links. In Sheffield, interview data identified links between 51 (43%) of 120 cases, whereas opa-typing suggested a more connected population: 95 (79%) of cases had shared profiles. There was a highly significant correlation between the two distributions with epidemiological clusters appearing as a subset of the opa clusters. Two large opa clusters, of 18 and 43 cases, accounted for 50% of local cases of gonorrhoea. Discordance between epidemiological and opa-typing data was observed at highly connected points in the sexual network. INTERPRETATION: Opa-typing is a more powerful tool for epidemiological investigation of gonorrhoea transmission than earlier methods. Opa-typing can link infections that would otherwise remain unlinked, and may aid interventions to control endemic disease.

Risks of acquiring and transmitting sexually transmitted diseases in sexual partner networks.

BACKGROUND: A person's risk for acquiring infection and their role in continued transmission has traditionally been assessed on the basis of individual characteristics. Recently, network studies have attempted to relate individual risks to position in the wider network. GOAL: To assess the importance of local and global network structures in assessing the risk of acquiring and transmitting infection. STUDY DESIGN: An individual-based simulation model was used to construct a variety of potential network structures and track the transmission of infection over time. Logistic and Poisson regression were used to identify which measures of network position influence a person's risk for acquiring and transmitting infection. RESULTS: Measures of local centrality were more important to risk of acquisition, whereas global centrality mattered more to transmission. Continuous snowball sampling, rather than a fixed number of waves, better estimates a person's risks. CONCLUSIONS: There is an asymmetry regarding the risk of acquiring and transmitting infection.

Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs.

BACKGROUND: Treatments combining T-cell activating agents and potent antiretroviral drugs have been proposed as a possible means of reducing the reservoir of long-lived HIV-1 infected quiescent CD4 T-cells. OBJECTIVE: To analyse the effect of such therapies on HIV-1 dynamics and T-cell homeostasis. DESIGN AND METHODS: A mathematical framework describing HIV-1 dynamics and T-cell homeostasis was developed. Three patients who were kept on a particularly potent course of highly active antiretroviral therapy (HAART) were treated with the anti-CD3 monoclonal antibody OKT3 and interleukin (IL)-2. Plasma HIV-RNA, and HIV-RNA and DNA in peripheral blood mononuclear cells and lymph node mononuclear cells were measured. These results and other published studies on the use of IL-2 alone were assessed using our mathematical framework. RESULTS: We show that outcome of treatment is determined by the relative rates of depletion of the infected quiescent T-cell population by activation and of its replenishment through new infection. Which of these two processes dominates is critically dependent on both the potency of HAART and also the degree of T-cell activation induced. We demonstrate that high-level T-cell stimulation is likely to produce negative outcomes, both by failing to reduce viral reservoirs and by depleting the CD4 T-cell pool and disrupting CD4/CD8 T-cell homeostasis. In contrast, repeated low-level stimulation may both aid CD4 T-cell pool expansion and achieve a substantial reduction in the long-lived HIV-1 reservoir. CONCLUSIONS: Our analysis suggests that although treatment that activates T-cells can reduce the long-lived HIV-1 reservoir, caution should be used as high-level stimulation may result in a negative outcome.