Showing papers by "Sally Blower published in 2004"

Modeling the emergence of the 'hot zones': tuberculosis and the amplification dynamics of drug resistance.

Abstract: 'Hot zones' are areas that have >5% prevalence (or incidence) of multidrug-resistant tuberculosis (MDRTB). We present a new mathematical model (the amplifier model) that tracks the emergence and evolution of multiple (pre-MDR, MDR and post-MDR) strains of drug-resistant Mycobacterium tuberculosis. We reconstruct possible evolutionary trajectories that generated hot zones over the past three decades, and identify the key causal factors. Results are consistent with recently reported World Health Organization (WHO) data. Our analyses yield three important insights. First, paradoxically we found that areas with programs that successfully reduced wild-type pansensitive strains often evolved into hot zones. Second, some hot zones emerged even when MDR strains were substantially less fit (and thus less transmissible) than wild-type pansensitive strains. Third, levels of MDR are driven by case-finding rates, cure rates and amplification probabilities. To effectively control MDRTB in the hot zones, it is essential that the WHO specify a goal for minimizing the amplification probability.

An attempt at a new analysis of the mortality caused by smallpox and of the advantages of inoculation to prevent it

Abstract: ‘I simply wish that, in a matter which so closelyconcerns the wellbeing of the human race, no deci-sion shall be made without all the knowledge whicha little analysis and calculation can provide’Daniel Bernoulli 1760.INTRODUCTIONShould the general population be vaccinatedagainst smallpox (Variola Major)? Would the bene-fits of mass vaccination outweigh the risks? Howmany deaths would occur as the result of a massvaccination campaign against smallpox? Canmathematical models of smallpox vaccination beused to determine health policy? Although small-pox was declared eradicated by the World HealthOrganization in 1979, these questions have all beenrecently debated based upon the premise thatsmallpox may be used as a weapon of bioterror-ism. Hence, a series of analyses has recently beenpublished that use mathematical models to try todetermine the most effective public healthresponse in the event of such an attack [1–4]. How-ever, these same controversial public health ques-tions were debated in the 18th century whensmallpox was endemic and Reviews in Medical Vir-ology has published two classic papers describingthe natural history of smallpox in 1902 and 1913to help inform these discussions [5,6]. We nowpublish an even earlier paper.In 1760 Daniel Bernoulli (1700–1782), one of thegreatest scientists of the 18th century, wrote amathematical analysis of the problem in order totry to influence public health policy by encoura-ging the universal inoculation against smallpox;his analysis was first presented at the Royal Acad-emy of Sciences in Paris in 1760 and later pub-lished in 1766 [7]. Here, we republish anddiscuss both the historical and the current signifi-cance of Bernoulli’s classic paper. A detailed dis-cussion of the mathematics of Bernoulli’s analysishas previously been presented by Dietz andHeesterbeck [8].According to Creighton [9] smallpox firstappeared in England in the 16th century. Smallpoxwas known in Western Europe in medieval times,but a particularly virulent strain emerged in theearly 17th century and gradually the case fatalityrate increased [10]. By the 18th century smallpoxwas endemic. Bernoulli calculated that approxi-mately three quarters of all living people (in the18th century) had been infected with smallpox[7]. One-tenth of all mortality at that time wasdue to smallpox, although there was considerableannual variation in smallpox mortality due to epi-demic outbreaks overlaying the endemic smallpoxmortality rate. For example, in London during theperiod 1761–1796 the annual number of deathsdue to smallpox varied from 3000 to 15000. Wheresmallpox was endemic it was almost wholly a dis-ease of childhood, with a case-fatality rate of 20%–30%; the mean age of death due to smallpox hasbeen estimated as 2.6 years [10] or 4.5 years [11].

Could disease-modifying HIV vaccines cause population-level perversity?

Abstract: Most current candidate HIV vaccines seem to produce little protection against infection, but reduce viral load and slow the decline in CD4 lymphocyte numbers. Such diseasemodifying vaccines could potentially provide important population-level benefits by reducing transmission, but could possibly also increase transmission. We address the following question: could disease-modifying HIV vaccines cause population-level perversity (ie, increase epidemic severity)? By analysing a mathematical model and defining a new quantity—the fitness ratio—we show that diseasemodifying vaccines that provide only a low degree of protection against infection and/or generate high fitness ratios will have a high probability of making the epidemic worse. However, we show that if disease-modifying vaccines cause a 1·5 log10 reduction in viral load (or greater) then perversity cannot occur (assuming risk behaviour does not increase). Finally, we determine threshold surfaces for risk behaviour change that determine the boundary between beneficial and perverse outcomes; the threshold surfaces are determined by the fitness ratio, the proportion of the population that are “successfully vaccinated”, and the degree of change of risk behaviour in unvaccinated infected individuals. We discuss the implications of our results for designing optimal vaccination control strategies.

Potential Public Health Impact of New Tuberculosis Vaccines

Abstract: Developing effective tuberculosis (TB) vaccines is a high priority. We use mathematical models to predict the potential public health impact of new TB vaccines in highincidence countries. We show that preexposure vaccines would be almost twice as effective as postexposure vaccines in reducing the number of new infections. Postexposure vaccines would initially have a substantially greater impact, compared to preexposure vaccines, on reducing the number of new cases of disease. However, the effectiveness of postexposure vaccines would diminish over time, whereas the effectiveness of preexposure vaccines would increase. Thus, after 20 to 30 years, post- or preexposure vaccination campaigns would be almost equally effective in terms of cumulative TB cases prevented. Even widely deployed and highly effective (50%–90% efficacy) pre- or postexposure vaccines would only be able to reduce the number of TB cases by one third. We discuss the health policy implications of our analyses.

Calculating the contribution of herpes simplex virus type 2 epidemics to increasing HIV incidence: treatment implications.

Abstract: Herpes simplex virus type 2 (HSV-2) is the most prevalent sexually transmitted pathogen worldwide. There is considerable biological and epidemiological evidence that HSV-2 infection increases the risk of acquiring HIV infection and may also increase the risk of transmitting HIV. Here we use a mathematical model to predict the effect of a high-prevalence HSV-2 epidemic on HIV incidence. Our results show that HSV-2 epidemics can more than double the peak HIV incidence; that the biological heterogeneity in susceptibility and transmission induced by an HSV-2 epidemic causes HIV incidence to rise fall and then rise again; and that HSV-2 epidemics concentrate HIV epidemics creating a “core group” of HIV transmitters. Our modeling results imply that findings from HSV-2 intervention trials aimed at reduction of HIV incidence will be variable and that positive findings will be obtained only from trials in communities in which HIV incidence is steeply rising. (authors)

Modelling the genital herpes epidemic.

Abstract: Mathematical models are useful tools for summarizing and testing current knowledge about a system and predicting trends. Models have shown that medical and behavioural changes can substantially affect herpes simplex virus type 2 (HSV-2) transmission and can be used to develop rational epidemic control policies. The spread of the genital herpes epidemic and the potential impact of HSV antiviral treatment in the immunocompetent population have been addressed by four models. HSV drug resistance to antiviral drugs is predicted to be minimal. Assuming that drug-resistant mutants are attenuated both in infectivity and reactivity, one model predicted that even after 25 years, only 5 in 10,000 individuals will shed drug-resistant virus, even if rates of usage of antivirals are high. The models show that increased usage of episodic antiviral therapy will be beneficial in reducing the herpes epidemic. Results also show that the transmission rate can be reduced by preventing infection (safer sex), reduced time spent in non-monogamous relationships or the advent of effective therapeutic HSV vaccines. One model has indicated that suppressive therapy will have only a minimal impact on HSV prevalence; however, the results of this modelling study are limited as it assumed that suppressive therapy would only be given to incident infections. More recent research using a model based upon virological core groups (and treating both incident and prevalent infections) shows that suppressive therapy could cause a substantial reduction in HSV-2 incidence rates. Current modelling is also focused on modelling how HSV-2 antiviral treatment will impact the HIV epidemic.

Targeting Virological Core Groups: A New Paradigm for Controlling Herpes Simplex Virus Type 2 Epidemics

Abstract: Background. Classic modeling of sexually transmitted diseases has focused on modeling behavioral heterogeneity and designing epidemic control strategies targeted at behavioral core groups. Methods. We analyzed a new mathematical model of herpes simplex virus type 2 (HSV-2) epidemics that includes virological core groups (i.e., groups of individuals with high rates of viral reactivation) and suggest a new paradigm for epidemic control. We used our model, in conjunction with virological data, to determine the potential role of virological core groups in contributing to transmission and the effect that daily antiviral therapy (DAT) could have on reducing transmission if virological core groups were targeted. Results. We estimated that a virological core group (11% of infected individuals) can cause a disproportionately large percentage (44%) of new infections and that a median of only 6.4 person-years of DAT would be necessary to prevent 1 HSV-2 infection. We determined that relatively few individuals would need to receive DAT to substantially reduce the incidence of HSV-2 infection. Conclusion. Identifying and targeting individuals in the virological core group could be an effective and practical public health strategy for reducing transmission. Treating individuals who are high-frequency viral shedders should be evaluated as a strategy for reducing HSV-2 transmission.

Microbicides: anti-HIV efficacy and ethics.

Abstract: In their policy forum “regulatory challenges in microbicide development” (25 June, p. [1911][1]), P. M. Coplan et al. discuss the Food and Drug Administration's (FDA's) concern that use of HIV transmission—inhibiting microbicides in the future could decrease condom use and result in an