Sally Blower

The intrinsic transmission dynamics of tuberculosis epidemics.

In developed countries the major tuberculosis epidemics declined long before the disease became curable in the 1940s. We present a theoretical framework for assessing the intrinsic transmission dynamics of tuberculosis. We demonstrate that it takes one to several hundred years for a tuberculosis epidemic to rise, fall and reach a stable endemic level. Our results suggest that some of the decline of tuberculosis is simply due to the natural behaviour of an epidemic. Although other factors must also have contributed to the decline, these Causal factors were constrained to operate within the slow response time dictated by the intrinsic dynamics.

Control Strategies for Tuberculosis Epidemics: New Models for Old Problems

Tuberculosis, although preventable and curable, causes more adult deaths than any other infectious disease. A theoretical framework for designing effective control strategies is developed and used to determine treatment levels for eradication, to assess the effects of noneradicating control, and to examine the global goals of the World Health Organization. The theory is extended to assess how suboptimal control programs contribute to the evolution of drug resistance. A new evaluation criterion is defined and used to suggest how control strategies can be improved. In order to control tuberculosis, treatment failure rates must be lower in developing countries than in developed countries.

Narrative Review: Antiretroviral Therapy to Prevent the Sexual Transmission of HIV-1

The magnitude of the HIV epidemic has exceeded the worst early predictions. At the end of 2005, the Joint United Nations Programme on HIV/AIDS (UNAIDS) (1) estimated that 38.6 million persons were infected worldwide (4.1 million were incident HIV cases) and that 2.8 million HIV-related deaths occurred in that year alone. Currently, no vaccine to prevent HIV exists and it is unlikely that one will be developed during the next few years. Accordingly, a series of other preventive measures embracing a combination of biological and behavioral approaches have been and are being explored, with some demonstrable positive results (2, 3). Among prevention options, the use of antiretroviral therapy (ART) is particularly attractive because antibiotics have successfully stopped the spread of many other diseases. Antiretroviral therapy has dramatically increased survival for HIV-infected patients (4) and prevented vertical transmission of HIV (5). Antiretroviral therapy could be used for preventing sexual transmission of HIV in 3 ways: 1) effective treatment of infected persons to reduce HIV transmission to sexual partners, 2) nonoccupational postexposure prophylaxis, and 3) preexposure prophylaxis. We provide a current view of each approach, including work in progress. Literature Search Strategy We searched the Cochrane Library and PubMed for relevant publications. We searched the Cochrane Library under the topic HIV/AIDS and then limited results by using the term biomedical prevention. We located a proposal to review the safety and efficacy of nonoccupational postexposure prophylaxis that was not yet completed. We searched PubMed by using the terms HIV and antiretroviral in the Medical Subject Heading (MeSH) database and then limited the results by using the terms prevention and control, transmission, and anti-retroviral agents. We reviewed publications retrieved from this search and selected those that we judged to be relevant. The MeSH terms are part of a distinct vocabulary created by the National Library of Medicine to index articles for MEDLINE and PubMed that provides a consistent way to retrieve information using different terminology. We also searched PubMed using the terms post-exposure, pre-exposure, prophylaxis, prevention, PEP, PREP, nPEP, and HIV. We primarily selected articles published within the past 5 years but did not exclude commonly referenced publications outside of this time period. We also reviewed abstracts from the 10th, 11th, 12th, and 13th Clinical Retrovirus and Opportunistic Infections (CROI) Conferences and the XIV and XVI International AIDS Conferences by using the terms mentioned. We included English-language articles only. We excluded studies of children, adolescents, or both, except when these populations were included in studies on nonoccupational postexposure prophylaxis after sexual assault. We selected studies on the effect of ART on HIV transmission among serodiscordant couples if this was a primary aim of the study and on the basis of the studys sample size. We selected population-level epidemiology studies of the effect of ART on HIV transmission if their study designs included sufficient power to determine statistical significance. We chose publications on animal models of postexposure prophylaxis and preexposure prophylaxis for scientific rigor and for the mode of HIV exposure most closely assimilating sexual HIV exposure in humans. We selected publications of observational studies on nonoccupational postexposure prophylaxis if they evaluated at least 1 of the following outcomes: 1) seroconversions, 2) adherence, 3) repeated treatment requests, or 4) effect on behavioral disinhibition. The Table summarizes these publications (615). We excluded solely descriptive articles on the uptake and prescribing practices of nonoccupational postexposure prophylaxis and articles of cost-effectiveness, ethics, policy, and case reports, except for 1 study describing a failure of nonoccupational postexposure prophylaxis. We reviewed all modeling studies but included only a few representative examples because recent studies use similar methods and differ primarily on the basis of data assumptions, as discussed. Table. Studies on Antiretroviral Nonoccupational Postexposure Prophylaxis* Using ART to Reduce Infectiousness Researchers have extensively studied the probability of sexual transmission of HIV (16). Transmission of HIV depends on the infectiousness of the host and the susceptibility of the sexual partner. Sexual transmission of HIV has been most closely linked to blood viral burden in the infected host (17, 18), which probably serves as a surrogate for HIV concentration in the genital tract (19). In a landmark study (18) of 415 serodiscordant couples conducted in Uganda, the probability of HIV transmission increased directly with blood HIV RNA concentrations. Increased transmission was not observed when HIV RNA level was less than 1500 copies/mL (18). Other studies confirm this observation (20, 21). In addition, a disproportionate number of incident cases of HIV occur with acute or early infection (22), probably because of the high viral burden associated with this stage of infection (23). Researchers have demonstrated increased genital tract shedding of HIV-1 during acute HIV infection (23, 24) and with concurrent sexually transmitted infections (2527). Antiretroviral therapy can be expected to reduce HIV RNA concentrations in blood and seminal plasma (28), female genital tract secretions (29), and rectal secretions (30). Therefore, by extension, ART would be expected to reduce infectiousness when used for treatment. However, the success of such therapy depends on the sensitivity of the virus to the agents selected, patient adherence, and the patients long-term commitment to therapy. Although some studies have shown durable longitudinal suppression of HIV (28, 31), others have demonstrated breakthrough genital tract HIV shedding (32). In addition, the magnitude of HIV suppression can be expected to reflect the differential penetration of antiviral agents into the male and female genital tracts. Accordingly, large differences between the pharmacology of antiretroviral agents in the male and female genital tracts deserve special attention (Figure 1) (31, 3341). Figure 1. Antiretroviral drug concentrations in the male and female genital tract relative to blood plasma concentrations (ratio of genital to blood plasma concentrations). Data from references 31 and 33 to 41. 3TC = lamivudine; ABC = abacavir; APV = amprenavir; ATV = atazanavir; d4T = stavudine; ddI = didanosine; DLV = delavirdine; EFV = efavirenz; ENF = enfuvirtide; FI = fusion inhibitor; FTC = emtricitabine; IDV = indinavir; LPV = lopinavir; ND = not detected; NFV = nelfinavir; NNRTI = nonnucleoside reverse transcriptase inhibitor; N(t)RTI = nucleotide reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RTV = ritonavir; SQV = saquinavir; TDF = tenofovir; ZDV = zidovudine. Penetration of antiviral agents into genital tract secretions is dictated by the degree of protein binding and by a drugs affinity for albumin and 1-acid glycoprotein. Highly protein-bound drugs (>80%) are recovered in lower concentrations in genital tract secretions compared with those in blood plasma. For example, male and female genital tract concentrations of protease inhibitors, with the exception of indinavir, are less than 10% and 50% of blood plasma, respectively. The limited penetration of protease inhibitors into the genital tract probably explains earlier reports of protease resistance in HIV isolates from seminal plasma and vaginal lavage fluid (33, 42, 43). Conversely, most nucleoside and nucleotide reverse transcriptase inhibitors, which have limited protein binding, attain genital tract concentrations that are 2- to 6-fold greater than plasma concentrations (Figure 1) (31, 3341). In addition, the active component of the nucleosides and nucleotides is the phosphorylated intracellular form and not the parent drug routinely measured. Data are available for the levels of intracellular phosphorylated forms of tenofovir, zidovudine, and lamivudine in mononuclear cells isolated from the male genital tract (34, 35). Intracellular tenofovir diphosphate concentrations are 5 to 10 times higher in male genital tract mononuclear cells than in peripheral blood mononuclear cells, whereas lamivudine triphosphate concentrations are similar to peripheral blood mononuclear cell concentrations. Zidovudine triphosphate concentrations are approximately 50% of peripheral blood mononuclear cell concentrations. The critical question is, of course, whether therapy that effectively suppresses HIV replication in the genital tract will prevent sexual transmission of HIV. To date, 2 lines of evidence have been explored to study this question: retrospective and prospective evaluation of HIV transmission in serodiscordant couples and population-level epidemiology studies. Musicco and colleagues (44) studied HIV transmission in 436 serodiscordant couples. A few men (15%) with more advanced disease took zidovudine and had a decrease in the relative risk for HIV transmission to a female sexual partner (odds ratio, 0.5 [95% CI, 0.1 to 0.9]). Castilla and colleagues (45) evaluated HIV transmission in 393 couples during prehighly active antiretroviral therapy (HAART), early HAART, and post-HAART periods (1991 to 2002) and observed an 80% reduction in HIV transmission after introduction of HAART (odds ratio, 0.14 [CI, 0.03 to 0.66]). More recently, Kayitenkore and colleagues (46) reported on HIV transmission in a cohort of 1034 serodiscordant couples from Zambia and Rwanda. In 248 couples, index partners received ART because CD4+ T-cell counts were less than 0.200109 cells/L. Only 2 of 42 partners who acquired HIV infection since 2003 had an HIV-positive partner who received ART. This is fewer than that occurring in the rest of the cohort (odds ratio, 0.19 [C

Predicting the unpredictable: Transmission of drug-resistant HIV

We use a mathematical model to understand (from 1996 to 2001) and to predict (from 2001 to 2005) the evolution of the epidemic of drug-resistant HIV in San Francisco. We predict the evolutionary trajectories for 1,000 different drug-resistant strains with each strain having a different fitness relative to a drug-sensitive strain. We calculate that the current prevalence of resistance is high, and predict it will continue to rise. In contrast, we calculate that transmission of resistance is currently low, and predict it will remain low. We show that the epidemic of resistance is being generated mainly by the conversion of drug-sensitive cases to drug-resistant cases, and not by the transmission of resistant strains. We also show that transmission of resistant strains has not increased the overall number of new HIV infections. Our results indicate that transmission of resistant strains is, and will remain, a relatively minor public health problem.

Could widespread use of combination antiretroviral therapy eradicate HIV epidemics

Current combination antiretroviral therapies (ARV) are widely used to treat HIV. However drug-resistant strains of HIV have quickly evolved, and the level of risky behaviour has increased in certain communities. Hence, currently the overall impact that ARV will have on HIV epidemics remains unclear. We have used a mathematical model to predict whether the current therapies: are reducing the severity of HIV epidemics, and could even lead to eradication of a high-prevalence (30%) epidemic. We quantified the epidemic-level impact of ARV on reducing epidemic severity by deriving the basic reproduction number (R(0)(ARV)). R(0)(ARV) specifies the average number of new infections that one HIV case generates during his lifetime when ARV is available and ARV-resistant strains can evolve and be transmitted; if R(0)(ARV) is less than one epidemic eradication is possible. We estimated for the HIV epidemic in the San Francisco gay community (using uncertainty analysis), the present day value of R(0)(ARV), and the probability of epidemic eradication. We assumed a high usage of ARV and three behavioural assumptions: that risky sex would (1) decrease, (2) remain stable, or (3) increase. Our estimated values of R(0)(ARV) (median and interquartile range [IQR]) were: 0.90 (0.85-0.96) if risky sex decreases, 1.0 (0.94-1.05) if risky sex remains stable, and 1.16 (1.05-1.28) if risky sex increases. R(0)(ARV) decreased as the fraction of cases receiving treatment increased. The probability of epidemic eradication is high (p=0.85) if risky sex decreases, moderate (p=0.5) if levels of risky sex remain stable, and low (p=0.13) if risky sex increases. We conclude that ARV can function as an effective HIV-prevention tool, even with high levels of drug resistance and risky sex. Furthermore, even a high-prevalence HIV epidemic could be eradicated using current ARV.

The antiretroviral rollout and drug-resistant HIV in Africa: insights from empirical data and theoretical models

The U.S. Government has pledged to spend

Modeling influenza epidemics and pandemics: insights into the future of swine flu (H1N1)

15 billion in Africa and the Caribbean on AIDS. A central focus of this plan is to provide antiretroviral treatment (ART) to millions. Here, we evaluate whether the plan to rollout ART in Africa is likely to generate an epidemic of drug-resistant strains of HIV. We review what has occurred as a result of high usage of ART in developed countries in terms of changes in risky behavior, and the emergence and transmission of drug-resistant HIV. We also review how mathematical models have been used to predict the evolution of drug-resistant HIV epidemics. We then show how models can be used to predict the likely impact of the ART rollout on the evolution of drug-resistant HIV in Africa. At currently planned levels of treatment coverage, we predict that (over the next decade) in Africa: (i) the impact of ART on reducing HIV transmission (and prevalence) is likely to be undetectable (unless accompanied by substantial changes in behavior), (ii) the transmission rate of drug-resistant HIV will be below the WHO surveillance threshold of 5%, and (ii) the majority of cases of drug-resistant HIV that will occur will be due to acquired (and not transmitted) resistance. For the next decade, large-scale surveillance for detecting transmitted resistance in Africa is unnecessary. Instead, we recommend that patients should be closely monitored for acquired resistance, and sentinel surveillance (in a few urban centers) should be used to monitor transmitted resistance.

Infectious syphilis in high-income settings in the 21st century

Here we present a review of the literature of influenza modeling studies, and discuss how these models can provide insights into the future of the currently circulating novel strain of influenza A (H1N1), formerly known as swine flu. We discuss how the feasibility of controlling an epidemic critically depends on the value of the Basic Reproduction Number (R0). The R0 for novel influenza A (H1N1) has recently been estimated to be between 1.4 and 1.6. This value is below values of R0 estimated for the 1918–1919 pandemic strain (mean R0~2: range 1.4 to 2.8) and is comparable to R0 values estimated for seasonal strains of influenza (mean R0 1.3: range 0.9 to 2.1). By reviewing results from previous modeling studies we conclude it is theoretically possible that a pandemic of H1N1 could be contained. However it may not be feasible, even in resource-rich countries, to achieve the necessary levels of vaccination and treatment for control. As a recent modeling study has shown, a global cooperative strategy will be essential in order to control a pandemic. This strategy will require resource-rich countries to share their vaccines and antivirals with resource-constrained and resource-poor countries. We conclude our review by discussing the necessity of developing new biologically complex models. We suggest that these models should simultaneously track the transmission dynamics of multiple strains of influenza in bird, pig and human populations. Such models could be critical for identifying effective new interventions, and informing pandemic preparedness planning. Finally, we show that by modeling cross-species transmission it may be possible to predict the emergence of pandemic strains of influenza.

Imperfect vaccines and herd immunity to HIV

In high-income countries after World War II, the widespread availability of effective antimicrobial therapy, combined with expanded screening, diagnosis, and treatment programmes, resulted in a substantial decline in the incidence of syphilis. However, by the turn of the 21st century, outbreaks of syphilis began to occur in different subpopulations, especially in communities of men who have sex with men. The reasons for these outbreaks include changing sexual and social norms, interactions with increasingly prevalent HIV infection, substance abuse, global travel and migration, and underinvestment in public-health services. Recently, it has been suggested that these outbreaks could be the result of an interaction of the pathogen with natural immunity, and that syphilis epidemics should be expected to intrinsically cycle. We discuss this hypothesis by examining long-term data sets of syphilis. Today, syphilis in western Europe and the USA is characterised by low-level endemicity with concentration among population subgroups with high rates of partner change, poor access to health services, social marginalisation, or low socioeconomic status.

Global elimination of trachoma: how frequently should we administer mass chemotherapy?

A number of prophylactic vaccines against human immunodeficiency virus (HIV) have passed through phase I clinical trials, and phase II clinical trials are now being planned. These vaccines are not expected to be perfect and might fail in a number of different ways. This paper shows how to equate different aspects of imperfection in a prophylactic vaccine in terms of impact upon levels of herd immunity, and hence upon the vaccine coverage required for eradication. Such comparisons reveal that an otherwise perfect vaccine that gives protection which wanes with a half-life of 10 years is only as good as a vaccine that works in 30% of people giving them complete, lifelong protection. The paper goes on to compare predicted patterns of seroconversion that would be observed in clinical trials and in community-wide vaccination campaigns for vaccines that confer the same levels of herd immunity but are imperfect in different ways.