Tuberculosis: vaccines in the pipeline

TB is presenting new challenges as a global health problem, especially with new threats of HIV coinfection and multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis. The current TB vaccine, Mycobacterium bovis bacillus Calmette-Guerin (BCG), is the most widely used vaccine worldwide but its efficacy against pulmonary TB in adults in many high-burden countries is limited. Different vaccine strategies will probably be required for the various needs that exist within a population in which some individuals have been previously immunized with BCG, coinfected with HIV and/or latently infected with M. tuberculosis. In the last 15 years, new strategies to improve or replace BCG in the laboratory have led to several promising vaccine candidates that are actively being evaluated in human clinical trials. Some of these new vaccines may eventually be recommended for travelers to TB high-burden countries. This paper summarizes the progress of vaccine candidates in animal models to improve, replace or augment BCG vaccination.     

Direct Detection of Mycobacterium tuberculosis in Clinical Specimens Using Nucleic Acid Amplification Tests

Tuberculosis continues to be a significant cause of morbidity and mortality worldwide. Rapid detection of Mycobacterium tuberculosis directly in clinical specimens using nucleic acid amplification tests enables infected patients to be placed on appropriate therapy much sooner than when results of conventional culture methods are used. The availability of rapid results also facilitates infection control measures to interrupt transmission of tuberculosis in healthcare settings. The era of commercially available molecular diagnostics for detection of M. tuberculosis began 25 years ago and now encompasses multiple assays that can detect organisms in the M. tuberculosis complex. Several assays also detect chromosomal mutations associated with antimicrobial resistance to further refine therapeutic strategies early in the course of disease. NAATs have revolutionized the diagnosis of TB across the globe and have become the standard of care in many high-burden developing countries.     

Lay workers in directly observed treatment (DOT) programmes for tuberculosis in high burden settings: Should they be paid? A review of behavioural perspectives

The current global tuberculosis (TB) epidemic has pressured health care managers, particularly in developing countries, to seek for alternative, innovative ways of delivering effective treatment to the large number of TB patients diagnosed annually. One strategy employed is direct observation of treatment (DOT) for all patients. In high-burden settings innovation with this strategy has resulted into the use of lay community members to supervise TB patients during the duration of anti-TB treatment. However, community involvement in health programmes is not a simple matter. There is often a need for continued motivation of community members in order to ensure sustainability of such projects. Lay workers may demand payment for work done particularly if this takes up a reasonable proportion of their time. TB treatment, by its very nature, lasts for a considerable period and this paper seeks to examine behavioural perspectives that attempt to address the issue of whether lay workers in such programmes should be paid for their services. The theories explored suggest intrinsic and extrinsic motivation as factors that lead people to volunteer for health programmes. Intrinsic motivation encompasses such feelings as empathy and altruism as well as other factors such as religious and cultural conviction. The authors argue however that in high-burden TB settings, these factors alone may be inadequate to provide continued motivation for lay worker involvement in health programmes. Extrinsic motivators, of which money is the strongest example, then also serve to keep sustained interest particularly in resource-limited settings where people expect payment for work done. The debate on whether lay workers in health programmes should be paid is thus compounded by issues such as what factors one believes are responsible for motivation in particular contextual settings; how long lay persons are expected to perform tasks at hand; the capacity that exists to pay them and the sustainability of the motivating option chosen. We recommend more qualitative research to be done on this issue in high TB burden settings.     

International Tuberculosis Laboratory Consulting

Improving tuberculosis (TB) laboratory test capacity internationally is essential to combat the increasing prevalence of drug-resistant TB in many countries throughout the world, which poses a direct public health threat to the United States. Microbiologists from the U.S. who plan to serve as consultants to assist in improving TB laboratories in resource-challenged countries should prepare for such work using available resources that are readily available from the Centers for Disease Control and Prevention, as well as the Global Laboratory Initiative of the World Health Organization (WHO). Identifying and networking with potential collaborators in various countries can help ensure success. Consultants should also become familiar with WHO-recommended TB laboratory test methods, available training programs, and tools for laboratory accreditation.     

Improving the Diagnosis of Tuberculosis: From QuantiFERON to New Techniques to Diagnose Tuberculosis Infections

The diagnosis of latent and active tuberculosis in the HIV-positive population is challenged by diminished sensitivity of conventional tests, atypical presentations, and the lack of culture methods in the developing world, where the burden of co-infection is greatest. In response to these challenges, a variety of new diagnostics have emerged. These include interferon-gamma release assays for the diagnosis of latent tuberculosis (TB) infection and novel culture methods and molecular assays for the diagnosis of active tuberculosis. Although some tests (such as interferon-gamma release assays) are not clearly superior to existing diagnostics, other novel diagnostics, such as real-time polymerase chain reaction and the microscopic observed direct susceptibility assay hold much promise for prompt and accurate TB diagnosis in this population. Line-probe, nitrate reductase, and mycobacteriophage assays have also provided rapid alternatives to conventional time-consuming drug susceptibility testing and are critical to curtailing the spread of multidrug-resistant TB.     

The campaign against TB: governments must commit themselves. TB in Africa

This article presents an interview with Pierre Chaulet on the campaign against tuberculosis (TB) in Africa. Chaulet noted during the 9th IUATLD Conference of the Africa Region that the national TB control programs have taken on a new commitment in Africa since the declaration of TB as a global emergency in the 1990s. The TB control program package consists of five principal components: 1) political will of the government and its commitment to support the program; 2) case detection; 3) initiation of short course chemotherapy among detected cases; 4) ensuring the regular supply of essential anti-TB drugs; and 5) establishing a registry and reporting system for program monitoring and evaluation. Of the 40 African countries participating in the conference, 30 have efficient programs. Comparing the management of National TB Control Programs in Francophone and Anglophone Africa, it is noted that both are complementary, although generally, public health issues are more easily integrated into the medical training in the Anglophone countries than they are in the Francophone. Anglophone uses a more comprehensive approach to public health while countries in the Francophone practiced a more traditional university centralization. Finally, Chaulet gives his comment on the role of WHO in addressing concerns over the financial issues involved in TB Control Programs, particularly in the mobilization of resources from nongovernmental organizations and international institutions.     

Mycobacterium tuberculosis transmission in a country with low tuberculosis incidence: role of immigration and HIV infection

Immigrants from high-burden countries and HIV-coinfected individuals are risk groups for tuberculosis (TB) in countries with low TB incidence. Therefore, we studied their role in transmission of Mycobacterium tuberculosis in Switzerland. We included all TB patients from the Swiss HIV Cohort and a sample of patients from the national TB registry. We identified molecular clusters by spoligotyping and mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) analysis and used weighted logistic regression adjusted for age and sex to identify risk factors for clustering, taking sampling proportions into account. In total, we analyzed 520 TB cases diagnosed between 2000 and 2008; 401 were foreign born, and 113 were HIV coinfected. The Euro-American M. tuberculosis lineage dominated throughout the study period (378 strains; 72.7%), with no evidence for another lineage, such as the Beijing genotype, emerging. We identified 35 molecular clusters with 90 patients, indicating recent transmission; 31 clusters involved foreign-born patients, and 15 involved HIV-infected patients. Birth origin was not associated with clustering (adjusted odds ratio [aOR], 1.58; 95% confidence interval [CI], 0.73 to 3.43; P = 0.25, comparing Swiss-born with foreign-born patients), but clustering was reduced in HIV-infected patients (aOR, 0.49; 95% CI, 0.26 to 0.93; P = 0.030). Cavitary disease, male sex, and younger age were all associated with molecular clustering. In conclusion, most TB patients in Switzerland were foreign born, but transmission of M. tuberculosis was not more common among immigrants and was reduced in HIV-infected patients followed up in the national HIV cohort study. Continued access to health services and clinical follow-up will be essential to control TB in this population.     

Rapid drug resistance detection in Mycobacterium tuberculosis: a review of colourimetric methods

Several new methods to detect drug resistance in Mycobacterium tuberculosis have been proposed in recent years. Colourimetric methods that use redox indicators or the nitrate reduction assay have received increasing attention because of their simplicity and the absence of any requirement for sophisticated equipment or highly trained personnel. Several studies have evaluated their accuracy and performance in comparison with reference standard methods, particularly for the detection of resistance to rifampicin and isoniazid, which are the two most important drugs used for the treatment of tuberculosis. This review describes the development, evaluation and implementation of these methods as rapid alternative tests for the detection of multidrug resistance in M. tuberculosis. Based on published evidence and the high accuracy of colourimetric methods for detecting drug resistance in M. tuberculosis, these methods seem to be appropriate for implementation in high-burden low-resource countries.     

Host Responses and Antigens Involved in Protective Immunity to Mycobacterium tuberculosis

Tuberculosis (TB) is the largest single infectious cause of human mortality. The incidence of TB has remained high in most of the developing world and the disease has recently re-emerged as a public health problem in industrialized countries. The development of a new improved TB vaccine is a highly prioritized international research area, which has been further stimulated by the appearance of multi-drug resistant strains of Mycobacterium tuberculosis . The present status of the attempts to characterize the protective immune response to TB will be reviewed with special emphasis on recent progress in the identification and characterization of target molecules recognized by protective cells. This paper will focus on proteins released from live bacteria and discuss their role in the host–pathogen interaction and the ongoing attempts to use these molecules in TB subunit vaccines.     

Tuberculosis and HIV: Implications in the developing world

Developing countries bear the brunt of the epidemics of AIDS and tuberculosis (TB), and the management of patients with both diseases poses a particular challenge in these settings. In this article, we review implications for the twin epidemics of HIV and TB for the developing world with respect to diagnosis, prevention, treatment and integration of national TB and HIV programs.     

Drug resistant tuberculosis: ten years of surveillance in Croatia

Drug resistant and multidrug resistant tuberculosis is a consequence of human activity. Resistant strains of M. tuberculosis are mainly prevalent in regions with weak national TB programs or poor socioeconomic environment. Therefore an effective surveillance of the resistance patterns of TB bacilli is an essential tool for the quality of tuberculosis control programs and a demanding task in all countries. Surveillance of tuberculosis in Croatia is based on individual notifications of every newly diagnosed patient by the physicians, followed by laboratory notifications. Data are collected at the Epidemiology Service, National Institute of Public Health Tuberculosis Register (TR). TR is part of the World Health Organization informational system and Surveillance of Tuberculosis in Europe (EuroTB). The results of the ten-year surveillance of the prevalence of drug resistant (5.7%) and multidrug resistant (1.6%) tuberculosis show that Croatia has a favorable situation which should be kept up strictly following the measures of the national TB program.     

Diagnosis of tuberculosis in an era of HIV pandemic: a review of current status and future prospects

HIV and tuberculosis co-infection interact in fundamentally important ways. This interaction is evident patho-physiologically, clinically and epidemiologically. There are several differences between HIV-infected and HIV-uninfected patients with tuberculosis (TB) that have practical diagnostic implications. TB is more likely to be disseminated in nature and more difficult to diagnose by conventional diagnostic procedures as immunosuppression progresses. As TB rates continue to increase in HIV-endemic regions, improved diagnostic techniques merit consideration as TB-control strategies. There is a need to develop more user friendly techniques, which can be adapted for use in the high-burden and low-income countries. This review focuses on the diagnostic challenges in HIV-TB co-infection with an update on the current techniques and future prospects in an era of HIV pandemic.     

Direct colorimetric assay for rapid detection of rifampin-resistant Mycobacterium tuberculosis

The colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was standardized for direct detection of rifampin-resistant Mycobacterium tuberculosis in sputum samples. The sensitivity and specificity of the direct MTT assay matched those of the standard indirect susceptibility assay on 7H10 medium, and interpretable results were obtained for 98.5% of the samples within 2 weeks. Traditional methods of in vitro drug susceptibility testing are time consuming and laborious. Susceptibility tests on clinical isolates require 6 to 9 weeks, and tests conducted directly on smear-positive samples take about 3 weeks (International Union Against Tuberculosis and Lung Disease, The public health service national tuberculosis reference laboratory and the national laboratory network. Minimum requirements, role and operation in a low-income country, Paris, France, 1998, and P. T. Kent and G. P. Kubica, Public health mycobacteriology. A guide for the level III laboratory, Centers for Disease Control and Prevention, Atlanta, Ga., 1985). More-rapid methods are available but are very expensive for routine use under program conditions in countries with high levels of tuberculosis endemicity.     

Patient-centred tuberculosis treatment delivery under programmatic conditions in Tanzania: a cohort study

Background  

Directly observed therapy (DOT) remains the cornerstone of the global tuberculosis (TB) control strategy. Tanzania, one of the 22 high-burden countries regarding TB, changed the first-line treatment regimen to contain rifampicin-containing fixed-dose combination for the full 6 months of treatment. As daily health facility-based DOT for this long period is not feasible for the patient, nor for the health system, Tanzania introduced patient centred treatment (PCT). PCT allows patients to choose for daily DOT at a health facility or at their home by a supporter of choice. The introduction of fixed dose combinations in the intensive and continuation phase made PCT feasible by eliminating the risk of selective drug taking by patients and reducing the number of tablets to be taken. The approach was tested in three districts with the objective to assess the effect of this strategy on TB treatment outcomes     

PEPFAR support for the scaling up of collaborative TB/HIV activities

The US President's Emergency Plan for AIDS Relief (PEPFAR) has supported a comprehensive package of care in which interventions to address HIV-related tuberculosis (TB) have received increased funding and support in recent years. PEPFAR's TB/HIV programming is based on the World Health Organization's 12-point policy for collaborative TB/HIV activities, which are integrated into PEPFAR annual guidance. PEPFAR implementing partners have provided crucial support to TB/HIV collaboration, and as a result, PEPFAR-supported countries in sub-Saharan Africa have made significant gains in HIV testing and counseling of TB patients and linkages to HIV care and treatment, intensified TB case finding, and TB infection control. PEPFAR's support of TB/HIV integration has also included significant investment in health systems, including improved laboratory services and educating and enlarging the workforce. The scale-up of antiretroviral therapy along with support of programs to increase HIV counseling and testing and improve linkage and retention in HIV care may have considerable impact on TB morbidity and mortality, if used synergistically with isoniazid preventive therapy, intensified case finding, and infection control. Issues to be addressed by future programming include accelerating implementation of isoniazid preventive therapy, increasing access and ensuring appropriate use of new TB diagnostics, supporting early initiation of antiretroviral therapy for HIV-infected TB patients, and strengthening systems to monitor and evaluate program implementation.     

Integrating Human Immunodeficiency Virus and Reproductive,Maternal and Child,and Tuberculosis Health Services Within National Health Systems

Joint United Nations Programme on HIV/AIDS (UNAIDS) established 90–90–90 HIV treatment targets for 2020 including the following: 90 % of HIV-infected people know their HIV status, 90 % of HIV-infected people who know their status are on treatment, and 90 % of people on HIV treatment have a suppressed viral load. Integration of HIV and other programs into the national health system provides an important pathway to reach those targets. We examine the case for integrating HIV and other health services to ensure sustainability and improve health outcomes within national health systems. In this non-systematic review, we examined recent studies on integrating HIV, tuberculosis (TB), maternal-child health (MCH), and sexually transmitted infection (STI) programs. Existing evidence is limited about the effectiveness of integration of HIV and other services. Most studies found that service integration increased uptake of services, but evidence is mixed about the effect on health outcomes or quality of health services. More rigorous studies of different strategies to promote integration over a wider range of services and settings are needed. Research on how best to maximize benefits, including sustainability, of integrated services is necessary to help inform international and national policy. We recommend additional interventions to test how best to integrate HIV and MCH services, HIV and TB services, HIV testing and treatment, and STI testing and treatment.     

Tuberculosis in the AIDS era.

A resurgence of tuberculosis has occurred in recent years in the United States and abroad. Deteriorating public health services, increasing numbers of immigrants from countries of endemicity, and coinfection with the human immunodeficiency virus (HIV) have contributed to the rise in the number of cases diagnosed in the United States. Outbreaks of resistant tuberculosis, which responds poorly to therapy, have occurred in hospitals and other settings, affecting patients and health care workers. This review covers the pathogenesis, epidemiology, clinical presentation, laboratory diagnosis, and treatment of Mycobacterium tuberculosis infection and disease. In addition, public health and hospital infection control strategies are detailed. Newer approaches to epidemiologic investigation, including use of restriction fragment length polymorphism analysis, are discussed. Detailed consideration of the interaction between HIV infection and tuberculosis is given. We also review the latest techniques in laboratory evaluation, including the radiometric culture system, DNA probes, and PCR. Current recommendations for therapy of tuberculosis, including multidrug-resistant tuberculosis, are given. Finally, the special problem of prophylaxis of persons exposed to multidrug-resistant tuberculosis is considered.     

Community participation in primary health care (PHC) programmes: lessons from tuberculosis treatment delivery in South Africa

Background

Currently, there is renewed interest in the role community participation can play in Primary Health Care (PHC) programmes such as the delivery of effective anti-TB treatment to patients in high-burden settings.

Objectives

To explore the feasibility of community participation in a high-burden Tuberculosis Control Programme and to establish how supervision of treatment by lay volunteers compares with other methods of tuberculosis treatment delivery in the Northern Cape province of South Africa.

Methods

Prospective study involving 769 patients with confirmed pulmonary TB who were followed-up over a one-year period. Questionnaire interviews were also carried out with 135 lay volunteers participating in the TB programme.

Results

One-third of the TB patients in the study received their treatment from lay volunteers in the community. Treatment outcomes for new patients supervised from the community were found to be equivalent to those who received treatment through other modes of treatment delivery (RR=1.04[0.94–1.16], p=0.435). For the re-treatment patients, community-based treatment was found to be superior (RR=5.89[2.30–15.09], p<0.001), to self-administered therapy.

Conclusions

Health care planners should consider community participation as a viable way of ensuring accessibility and effectiveness in PHC programmes. There is need for more research into ways of achieving sustainability in resource-limited but high disease burden settings.     

Rapid and simple detection of a Mycobacterium tuberculosis circulating antigen in serum using dot-ELISA for field diagnosis of pulmonary tuberculosis

Tuberculosis (TB) has re-emerged as a major health problem worldwide. Developing an easy, inexpensive immunodiagnostic test is extremely important for TB diagnosis, especially in developing countries. A target mycobacterial circulating antigen of 55-kDa molecular weight was identified in sera from confirmed Mycobacterium tuberculosis infected individuals by using Western blotting based on a specific mouse IgG anti-M. tuberculosis monoclonal antibody (TB-55 mAb). No bands were identified in sera of healthy individuals. The target TB antigen was isolated and characterized as a protein. It consists of 15 amino acids; 24.6% of the amino acids are hydrophobic and 46.4% are hydrophilic. A dot-ELISA format, based on TB-55 mAb, was developed for the direct demonstration of the 55-kDa TB antigen in serum samples of pulmonary TB patients. The technical aspects of the developed dot-ELISA are simple, rapid (5 min), and reproducible, as well as sensitive (87%) and specific (93%). Using the more sensitive immunoassay; Western blot, the 55-kDa TB antigen was detected in all (100%) sera that have been shown false negative by dot-ELISA, as well as in true positive sera. In conclusion, we have developed a simple and rapid immunoassay for the direct detection of a circulating mycobacterial antigen in sera of TB infected individuals and, therefore, the developed assay can be applied for laboratory and field diagnosis of TB infection in developing countries.     

Molecular Characterization and Second-Line Antituberculosis Drug Resistance Patterns of Multidrug-Resistant Mycobacterium tuberculosis Isolates from the Northern Region of South Africa

Despite South Africa being one of the high-burden multidrug-resistant tuberculosis (MDR-TB) countries, information regarding the population structure of drug-resistant Mycobacterium tuberculosis strains is limited from many regions of South Africa. This study investigated the population structure and transmission patterns of drug-resistant M. tuberculosis isolates in a high-burden setting of South Africa as well as the possible association of genotypes with drug resistance and demographic characteristics. A total of 336 consecutive MDR-TB isolates from four provinces of South Africa were genotyped using spoligotyping and mycobacterial interspersed repetitive-unit-variable number tandem repeat (MIRU-VNTR) typing. Drug susceptibility testing for ofloxacin, kanamycin, and capreomycin was performed using the agar proportion method. The results showed that 4.8% of MDR-TB isolates were resistant to ofloxacin, 2.7% were resistant to kanamycin, and 4.5% were resistant to capreomycin, while 7.1% were extensively drug resistant (XDR), and the remaining 83.6% were susceptible to all of the second-line drugs tested. Spoligotyping grouped 90.8% of the isolates into 25 clusters, while 9.2% isolates were unclustered. Ninety-one percent of the 336 isolates were assigned to 21 previously described shared types, with the Beijing family being the predominant genotype in the North-West and Limpopo Provinces, while the EAI1_SOM family was the predominant genotype in the Gauteng and Mpumalanga Provinces. No association was found between genotypes and specific drug resistance patterns or demographic information. The high level of diversity and the geographical distribution of the drug-resistant M. tuberculosis isolates in this study suggest that the transmission of TB in the study settings is not caused by the clonal spread of a specific M. tuberculosis strain.