Understanding, predicting and controlling the emergence of drug-resistant tuberculosis: a theoretical framework

The high prevalence of tuberculosis in developing countries and the recent resurgence of tuberculosis in many developed countries suggests that current control strategies are suboptimal. The increase in drug-resistant cases exacerbates the control problems. Currently employed epidemic control strategies are not devised on the basis of a theoretical understanding of the transmission dynamics of Mycobacterium tuberculosis. We describe and discuss a theoretical framework based upon mathematical transmission models that can be used for understanding, predicting, and controlling tuberculosis epidemics. We illustrate how the theoretical framework can be used to predict the temporal dynamics of the emergence of drug resistance, to predict the epidemiological consequences of epidemic control strategies in developing and developed countries, and to design epidemic control strategies. Received: 11 June 1997 / Accepted: 6 March 1998     

Modelling the genital herpes epidemic

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.     

Lessons drawn from recent HIV vaccine efficacy trials

A safe and effective HIV vaccine is needed to curtail the US and global epidemics. However, the search for one has been elusive despite more than 25 years of focused research. Results from the RV144 Thai efficacy trial have renewed hope that a vaccine may protect against HIV acquisition. We can draw several scientific and operational lessons from RV144 and other recent tests-of-concept efficacy trials. Here we describe how trial results, some unexpected, highlight the fundamental role these clinical studies play in HIV vaccine discovery. These trials also teach us that transparency in data analysis and results dissemination can yield substantial rewards and that efforts to engage communities, particularly those most heavily affected by the epidemic, are needed to augment research literacy and trial recruitment. Future efficacy trial designs may incorporate novel, partially effective prevention strategies. Although greater in size and complexity, these trials may offer unique opportunities to explore synergies with vaccines under study.     

Predictive value of primate models for AIDS

A number of obstacles remain in the search for an animal model for HIV infection and pathogenesis that can serve to predict efficacy in humans. HIV-1 fails to replicate and cause disease except in humans or chimpanzees, thereby limiting our ability to evaluate compounds or vaccines prior to human testing. Despite this limitation, nonhuman primate lentivirus models have been established that recapitulate the modes of infection, disease course, and antiviral immunity that is seen in HIV infection of humans. These models have been utilized to understand key aspects of disease and to evaluate concepts in therapies and vaccine development. By necessity, animal models can only be validated after successful trials in humans and the determination of correlates of protection. Because the only vaccine product tested in phase III trials in humans failed to achieve the desired protective threshold, we are as yet unable to validate any of the currently used nonhuman primate models for vaccine research. In the absence of a validated model, many experts in the field have concluded that prophylactic vaccines and therapeutic concepts should bypass primate models, and rely solely upon the systematic testing of each individual and combined vaccine element in human phase I or I/II trials to determine their relative merits. Indeed, a large effort is underway to expand efforts to test all products as part of an international effort termed "The HIV Vaccine Enterprise", with major contributions from the Bill and Melinda Gates Foundation. This Herculean task could potentially be reduced if it were possible to utilize even partially validated nonhuman primate models as part of the screening efforts. The purpose of this article is to review the data from nonhuman primate models that have contributed to our understanding of lentivirus infection and pathogenesis, and to critically evaluate how well these models have predicted outcomes in humans. Key features of the models developed to date are described and their contributions to HIV pathogenesis, therapeutics, and vaccines, are compared. This analysis shows that many of the models at hand have yielded data on drug action and immune responses to vaccines that are congruent with clinical data. This finding suggests that primate models are valuable as adjunctive testing systems to prioritize future therapeutic and vaccine strategies. Nonhuman primate testing of vaccine approaches in particular has provided valuable information and can significantly enhance and accelerate the evaluation of novel concepts necessary to achieve acceptable levels of efficacy. Because major gaps remain in the quest for fully effective vaccines and therapies, it seems prudent to continue aggressive research programs in the nonhuman primate models.     

Antiretroviral therapy: a promising HIV prevention strategy?

The use of antiretroviral therapy (ART) has been associated with significant improvement in morbidity and survival of persons living with HIV. In addition, recently, there has also been intense interest in the potential impact of ART on HIV transmission and consequently on the trajectory of the HIV epidemic globally. Evidence from mathematical modeling analyses and observational and ecological studies supports the potential for ART as prevention. However, definitive data from clinical trials are awaited. In the United States, the feasibility and potential of using ART as a prevention strategy presents particular challenges: the large number of individuals with undiagnosed HIV; the predominance of disenfranchised individuals affected by the epidemic; evidence of delay in engagement in HIV care after diagnosis with attendant late initiation of ART; and difficulties with consistent long-term adherence to ART and concerns regarding long-term risk-behavior change. Thus, for this novel effort to succeed, a multidimensional approach is necessary that must include policy changes, social mobilization, and improved access to clinical and supportive services for persons living with HIV, with a particular focus on the unique needs of at-risk populations, combined with engagement of all cadres of health care providers and community constituencies.     

Predicting the impact of a partially effective HIV vaccine and subsequent risk behavior change on the heterosexual HIV epidemic in low- and middle-income countries: A South African example

We developed a mathematical model to simulate the impact of various partially effective preventive HIV vaccination scenarios in a population at high risk for heterosexually transmitted HIV. We considered an adult population defined by gender (male/female), disease stage (HIV-negative, HIV-positive, AIDS, and death), and vaccination status (unvaccinated/vaccinated) in Soweto, South Africa. Input data included initial HIV prevalence of 20% (women) and 12% (men), vaccination coverage of 75%, and exclusive male negotiation of condom use. We explored how changes in vaccine efficacy and postvaccination condom use would affect HIV prevalence and total HIV infections prevented over a 10-year period. In the base-case scenario, a 40% effective HIV vaccine would avert 61,000 infections and reduce future HIV prevalence from 20% to 13%. A 25% increase (or decrease) in condom use among vaccinated individuals would instead avert 75,000 (or only 46,000) infections and reduce the HIV prevalence to 12% (or only 15%). Furthermore, certain combinations of increased risk behavior and vaccines with <43% efficacy could worsen the epidemic. Even modestly effective HIV vaccines can confer enormous benefits in terms of HIV infections averted and decreased HIV prevalence. However, programs to reduce risk behavior may be important components of successful vaccination campaigns.     

Analytic insights into the population level impact of imperfect prophylactic HIV vaccines

The population level implications of imperfect HIV vaccines were studied using a mathematical model. A criterion for determining the utility of a vaccine at the population level is introduced, and 2 useful summary measures, namely, vaccine utility (phi) and vaccine infection fitness (psi), are derived and shown to characterize the population-level utility once vaccine efficacies are determined. The utility of the vaccine alone does not guarantee a substantial impact, however, because the effectiveness of partially effective vaccines also depends on the prevailing level of HIV infectious spread. Therefore, a second criterion is introduced through a third summary measure, the hazard index (xi), to describe the effectiveness of a vaccine in substantially reducing HIV incidence. The qualitative features of the impact are delineated by studying 4 distinct scenarios of HIV vaccination. Accordingly, our work delineates the link between vaccine efficacies and the impact of vaccination at the population level and provides the tools for vaccine developers to assess the utility and effectiveness of a given imperfect vaccine straightforwardly and rapidly.     

HIV/AIDS in Central Africa: pathogenesis, immunological and medical issues

The estimated worldwide prevalence of human immunodeficiency virus (HIV) infections topped 52.5 million in June 2003, a mere 20 years after the aetiological agent was shown to be a sexually transmissible virus with a predilection for CD4+ T lymphocytes. More than 22 million people have died of the acquired immunodeficiency syndrome (AIDS) and the condition has in one generation become the most devastating and persistent epidemics in recorded history. More than two thirds of the world total of HIV-infected people live in Sub-Saharan Africa. In Central and Southern Africa at least 20% of the adult population is infected. As these adults die, they leave increasing numbers of orphans. Life expectancy at birth declined by 10 years per decade since the late 1980s to 50 years in the late 1990s, and in Botswana it is estimated to be as low as 33 years by 2010. The epidemic is increasing unabated and prospects for a curative or protective vaccine remain remote. The impact on HIV in Africa has been so profound that it influences political, economic, agriculture/food security, social, education, defence, science and health considerations. The medical and in particular immunology communities in Central Africa have the invidious challenge of on the one hand diagnosing the condition, monitoring its impact and contributing to treatment and management efforts. The science and clinical practice of immunology is challenged to find answers to the epidemic, perhaps including a vaccine. In this review we address the peculiarities of the HIV epidemic in Africa, its epidemiology and immunopathogenesis. We address the effect of the epidemic on individual patients, in their homes, workplaces and the knock-on effects on families and friends of the infected. Respective specialists discuss special groups (women, children) that are predominantly seen in Africa. We also discuss the impact of the epidemic on the clinical practice of medicine in general and challenges faced in the introduction of antiretroviral medicines. We also discuss options available for the diagnosis, treatment and monitoring of HIV-infected patients in this region.     

Experimental models in vaccine research: malaria and leishmaniasis

Animal models have a long history of being useful tools, not only to test and select vaccines, but also to help understand the elaborate details of the immune response that follows infection. Different models have been extensively used to investigate putative immunological correlates of protection against parasitic diseases that are important to reach a successful vaccine. The greatest challenge has been the improvement and adaptation of these models to reflect the reality of human disease and the screening of vaccine candidates capable of overcoming the challenge of natural transmission. This review will discuss the advantages and challenges of using experimental animal models for vaccine development and how the knowledge achieved can be extrapolated to human disease by looking into two important parasitic diseases: malaria and leishmaniasis.     

Meningococcal serogroup W135 in the African meningitis belt: epidemiology, immunity and vaccines

In the sub-Saharan African meningitis belt there is a region of hyperendemic and epidemic meningitis stretching from Senegal to Ethiopia. The public health approaches to meningitis epidemics, including those related to vaccine use, have assumed that Neisseria meningitidis serogroup A will cause the most disease. During 2001 and 2002, the first large-scale epidemics of serogroup W135 meningitis in sub-Saharan Africa were reported from Burkina Faso. The occurrence of N. meningitidis W135 epidemics has led to a host of new issues, including the need for improved laboratory diagnostics for identifying serogroups during epidemics, an affordable supply of serogroup W135-containing polysaccharide vaccine for epidemic control where needed, and re-evaluating the long-term strategy of developing a monovalent A conjugate vaccine for the region. This review summarizes the existing data on N. meningitidis W135 epidemiology, immunology and vaccines as they relate to meningitis in sub-Saharan Africa.     

Amplification dynamics: predicting the effect of HIV on tuberculosis outbreaks.

HIV affects the pathogenesis and the transmission of Mycobacterium tuberculosis. We used a discrete event simulation model to predict the potential impact of HIV on increasing the probability and the expected severity of tuberculosis outbreaks. Our predictions reveal that an HIV epidemic can significantly increase the frequency and severity of tuberculosis outbreaks, but that this amplification effect of HIV on tuberculosis outbreaks is very sensitive to the tuberculosis treatment rate. At moderate or low treatment rates, even a moderate HIV epidemic can cause the average size of tuberculosis outbreaks to almost double in comparison with the expected outbreak size when HIV is absent. However, we determined that the amplification effect of HIV can be substantially reduced if the treatment rate of tuberculosis is very high. We discuss the significant implications of these results for the global control of tuberculosis. Our results also reveal that occasionally a "normal-virulence" strain of M. tuberculosis can be expected to generate a large outbreak. We discuss the implications of these results in understanding the virulence of M. tuberculosis and in the planned elimination of tuberculosis in the United States.     

Simulating the effect of vaccine-induced immune responses on HIV infection

The need for anti-HIV-1 vaccines is universally recognized. Although several potential vaccine formulations are being tested in clinical trials, the complexity of the viral system and the length of the experimentation required and its costs makes the goal of obtaining such a vaccine still elusive. We have built a mathematical model for the simulation of HIV-1 infection spreading into the body, which allows us study in silico the effect of hypothetical anti-HIV-1 vaccines having different properties. In particular, vaccines eliciting a cytolytic T-cell response, a humoral response, or both can be simulated. The vaccines considered can be envisaged either as preventive or therapeutic and can have different strength. The kinetic parameters used for solving the model are those of HIV-1 infection obtained from experimental and clinical observations. The vaccines are instead characterized by parameters that can be varied in order to mimic different behaviors: the rate of killing of the single effector cell and the rate of neutralization of the single antibody molecule; and the level of the immune response raised. The model allows us to predict which characteristics of immunogenicity a preventive or therapeutic vaccine should possess to be efficacious, and which are the key factors that most likely will affect its ability to control the spread of the infection. We discuss here the conclusions that can be drawn from a such a model and some of its limitations.     

Epidemiology of communicable disease in small populations

 We have recently shown how the outbreaks of measles virus infection in small isolated island communities exhibit an organised pattern in the distribution of epidemic sizes and distribution of epidemic durations. More conventional epidemiological analysis tends not to be useful in such highly intermittent dynamical regimes where there is frequent fade-out of infection. In this paper we discuss how our approach can be applied to an analysis of measles epidemics in highly vaccinated communities where susceptibles build up due to lack of vaccine uptake and also because of occasional vaccine failure. Received: 25 November 1996 / Accepted: 9 May 1997     

Knowledge about vaccines and willingness to participate in preventive HIV vaccine trials: a population-based study, Rakai, Uganda

The purpose of the study was to assess knowledge and beliefs regarding vaccines and willingness to participate in HIV vaccine trials. A baseline survey assessed knowledge and attitudes toward vaccination and potential HIV vaccines among 14,177 participants aged 15-49 years, in a population cohort. Willingness to participate in HIV-preventive vaccine trials was assessed during a follow-up survey 10 months later after providing community education on HIV vaccines. Knowledge of the preventive utility of vaccines was high (71%), but higher in men than women (P<0.001), and increased with education levels (P<0.001). Vaccines were considered appropriate for children and women (99 and 88%, respectively), but not for adult men (28%). Participants felt that adolescents were the most appropriate subjects for HIV preventive vaccine trials (93.7%) but also thought that HIV-positive persons were eligible for trials (60.2%), and only 20% thought a preventive vaccine could help control HIV. HIV vaccine awareness increased from 68% at baseline to 81% at follow-up (P<0.001). Willingness to participate in HIV-preventive vaccine trials was 77%. Vaccine knowledge and willingness to participate in trials are high in this population. However, there still is need for education on the potential role of preventive HIV vaccines in the control of the epidemic and the importance of vaccination for men, especially in the context of an HIV vaccine.     

AIDS vaccine development: the long and winding road

Development of a vaccine that provides sterilizing immunity against HIV infection remains an elusive goal, due primarily to the difficulty in generating neutralizing antibodies to primary HIV isolates. In lieu of a present solution to this problem, recent approaches to develop vaccines against HIV/AIDS have focused not on preventing infection outright, but on eliciting potent antiviral CD8+ T-cell responses to limit HIV replication in individuals who become infected after vaccination. Successful control of HIV replication in vivo, enabled by vaccine-elicited immune responses should, in turn, attenuate an individual's rate of progression to AIDS while reducing their likelihood of subsequently transmitting HIV. Recent pre-clinical evaluation of CTL-based vaccines in non-human primate models of AIDS has shown several different vaccine modalities (e.g. heterologous 'prime/boost' strategies such as DNA + recombinant viral vectors) to be capable of eliciting high-level cellular immune responses that are associated with limitation of virus replication and protection against disease following challenge with select pathogenic virus isolates. However, it is not currently known to what extent these protective effects, observed under optimal experimental conditions in select animal models, can be translated into relevant protection of humans against AIDS. In this article we discuss the promise, potential limitations, and scientific challenges that currently provide the context for efforts to develop and successfully employ a safe and effective AIDS vaccine.     

DNA vaccines for HIV: challenges and opportunities

In December 2005, the UNAIDS and WHO reported that the global epidemic known as acquired immunodeficiency syndrome (AIDS) has claimed the lives of more than 25 million adults and children over the past 26 years. These figures included an estimated 3.1 million AIDS-related deaths in 2005. Despite enormous efforts to control the spread of human immunodeficiency virus (HIV) new infection rates are on the rise. An estimated 40.3 million people are now living with HIV, including 4.9 million new infections this past year. Nearly half of new HIV infections are in young people between the ages of 15 and 24. While drug therapies have helped sustain the lives of infected individuals in wealthy regions, they are relatively unavailable to the poorest global regions. This includes sub-Saharan Africa which has ∼25.8 million infected individuals, more than triple the number of infections of any other region in the world. It is widely believed that the greatest hope for controlling this devastating pandemic is a vaccine. In this review, we will discuss the current state of DNA-based vaccines and how they compare to other vaccination methods currently under investigation. We will also discuss innovative ideas for enhancing DNA vaccine efficacy and the progress being made toward developing an effective vaccine.     

Public health consequences of screening patients for adherence to highly active antiretroviral therapy

Improvements in HIV antiretroviral therapy (ART) have been accompanied by increasing recognition of the importance of adherence to treatment regimens for maximizing patient benefits while minimizing the emergence of drug-resistant virus. Whether clinicians should screen patients for adherence and only administer therapy to those believed likely to adhere has not been resolved. We first examine the implications of data drawn from a recent study reporting physicians' ability to predict whether patients will adhere to highly active antiretroviral therapy (HAART) or not. We then extend previously developed mathematical models of ART to include screening for adherence and focus on resulting drug resistance as well as on HIV and AIDS incidence at the population level. We show that although screening for adherence is likely to reduce the level of drug resistance compared with a policy of treating all HIV patients with HAART, rates of new HIV infections and AIDS cases in the population would likely increase unless screening accuracy is extremely (perhaps implausibly) high.     

HIV-1 therapeutic vaccine: a ray of hope

The human immunodeficiency virus (HIV) epidemic is still in its early stages, and a marked increase in global prevalence is projected for the next coming years. Neither behavioural therapies nor current antiretroviral drugs are likely to have an impact on this silent epidemic. Current antiretroviral drugs are too expensive for the developing countries, and there are major problems of adherence, resistance and toxicity, which limit their application and efficacy. The main problem facing us, as inhabitants of a single world, is to prevent further infections regardless of where they occur, and this requires a vaccine programme. A successful immunotherapeutic HIV vaccine has the potential to overcome these problems, and would be a valuable advance. To accelerate the development of an HIV vaccine, additional candidate vaccines must be evaluated in parallel in both industrialized and developing countries. This will require international collaboration and coordination and critical ethical issues will need to be addressed. The probable triple cocktail of the future for global HIV prevention will be vaccination, anti-retroviral therapy, and not the least, behavioural therapy.     

The impact of a partially effective HIV vaccine on a population of intravenous drug users in Bangkok, Thailand: a dynamic model

Because of the variability of HIV, the first AIDS vaccine is likely to be only partially effective. There is some concern among scientists that a low-efficacy vaccine could worsen the HIV epidemic if vaccinated individuals increase their risk behavior under the false assumption of immunity. To address this concern, we constructed a dynamic compartmental model that simulated the course of the HIV/AIDS epidemic in a population of injection drug users in Bangkok, Thailand. The model calculated long-term HIV prevalence, number of AIDS cases, and total population size for two scenarios: vaccination program versus no vaccination program. We used sensitivity analyses to evaluate the impact of postvaccination risk behavior change on HIV prevalence. A 75% effective vaccine led to a 40-year HIV prevalence of 37% with vaccination and 50% without vaccination. Postvaccination behavior change had only a limited effect on the results with a 75% effective vaccine but a significant effect with a 30% effective vaccine. If 90% of low-risk individuals responded to a 30% effective vaccine with increased high-risk behavior, the benefit of vaccination disappeared. These results agree with analyses of the epidemic among gay men. If injection drug behavior is indeed modifiable, our findings have significant policy and planning implications.