Priorities in tuberculosis research

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Priorities in tuberculosis research Keertan Dheda, Philip C Onyebujoh, Mahnaz Vahedi, and Alimuddin I Zumla

INTRODUCTION Although most TB cases can be cured with 6 months of appropriate multidrug treatment, TB kills about 1.8 million people each year. This failure is due to several reasons: control efforts have been hampered by suboptimal case finding and diagnosis (Fig. 73.1), a treatment regimen that is lengthy and has several drugs, poor adherence to treatment, development of drug resistance and coinfection with human immunodeficiency virus (HIV). The only available TB vaccine is ineffective in most countries. The main diagnostic method is sputum smear microscopy and has in practice a 50% yield. No new classes of anti-TB drugs have been researched for more than 40 years. It is obvious that new tools are required to control TB, and research into new drugs, diagnostics and vaccines has taken off in a big way during the past decade, and continues to build momentum. Working groups on new diagnostics, drugs, immunomodulators and vaccines convened by the STOP TB Partnership have set out to develop new improved tools for the detection, treatment and prevention of TB disease, drug resistance and latent infection. Research led by a number of international organizations and academic institutions is now pointing toward the discovery of new drug compounds, immunotherapeutics, immune markers of disease, diagnostics and vaccines. The revised Global TB Control Plan, of the World Health Organization (WHO) Stop TB Partnership announced in March 2006, has six elements, the sixth of which is enabling and promoting research for new tools and programme performance.1 Current UNDP/UNICEF/World Bank/WHO Special Programme in Research and Training, Scientific Working Group recommendations for priority research into TB are grouped into several areas (Table 73.1):2,3 1. improved diagnostics for TB, multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB; 2. improved clinical management of TB, MDR- and XDR-TB in HIV-infected and -uninfected individuals; 3. social, economic and behavioural research and the Global TB Agenda; 4. immunopathogenesis and vaccine studies; 5. operational and implementation research; 6. improved programme performance and capacity building; 7. epidemiological research in national TB programmes; and 8. cross-cutting issues. The main emphasis is currently on development of newer drugs, immunotherapeutics, diagnostics and vaccines for improved outcomes

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in the clinical management of TB in HIV-infected and uninfected individuals. There are several other areas in which further research is required, and these are discussed later in this chapter.

IMPROVED DIAGNOSTICS FOR TUBERCULOSIS One of the most frustrating challenges in TB management has been the lack of a specific, sensitive, inexpensive and rapid point of care test for the diagnosis of TB.4,5 For individual patients, the cost, complexity and potential toxicity of 6 months of standard TB treatment demands certainty in diagnosis. For communities, the risk of transmission from undetected cases requires widespread access to diagnostic services and early detection. Unfortunately, current diagnostic services in most TB-endemic settings fail both the individual and the community. Patients are commonly diagnosed after weeks to months of waiting, at substantial cost to themselves, and at huge cost to society as TB goes unchecked. Many patients are missed altogether, and contribute to the astonishing number of annual deaths from TB world-wide. Some of this failure could be corrected by better implementation of existing standards of clinical and laboratory practice. The WHO and its member states have made great gains in the expansion of the directly observed treatment, short-course (DOTS) strategy to control TB, with an important rise in rates of cure.6–8 Improving case detection rates has proven more difficult, largely because of limitations of existing diagnostic technologies. As many as 3 million cases of TB each year present as sputum smear-negative pulmonary disease and extrapulmonary disease, for which sputum smear microscopy is inadequate. As an indicator of the difficulty of implementing quality microscopy services, fewer than 45% of predicted incident smear-positive cases of TB are currently detected and notified (Fig. 73.1B). Paediatric TB and MDR- and XDR-TB pose additional diagnostic challenges not addressed by sputum-smear microscopy. Diagnostics need to be driven by the reality of health systems infrastructure (Fig. 73.2); well-engineered, simplified tests are needed at the point of care, at district hospital laboratories and at central laboratories (Fig. 73.3).4,5 Different diagnostic strategies – including sputum concentration methods, fluorescence microscopy, improved mycobacterial culture system – also need to be evaluated for their impact on case detection. Diagnostic algorithms, including the use of empiric antibiotic trials to exclude TB, need to be carefully reassessed and improved. Implementation research can also assess the potential of integrating health services at district and healthcare

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2002

2001

2000

1999

Year

1989

Rate per 100,000 population

0

1988

0

1987

25

1986

B

50

1985

A

50

1984

2.2 other

75

100

1983

2.7 other

Global case notification rate

150

1982

Not notified 4.7 million

100

Countries

1981

2.0 smear positives

Notified to public health authorities: 4.1 million

1.9 smear positives

Global case notification rate for smear-positive pulmonary TB is not improved by DOTS expansion alone

1980

Global caseload of new TB cases stratified by smear and notification status

Number of countries implementing DOTS

200

Fig. 73.1 Global case notification rates. (A) Despite geographic extension of the DOTS programme the gap between notified and estimated numbers of TB cases, an astounding 4.4. million cases, has not narrowed significantly over the past several years. (B) Inadequate case detection is a major constraint on TB control. Table 73.1 Tuberculosis research priorities Research priority area

Specific activities

1. Improved diagnostics for TB











2. Improved clinical management of TB in HIV-infected and -uninfected individuals a. New drug research b. New immunotherapeutics research c. More effective shortened drug treatment regimens d. More effective drug and adjunct therapeutics regimens e. Optimal treatment strategies for MDR- and XDRTB f. Safer and more effective highly active antiretroviral therapy (HAART)/anti-TB treatments g. Validated markers of TB disease activity




3. Immunopathogenesis, and vaccine studies






























4. Improved programme performance and capacity building














Improving and evaluating existing diagnostic tools Developing and evaluating new diagnostic tools (e.g. an inexpensive, rapid, simple, accurate, practical point-of-care test useful in HIV-associated and drug-resistant TB) Developing tools/markers for monitoring disease activity, cure and relapse Developing tools that predict which subjects with latent infection will progress to active disease Strengthening research capacity and operational research Establishing and maintaining research resources for sustained activities in this field Facilitating new TB drug research and development Enhancing clinical trials site capacity for evaluating new drugs, diagnostics and vaccines Building evidence base for country adoption of new, more effective and shortened drug treatment regimens Optimizing existing treatment strategies for different categories of TB (special populations of TB patients: HIV-infected TB, M(X)DR-TB, paediatric, pregnancy) Optimizing timing of HAART therapy relative to anti-TB treatment or developing newer and safer treatment regimens for use with HAART Developing newer adjunct immunotherapies for improved outcomes for treatment failures, MDR-TB and XDR-TB Developing and validating surrogate endpoints and biomarkers to shorten clinical trials Evaluating the potential of simulation mathematical models for efficacy and costs of new interventions to better inform clinical trials of investigational new drugs Identifying immune correlates of protection to facilitate vaccine and immunotherapy studies Investigating and utilizing new information on the immunopathogenesis of Mycobacterium tuberculosis infection (latency, dormancy, reactivation) to inform new interventions for improved TB control Developing approaches to detect and manage immune reconstitution inflammatory syndrome (IRIS) and antiretroviral (ARV)/TB drug interactions Investigating and documenting geographic diversity of pre-existing immune status of the vaccine target population through target-country vaccine preparatory studies Improved delivery of care including DOTS Individual and institutional capacity building in the least developed countries including improving national TB programme (NTP) management Integration of TB and HIV/acquired immunodeficiency virus (AIDS) treatment strategies Linking research with national TB programmes and coordination of TB/HIV research Inclusion of basic social, economic and behavioural research in national programmes Development and evaluation of alternative TB care delivery strategies Improved case finding in vulnerable populations and access to care Focusing on partnership with local, regional and international organizations Identifying determinants and reduction of risk and vulnerability to TB (Continued)

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Table 73.1 Tuberculosis research priorities—(cont’d) Research priority area

Specific activities

5. Social, economic and behavioural research and the Global TB Agenda






Addressing impact of poverty on health-seeking behaviour Determining effects of gender inequality on disease severity and case detection Identifying impact of community factors on health services and DOTS programmes

6. Operational and implementation research

Developing practical solutions to common and critical issues in implementation of TB-related interventions by:
Improving organization and management
Building a close collaboration between researchers, national TB control and HIV/AIDS programmes, Ministry of Health and others.
Engaging all healthcare providers
Empowering patients and communities
Generating political will and commitment
Improving human resources
Promoting (demand for) research
Evaluating adherence support strategies
Defining the macro- and micro-TB epidemiology

7. Epidemiological research in national TB programmes

















Lower diagnostic priority

• All forms of active TB disease • Detection of multidrug-resistant TB • Latent infection in high-risk groups Targeted at detecting and treating people with any form of tuberculosis (active or latent), with attention paid to: i) High-prevalence groups : socially marginalized/ people born in high-prevalence countries and ii) High-risk groups : HIV infected/close contacts of an active case/immunocompromised/ children under 5 years

• Latent infection in lower risk groups Identification of individuals found to be infected, or likely to be infected, including recent tuberculin skin test converters and individuals with certain medical conditions (diabetes, kidney failure)

Developed country

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Developing country • Low income • High prevalence • Goal: identify and treat cases • Pulmonary tuberculosis highly contagious patients Target the reservoir of highly contagious patients to intercept transmission by early diagnosis and treatment

• Pulmonary tuberculosis: less contagious patients (pulmonary smear negative) • TB in other organs (extrapulmonary TB) • Latent infection: surveillance purposes • Multidrug-resistant TB: surveillance purposes

Developing country

Higher diagnostic priority

Higher diagnostic priority

Developed country • High income • Low prevalence • Goal: elimination of TB

MDR- and XDR-TB (management and cost-effectiveness) Paediatric TB (new diagnostics, therapeutics and revised diagnostic algorithms) Regulatory issues (product registration) Biological banks (creation and monitoring) Ethics of research in developing countries

Lower diagnostic priority

8. Cross-cutting issues

Impact of early diagnosis on TB transmission Time to occurrence of TB disease after contracting HIV infection Development of systems to disaggregate NTP data for use in studying local and hard to reach populations Development of new diagnostic tools for identifying latent TB infection and conducting TB prevalence surveys Determinants of risk, poverty, gender and community factors

Fig. 73.2 Diagnostic priorities in high- and low-burden countries. Resource limitations in developing countries preclude the use of several diagnostic tests (liquid culture systems, nucleic acid amplification platforms, interferon (IFN)-g release assays, rapid tests for drug resistance, etc.). Here, the sputum smear is the backbone of TB diagnosis; fortunately, this century-old technique detects the most infectious patients, and, hence, those in most need of treatment. By contrast, in developed countries, where the goal is elimination of TB, identification and treatment of latent TB infection has assumed increasing importance.

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Types of testing • Surveillance • Reference methods • Network supervision • Resolution testing (current test: culture, drug susceptibility)

Health system levels

Fraction of patients seen at given level 5%

National reference laboratory Referral laboratory

Table 73.2 Priorities for tuberculosis diagnostics tool development Need for diagnostic tool

Type of TB disease to be detected

Case detection






10%




Drug susceptibility testing






Microscopy centre

• Screening • Primary care (current test: none)

Peripheral health clinic

25%




Latent TB infection





60%

Fig. 73.3 Tuberculosis diagnostic testing at different levels of the health system. In the public sector the laboratory capacity to perform different types of testing can usefully be divided into levels of the healthcare system. At the top of the pyramid is the national reference laboratory (sophisticated and limited in number but the percentage of TB cases diagnosed at this level is small), while the base comprises TB referral laboratories at district or regional level (provides resolution testing for patients not detected by screening methods at more peripheral clinics or laboratories; the latter are largest in number and diagnose the largest burden of disease).

centre levels as a means of overcoming infrastructural and manpower impediments to operating case detection services. Key factors to study include transportation, user fees, hunger, work and gender discrimination, and other barriers to accessing care. Better clinical diagnostic algorithms and case definitions are required for diagnosing TB in HIV-infected individuals and children. Thus, precisely in the areas of the world where TB microscopy has the poorest performance, the need for new early detection tests is the greatest. Current TB diagnostics research priorities include: 1. replacing or improving microscopy with a simpler technology for detecting smear-positive TB; 2. developing a faster alternative to culture for detecting smearnegative TB; 3. developing and evaluating tests for rapid antibiotic susceptibility testing; and 4. developing tests for detecting latent infection at risk for relapse. The priorities for developing more accurate and rapid tests for TB case detection, drug susceptibility testing and detection of latency are listed in the Table 73.2,4 in roughly rank order of importance to global TB control. To facilitate the relevant commercial activity, WHO, and later its Special Programme for Research and Training in Tropical Diseases (WHO-TDR), established an enabling infrastructure for industry that included banks of reference materials, diagnostic trial sites and market research. Subsequently, the Foundation for Innovative New Diagnostics (FIND), an independent non-profit foundation, was established to work in contractual partnership with industry and academic groups, acting as an engine to drive the development of new diagnostic technologies. Launched at the World Health Assembly in 2003 with initial funding from the Bill

and Melinda Gates Foundation, FIND works with WHO-TDR and other public sector agencies to fulfil its mission to accelerate the development, evaluation and appropriate use of high-quality yet affordable diagnostic tools for infectious diseases in developing countries. More detailed information about the emerging technologies is available on the FIND website (http://www.finddiagnostics. org). A major challenge in TB control is the diagnosis and treatment of latent TB infection. Until recently, there were no alternatives to the tuberculin skin test (TST) for diagnosing latent TB. However, an alternative has now emerged in the form of a new in vitro test: the interferon-g (IFN-g) assay.6–8 A systematic review for assessing the performance of IFN-g assays in the immunodiagnosis of TB was performed by Pai et al.8 Current evidence suggests that IFN-g assays based on cocktails of RD1 antigens have the potential to become useful diagnostic tools. Whether this potential can be realized in practice remains to be confirmed in well-designed, long-term studies. IFN-g release assay-specific research priorities,

Serology

Ease of use

• Passive case finding (current test: microscopy) • Detect and treat

Pulmonary TB with high bacterial load Pulmonary TB with low bacterial load Extrapulmonary and paediatric TB Paediatric TB MDR-TB for treatment MDR-TB for surveillance XDR-TB for treatment XDR-TB for surveillance Latent TB for treatment Latent TB for surveillance

Microscopy

Desired

X-ray Culture

NAAT

Performance 1. Performance is a compilation of sensitivity, specificity and speed. 2. Ease of use is a compilation of safety, number of steps, cost, robustness and training simplicity

Fig. 73.4 There are drawbacks and advantages of each existing diagnostic modality. Unfortunately, however, no test that can meet target specification (a simple easy-to-use test with high-performance outcome) is currently available. Several new tests in development, e.g. urine antigen detection or lateral flow immunoassays, have potential to meet these requirements.

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for improving the utility and interpretation of the assay, are outlined in a document summarizing the views of experts in the field.7 Good performance of diagnostic tests under trial conditions does not always translate into effectiveness after implementation. Demonstration projects are needed to evaluate the feasibility, impact and cost-effectiveness of new diagnostic interventions after scale-up in national control programmes. The outcome of these projects should provide evidence for policy, so that useful technologies can be rapidly adopted, and impractical or ineffective technologies improved or dropped. These tests that would have the greatest impact on TB control, point-of-care tests, are in early development. New diagnostics that increase the sensitivity or simplicity of diagnosing active disease are in later development. There are advantages and limitations of each diagnostic method and no test yet available meets the target specification (Fig. 73.4). Rapid implementation of proven new technologies will also be critical to meet the urgent public health need and TB control targets.

RESEARCH PRIORITIES FOR IMPROVED CLINICAL MANAGEMENT OF TUBERCULOSIS IN HIV-UNINFECTED AND -INFECTED INDIVIDUALS Table 73.3 depicts research topics of importance on improving clinical management of TB that require further study.

OPTIMIZING CURRENT TREATMENT OUTCOMES: IMPROVING CLINICAL MANAGEMENT OF TUBERCULOSIS IN HIV-INFECTED AND -UNINFECTED INDIVIDUALS The increasing numbers of new TB cases each year is attributable largely to HIV infection.9 Currently available short-course chemotherapy still requires 6 months of drug adherence with suboptimal toxicity profiles. Treatment failures do occur in drug-susceptible

Table 73.3 Research topics for improving clinical management of tuberculosis Item

Research topic

Treatment simplification and monitoring: more effective treatment with shorter duration therapy and more effective treatment for MDR/XDR-TB 1 a. Development and evaluation of efficacy of newer drugs for TB treatment b. Evaluation of newer drug regimens for shortening TB treatment from 6 to 4 months c. Evaluation of newer drug regimens for the treatment of MDR- and XDR-TB d. Development and evaluation of immunotherapies as adjunct treatment for MDR- and XDR-TB and TB treatment failures 2 Assessment of the efficacy and safety of fixed-dose versus ‘loose’ anti-TB medications in improving treatment compliance 3 Biomarkers/surrogate markers: a. Identification and evaluation of specific biomarkers and surrogate markers of disease activity in HIV-infected and -uninfected patients with active TB b. Evaluation of markers to monitor disease activity, cure, relapse and latency Treatment of TB/HIV coinfection 4 Evaluation of optimal treatment initiation (timing, dosing, specific drugs) of HAART, in randomized controlled trials, for TB/HIV coinfected patients 5 Evaluation of optimal duration of treatment using existing regimens for pulmonary and extrapulmonary TB in HIV-infected people 6 Pharmacokinetic and pharmacodynamic studies of treatment regimens in TB/HIV coinfected patients 7 Evaluation of optimal protocols for isoniazid preventive treatment, or alternative regimens, in HIV-infected people with latent TB infection 8 Evaluation of optimal protocols for cotrimoxazole treatment in TB/HIV coinfection 9 Development and validation of case definitions for immune reconstitution inflammatory syndrome (IRIS) in TB/HIV coinfected patients under ARV treatment 10 Epidemiological studies of IRIS in TB/HIV coinfected patients under ARV treatment 11 IRIS in TB/HIV coinfected patients under ARV treatment 12 Evaluation of clinical management strategies of IRIS in TB/HIV coinfected patients under ARV treatment Diagnosis of MDR- and XDR-TB 16 What is the optimal diagnostic algorithm for persons with suspected MDR- and XDR-TB? 17 Development and evaluation of rapid tests for drug resistance 18 What is the role of rapid rifampicin resistance tests in the management and control of MDR- and XDR-TB? Treatment of paediatric TB 19 Evaluation of safety and efficacy of current drug formulations in paediatric TB infection What is the optimal diagnostic algorithm for children with suspected TB? Can nucleic acid amplification tests (NAATs), IFN-g and urine DNA tests be utilized together to improve the diagnostic sensitivity for TB in children? All studies mentioned for adults apply to children as well Patient support strategies 20 Assessment of effectiveness of patient ‘treatment literacy’ programmes prior to treatment initiation 21 Evaluation of impact of DOTS and other adherence support strategies (including site-based vs community-based support, frequency and duration of support interventions) on treatment outcomes 22 Evaluation of impact of DOTS and other adherence support strategies on treatment outcomes in TB/HIV coinfection Implementation research: health systems and operations 23 How can the uptake of proven new diagnostic tests be accelerated in both public and private settings? 24 What measures will be helpful in shortening the duration of TB work-up (diagnostic pathway) and the number of consultation visits before a diagnosis is made? 25 How can laboratory workload be reduced, and communication of test results and quality improved in high-burden countries?

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TB due to poor patient compliance, drug availability and side effects among others. The need for shorter courses of anti-TB therapy is obvious. In HIV-infected individuals with active TB, drug interactions between anti-mycobacterial drugs and antiretroviral drugs for HIV treatment represent a major new challenge,10,11 and there is no proven, simple regimen for simultaneous treatment. How can current treatment outcomes be optimized to minimize morbidity and mortality rates from TB? Priorities for research to improve clinical management of TB include: a. new anti-TB drug research; b. new immunotherapeutics research leading to products that can be used as adjuncts to drug therapy; c. more effective shortened drug treatment regimens; d. more effective drugs with adjunct therapeutics regimens; e. optimal strategies for treatment failures and MDR- and XDR-TB with newer drug combinations or with drugs and adjunct immunotherapy; f. safer and more effective highly active antiretroviral therapy (HAART)/anti-TB treatments; and g. monitoring disease and relapse by developing accurate markers of TB disease activity.

RESEARCH AND DEVELOPMENT OF NEWER ANTITUBERCULOSIS DRUGS The current efforts at developing and evaluating new anti-TB drugs are discussed in Chapter 59. Waksman’s discovery of streptomycin in 1940 was the beginning of the modern era of anti-TB treatment. Following the successful application of multidrug therapy, the death rate from TB dropped rapidly in settings where diagnosis and treatment were available. Tuberculosis sanatoria closed. Research into developing new drugs, diagnostics and vaccines then stagnated. Despite early success, treatment costs, treatment duration and poor implementation prevented TB-infected people living in conditions of widespread poverty benefiting from multidrug treatment. No new classes of TB drugs were developed for 40 years. This complacency is now reflected by 1.8 million deaths from TB each year, evoking a renaissance of interest over the past decade, which is leading to several new compounds being made available for potential use in the treatment of TB and for shortening treatment regimens. The usefulness and effectiveness of new anti-TB drugs needs to be carefully reviewed – meta-analyses of prior trials and of new trials based on reasonable expectations of benefit and well-defined endpoints. The challenges of HIV coinfection, poor case detection, poor adherence and the reduced capacity of health systems to cope with the increasing burden of TB necessitate new drugs and adjunct immunotherapies with novel modes of action.12–15 The strategic treatment goals include shortening and simplification of TB treatment regimens, improved treatment outcome for MDR- and XDR-TB and management of TB/HIV coinfection with drugs which can be safely co-administered with antiretroviral drugs. For diagnostic, drug and vaccine development to succeed, a series of enabling factors must be in place. Studies must conform to international standards of quality. Pivotal trials will require a well-resourced infrastructure, including adequately trained staff; current clinical trial capabilities are insufficient to absorb all of the products in pre-clinical and clinical phases of development. This points to the need to strengthen research capacities in high-burden countries. Several efforts at capacity development in high-TB-burden countries are

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currently underway, funded by institutions supported by the European Commission, DFID, Gates Foundation and the National Institutes of Health (NIH).

TREATMENT SIMPLIFICATION EFFORTS Poor compliance, especially among HIV-infected TB cases, is primarily due to an increased rate of adverse drug events, length of treatment and pill burden for TB treatment.11,16–18 Two important research streams are exploring the feasibility of shortening TB treatment from 6 to 4 months through the use of gatifloxacin or moxifloxacin,13,14 as well as assessing the efficacy and safety of currently recommended fixed-dose combination therapy versus ‘loose’ anti-TB medications in improving treatment compliance among HIV-uninfected and -infected TB cases. In addition, the work builds institutional and research capacity within national control programmes for TB clinical trials in the conduct of such research.

DEVELOPMENT AND EVALUATION OF IMMUNOMODULATORS FOR ADJUNCT THERAPY OF TUBERCULOSIS Given the relative lack of new drugs for TB treatment and long (6 months) duration of current standard short-course chemotherapy, other investigators have pursued the development of other therapeutic vaccines or immunotherapeutic agents that could boost the host immune response, and enhance bacillary clearance leading to improved treatment outcomes and possibly the shortening of the required duration of treatment. There are several potential roles for immunotherapy in TB treatment in this context.

Containing bacillary replication and preventing emergence of resistance Therapeutic options for patients with MDR-TB are limited at present; adjunctive immunotherapy in combination with secondline drugs would be welcome in this setting. Ameliorating symptoms Tuberculosis is characterized by tissue necrosis and fibrocavitary disease with loss of functioning lung tissue. Adjunctive immunotherapy that could decrease host inflammation and decrease tissue necrosis and fibrosis, which lead to significant morbidity and mortality in patients with severe pulmonary TB, would be beneficial. Preventing deleterious immune activation in TB/HIV coinfection In HIV coinfection, an additional role of immunotherapy might be to modulate a host immune response that otherwise promotes T-cell activation and HIV expression. Eliminating persisters The development of new treatments capable of shortening TB treatment is a major objective of TB drug discovery.19–22 Immunotherapy that could enhance host responses against slowly replicating persistent tubercle bacilli, a subpopulation not effectively targeted by current therapy, could potentially shorten the required duration of TB treatment and decrease the risk of relapse. Alternatively, if host responses cannot effectively eradicate these persisting bacilli, but instead create the conditions leading to persistence, immunotherapy directed against the granulomatous host response might accelerate the response to treatment by increasing drug bioavailability and enhancing microbial susceptibility.

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Cytokine regulation of macrophage activation Tumour necrosis factor (TNF), IFN-g, interleukin (IL)-12, CD4 and CD8 cytokines act in an autocrine fashion to limit intracellular mycobacterial growth. Macrophage activation for killing intracellular M. tuberculosis is enhanced by interaction with antigen-specific T cells and local production of IFN-g. Nitric oxide (NO), the production of which is induced by IFN-g, is thought to be an important anti-mycobacterial effector mechanism of activated macrophages in both mice and humans. Other products of activated macrophages, including superoxide, IL-6 and calcitriol (1,25-dihydroxy-vitamin D3), also restrict intracellular mycobacterial growth. Administration of endogenous IFN-g or IL-2 and other agents have been investigated for their role in augmenting host cellmediated immune (CMI) responses in active TB, improving or accelerating clearance of tubercle bacilli and improving clinical outcomes. A substantial body of evidence indicates that the response to therapy in drug-sensitive disease may be accelerated, and treatment potentially shortened, by anti-granuloma strategies targeted at eliminating dormancy. Immunomodulators such as corticosteroids,23 HSP65DNA, transforming growth factor (TGF)-b inhibitors, HE2000, IL-4 inhibitors, intravenous immunoglobulin, rHuIFNg, and other drugs and biologicals have the potential to shorten TB treatment by modulating the host response, and helping the immune system eliminate persistent organisms. Immunotherapy is a novel approach to treatment shortening. Strategies studied to date in mouse models have been found to reduce the T-helper (Th)-2 inhibitory effect on the protective Th-1 response, either by inhibiting IL-4 production or by downregulating the Th-2 response.24,25 In animal models, impressive treatment shortening times have been observed, and further human testing under appropriate study designs is warranted.22 In addition to treatment shortening described above, treatment outcomes might be improved by using immunomodulators as adjunctive therapies to existing regimens in all groups of TB patients including those with MDR- and XDR-TB. The current understanding of severe TB is that the host inflammatory response induces pathology that contributes to mortality.25 The use of novel immunomodulators or adjunctive corticosteroids could downregulate this response. Adjunctive corticosteroids are widely used and have been shown to be beneficial in selected severe forms of TB. The level of evidence is incomplete in other forms of TB,23 and limited for HIV coinfected patients. Additional studies are warranted. Several claims have been made of immunomodulators which could shift Th-2 responses to Th-1. When subject to scrutiny through testing under randomized clinical trials, the mistletoe extract, South African potato and a single dose of a killed preparation of Mycobacterium vaccae did not do better than placebo. Newer immunomodulators, including multiple-dose M. vaccae and M.w, require evaluation through phase 1, 2 and 3 studies. The findings of the DAR study (published in extract form at the time of writing) are encouraging. RESEARCH ON DEVELOPMENT AND EVALUATION OF BIOMARKERS OF DISEASE Currently there are no practical accurate clinical, biochemical, immunological or molecular markers of TB disease activity, TB cure or TB relapse. The determination of a consistent global host immune response, or ‘immunological marker’, reflective of active TB has the potential to evolve into a useful tool for monitoring infection, disease activity, cure and relapse.

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The response to infection with M. tuberculosis in humans is multifactorial and includes pathogen factors, environmental factors, genetically determined host factors and immune host factors involved in innate and adaptive immune responses. These determine the change from latent to active or reactivated TB:


Microbial markers: key indicators of outcome: culture and early bactericidal activity, colony-forming units, mycobacterial acid-fast bacilli load; and ○ qualitative/quantitative assays for mycobacterial DNA (67bpDNA), RNA, peptides (Ag85), glycolipids (LAM).
Host markers: chemotherapy results in downregulation of protective mechanisms: ○ inflammatory/activation biomarkers, chemokines (e.g. MIF), apoptosis mediators, serological markers; ○ cytokines associated with protection or pathogenesis (e.g. IL-12, IFN-g, TFN, IL-4 and IL-4d2); and ○ antibodies to microbial antigens. Early bactericidal activity in sputum by colony counts and mycobacterial DNA detection are two biomarkers currently being studied. A major challenge to drug, immunotherapeutic and vaccine development is the length of time for assessment of efficacy through dependence on long-term clinical outcomes. New biomarkers of treatment success or failure would provide useful surrogates in newer drug regimen trials, adjunct immunotherapy studies and vaccine studies, reducing costs, and decreasing the long development timeline.26–31 Particularly important will be surrogate biomarkers that can reduce the 2-year follow-up currently used to monitor relapse. ○

ANTIRETROVIRAL AND ANTITUBERCULOSIS THERAPY FOR PEOPLE LIVING WITH HIV/AIDS WHO HAVE TUBERCULOSIS Tuberculosis/HIV treatment is far from being a reality for people living with HIV/acquired immunodeficiency syndrome (AIDS) who have TB or develop TB while on antiretroviral therapy.10,11 Clear recommendations on the best-informed practice is needed. Given that limited data are available, there is a need to move from evidence-based individual clinical interventions to a public health approach that will be informed by emerging evidence. 1. Validating the optimal time to start antiretroviral therapy among people living with HIV/AIDS who have active TB (to improve efficacy and decrease toxicity). The frequent coexistence of TB and HIV, varying from about 35% to 70% in sub-Saharan Africa,32 implies the need to manage both diseases simultaneously. Managing TB alone in the absence of HIV treatment is associated with an increase in mortality during the treatment duration for TB. No prospective controlled study has examined the optimal timing of antiretroviral therapy after TB treatment is initiated. The decision about when to initiate antiretroviral therapy among people living with HIV/AIDS and TB must balance the risk of HIV disease progression, morbidity and mortality with the potential risk of drug toxicity and adverse events, including immune reconstitution inflammatory syndrome (IRIS) stratified by the stage of HIV disease. 2. Determining the best antiretroviral therapy regimens, with dose adjustment when required, to use with TB treatment regimens. Some evidence on the pharmacokinetics of efavirenz and nevirapine when co-administered with rifampicin-containing regimens is available. Additional studies to determine the

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clinical efficacy and safety profile of regimens containing efavirenz and nevirapine, to determine proper doses in the presence of rifampicin and to identify the best methods of monitoring them are needed. 3. Determining the efficacy and safety profile of alternative antiretroviral therapy regimens. Drug development should be an area of focus for research on effectively treating people living with HIV/AIDS who have TB in resource-constrained settings. In particular, the development of fixed-dose combinations of antiretroviral drugs (mainly efavirenz-containing fixed-dose combinations) for people with TB should also be pursued. Replacing rifampicin with rifabutin should also be considered. 4. Developing the best clinical definition for IRIS for use in resource-constrained settings (validation studies). Clinical data currently available are based on different definitions of IRIS. There is an urgent need to standardize the definition and to identify the risk factors and predictors for IRIS. Clear and standardized guidance on how to prevent and/or treat an episode of IRIS is essential. 5. Determining the cost-effectiveness of different regimens and strategies. 6. Determining the minimal requirements for clinical and laboratory monitoring for outcomes related to efficacy and safety. 7. Determining the best strategies (including DOTS) for measuring and enhancing adherence for people receiving TB therapy and antiretroviral therapy. For all these issues, consideration of special populations, including their co-morbidity and unique characteristics, is encouraged.

DIAGNOSIS AND TREATMENT OF PAEDIATRIC TUBERCULOSIS INFECTION Paediatric TB is a growing problem in developing countries.33 There is a clear gap in research for the paediatric population. All issues identified as priority research items for adults also remain a research element for children. Children rarely have sputum smearpositive TB, and diagnosing TB in children is difficult. Although a good TB control programme is the best way to prevent TB in children, studies are urgently needed to improve diagnosis of TB (both extrapulmonary and pulmonary) in children. The best way and models to integrate this revised algorithm into the WHO Practical Approach to Lung Health (PAL) and Integrated Management of Adult and Adolescent Illness (IMAI) strategies need to be explored. Many of the priorities for TB research in adult populations are applicable to children. There is a clear need for evidence of efficacy/safety of drug formulations in use, a need for information on paediatric pharmacokinetics in different epidemiological contexts and a need to focus on the special challenges of diagnosing TB in children:









treatment guidelines for MDR- and XDR-TB in children; the need for improved diagnostic methods for detecting active disease among infants and children; this requires investigating T-cell IFN-g assays and markers of disease activity in early detection of active disease; delineation and validation of clinical and laboratory diagnostic algorithms in children; the role of cotrimoxazole or other antibiotic treatment and prophylaxis in HIV-infected children with TB, including




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efficacy, incidence of side effects and how to manage complications in children; and establishment of clear guidelines for the use of anti-TB treatment with antiretrovirals in HIV-infected children with active TB.

IMMUNOPATHOGENESIS AND VACCINE STUDIES Mycobacterium tuberculosis is a successful pathogen that overcomes numerous challenges presented by the immune system of the host.19,20 This bacterium usually establishes a chronic infection in the host where it may silently persist until a failure in host defences leads to manifestation of the disease. None of the conventional anti-TB drugs are able to target these persisting bacilli. Development of drugs against such persisting bacilli is a constant challenge since the physiology of these dormant bacteria is still not understood at the molecular level.20 Some evidence suggests that the in vivo environment encountered by the persisting bacteria is anoxic and nutritionally starved. Based on these assumptions, anaerobic and starved cultures are used as models to study the molecular basis of dormancy. Research into the study of mycobacterial latency and dormancy is crucial for designing new drug treatment for latency and development of new TB vaccines.22–24 Now entering its ninth decade of use, Bacillus Calmette–Gue´rin (BCG) remains the only available vaccine against TB.25 The use of BCG to prevent TB, however, is limited to the prevention of severe paediatric disease; its efficacy against adult disease wanes in high-burden regions where TB protection is most needed. Nonetheless, with accelerating progress in deciphering the M. tuberculosis genome and proteome, and new insights into the immunopathogenesis of TB infection, significant progress has been made in TB vaccine development over the past 5 years. Several approaches to TB vaccine development have been made:24,25 1.‘Improved’ BCG: e.g. overexpression of protective antigens (AGs), or reconstitution of deleted genes. 2. Attenuated M. tuberculosis: targeted inactivation (‘knock-out’) of metabolic or virulence genes. 3. Adjuvanted protein subunit vaccines (also peptides or DNA vaccines): a. Hypothesis-driven selection: e.g. secreted AGs; and b. Empirical selection: e.g. T/B-cell recognition and/or major histocompatibility complex (MHC) binding, combination of AGs. 4. Other approaches: presentation of live-vectored AGs, e.g. vaccinia (MVP), adenovirus, Salmonella, or non-protein AGs, e.g. gd TCR or CD1-binding molecules; conjugates, etc. As of late 2005 at least five vaccine candidates are in phase I clinical trials (rBCG30; rBCG: D ureC-lloþ; MVA-85A; Ag85BESAT-6; Mtb72f);35 and several more candidates are in pre-clinical development. Many current vaccine candidates are based on modifications to BCG; yet our understanding of the immunobiology underlying BCG’s ineffectiveness remains incomplete.34 The understanding of the distinction between protective immune responses and immunopathology, though improving, remains blurred.35 In vaccine evaluation, study design is impeded by the lack of known immune correlates of protection against TB infection. Thus dependence on immunological endpoints for interpretation of vaccine efficacy is not reliable and difficult to interpret, whereas use of clinical endpoints delays assessment of vaccine efficacy – requiring several years and/or tens of thousands of

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subjects. Collectively, these gaps in knowledge make the design of vaccine assessment strategies difficult. The need for both pre-exposure vaccination (or ‘prime’ strategies) and post-exposure (or ‘boost’ strategies) is widely accepted, but the specific timing and vaccine component design remains to be established. Evaluation of vaccine candidates will require a transition through a series of clinical trials of increasing size, complexity and cost to progressively evaluate their safety, immunogenicity and eventual efficacy. Despite considerable progress, there is a need to expand discovery and translational research on vaccines. The early success of current clinical candidates does not signal an end of discovery research, but rather provides novel opportunities to link fundamental research to human studies.

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS) INDUCED BY ANTIRETROVIRAL TREATMENT The clinical picture of HAART in HIV-infected patients restores protective immune responses against a wide variety of pathogens and dramatically decreases mortality.11,17 In a subset of patients receiving HAART, immune reconstitution is associated with a pathological inflammatory response leading to substantial shortterm morbidity and even mortality. Some patients with HIV/TB coinfection who are on anti-TB treatment and HAART will also develop an exacerbation of symptoms, signs or radiological manifestations of TB not due to relapse or recurrence of their TB, or another opportunistic infection. This subject needs to be defined and appropriate treatments and markers of disease activity determined.

WHO’s Interim Policy on Collaborative TB/HIV Activities11 suggests specific activities to address the dual epidemic including: 1. the establishment of mechanisms for collaboration; 2. the decrease of burden of TB among people living with HIV/ AIDS – through earlier detection of active TB through intensified case-finding, provision of isoniazid preventive therapy (IPT) for coinfected patients, and ensuring TB infection control in healthcare and congregate settings; 3. the decrease of burden of HIV among TB patients – through provision of voluntary counselling and testing for people at risk of HIV, introducing HIV prevention methods and cotrimoxazole preventive therapy, ensuring HIV/AIDS care and support and introducing antiretroviral therapy; and 4. the improvement of care for people infected with both TB and HIV – through cross-training and collaborative care initiatives.

PATIENT SUPPORT FOR STANDARDIZED TREATMENT Adherence to therapy remains a central issue in determining therapeutic effectiveness of TB treatment. There is a well-recognized need to evaluate ways for broadening DOTS to include more effective strategies for providing adherence support. Examples include evaluation of:










IMPROVING PROGRAMME PERFORMANCE AND CAPACITY BUILDING: COORDINATION OF TUBERCULOSIS AND HIV/AIDS PROGRAMMES The increasing number of new TB cases each year – especially those propelled by the 5–10% annual increase in TB incidence in sub-Saharan Africa – is attributable largely to HIV infection. Coinfection rates in TB-infected patients in some countries are as high as 70%.11 The HIV epidemic is not merely increasing TB but also driving a significant increase in the proportion of TB cases that are smear-negative pulmonary and extrapulmonary disease; these presentations of TB pose considerable challenges to currently available diagnostic methods and to clinical management. Even when diagnosed, HIV-infected, smear-negative pulmonary TB patients have inferior treatment outcomes, including excessive early mortality.16 It is now widely recognized that collaboration between TB and HIV/AIDS disease programmes to provide patient-centred, integrated care and services is essential to controlling the TB epidemic.11 Collaboration between TB and HIV programmes is, however, hindered by a history of independent structures and functions in established national TB programmes and newly established HIV programmes, by the differential funding and by the inadequacies of primary care and general health systems on which to build integrated care in many countries. In responding to the challenge of the synergistic HIV/TB pandemic, a key strategic objective of the Second Global Plan to Stop TB (2006–2015) is to scale up implementation of collaborative TB/HIV activities in all countries with a high burden of TB/HIV.

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patient ‘treatment literacy’ preparation before initiation of therapy; adherence support provision by healthcare workers and/or community or family members; the most effective frequency and intensity of adherence support; combinations of these interventions; and assessment of the most effective method of supporting adherence in HIV/TB patients receiving ARV therapy. For example, does the co-administration of TB and HIV therapies require different or expanded adherence support strategies compared with TB or HIV alone?

For these studies outcome measures should include both standardized and validated measures of adherence as well as biological and clinical measures for TB (sputum conversion, treatment completion, case-holding, relapse, resistance, etc.) and adherence and biological and clinical outcomes for HIV (adherence assessment through standardized measures, viral load, clinical disease progression, mortality).

PREVENTIVE THERAPY FOR TUBERCULOSIS The following research priorities, which distinguish between population and individual levels, were also suggested by the WHO February 2005 meeting.3 At population level 1. Identify macro-level barriers to implementing isoniazid preventive therapy and mechanisms to overcome these barriers. 2. Evaluate the outcomes of a national isoniazid preventive therapy programme in Botswana: lessons learned. 3. Establish the effectiveness in special populations and regions with elevated isoniazid resistance. 4. Determine the optimal duration of isoniazid chemoprophylaxis, the optimal regime (including rifampicinbased regimes) and incorporation of these strategies, where appropriate, into HIV care programmes.

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At individual level 5. Develop the optimum algorithm to exclude TB disease. 6. Determine the added benefit of isoniazid preventive therapy among people receiving antiretroviral therapy. 7. Determine whether there are subgroups of people who are likely to benefit. 8. Determine effectiveness among infants and children.

COTRIMOXAZOLE PROPHYLAXIS FOR OPPORTUNISTIC INFECTIONS The routine use of cotrimoxazole in developing countries, especially sub-Saharan Africa, has been minimal despite provisional recommendations from WHO and UNAIDS that cotrimoxazole be given to everyone in Africa with HIV/AIDS, including those who have TB. The Interim Policy on Collaborative TB/HIV Activities promotes cotrimoxazole use among people living with HIV/AIDS who have TB.11

SOCIAL SCIENCE AND IMPLEMENTATION RESEARCH TOPICS IN CLINICAL MANAGEMENT OF TUBERCULOSIS Social science research for TB control refers to the contributions of the basic and applied social sciences to addressing fundamental social, economic and behavioural questions related to TB (Table 73.4). Social science questions arise in nearly every area of TB research and have been covered by other chapters in this book. They include questions such as identifying the constraints on healthseeking behaviour (constraints in accessing diagnosis and care); gender differentials in the epidemiology of the disease, in case detection and treatment success; and adherence issues related to treatment response, including the impact of user fees and treatment adherence support strategies. The central focus of social science research is on identifying the barriers to timely case detection, diagnosis and treatment in the context of poverty and social inequality, and enabling interventions that would reduce these constraints. Four key domains within which social science research on TB operates are identified:36–39 1. determinants of risk and vulnerability to TB; 2. impact of poverty on TB;38–41

Table 73.4 Social science and implementation research topics in clinical management of tuberculosis Implementation research: health systems and operations 1 Studies to define effectiveness of HIV case-finding in TB programmes, including availability and uptake of HIV testing. 2 Operations research studies (including mathematical and simulation models) of resource needs, delivery sites, care models, costs and impacts of TB/HIV programme integration. 3 Assessment of training needs and training effectiveness for HIV and TB treatment providers. 4 Development and validation of systems to generate, process and use pharmacovigilance data, and impact on treatment outcomes.

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3. effects of gender inequality on disease risk, disease severity and case detection; and 4. impact of community factors on TB control efforts.

OPERATIONAL AND IMPLEMENTATION RESEARCH Operational (or operations) research involves the use of advanced analytical techniques to solve optimization problems under conditions of uncertainty and constraints. Classic operational research has only recently been applied to public health problems. Applied to TB control, the research questions can be condensed to: how can TB interventions – case-finding, diagnosis and treatment – be optimized, given resource constraints (Table 73.5)? Operations research for TB control can greatly assist efforts to bring effective interventions to a greater number of people. As new tools are developed, operational research methods can also be used to guide implementation of new drug regimens, clinical trial design and vaccine trial design. Thus, the overall objective of this research is to significantly improve access to efficacious interventions against tropical diseases by developing practical solutions to common, critical problems in the implementation of these interventions.

Table 73.5 Research topics on access to care and case-finding Item number

Research topic

Case-finding 1 Which factors lead to delays in establishing a diagnosis of TB? Where are the missing cases? 2 Which factors contribute to the low global case detection rate (‘diagnostic gap’)? 3 What is the role of active case-finding, especially in hardto-reach populations and areas of high HIV prevalence? User fees 4 How do user fees affect access to care, case detection, diagnosis and treatment? Community-based research 5 How can community-based social research enhance the identification of the most vulnerable subgroups and define strategies to enrol them in quality TB care? Transportation and other opportunity costs 6 How significant are the barriers created by indirect costs of care, such as transportation costs, and what are the most effective strategies to remove the barriers they create? Case-finding and access to care in the private sector 7 What are the most effective ways for leveraging private sector capacity to achieve TB control goals? Diagnostics in support of case-finding 8 What are the implications of changing current symptombased and laboratory-based diagnostic algorithms for case-finding? 9 What is the sensitivity and specificity of various thresholds for chronic cough (e.g. 2 vs 3 weeks) as screening tests for TB? 10 What is the role of culture-based detection methods in case-finding?

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EPIDEMIOLOGICAL RESEARCH IN NATIONAL TUBERCULOSIS PROGRAMMES MACRO-EPIDEMIOLOGY OF TUBERCULOSIS Global prevalence of latent TB infection is estimated at 32% of the world’s population, some 1.86 billion people. The total number of new cases is estimated at 8.8 million per year, including 3.9 million cases of infectious pulmonary disease; point-prevalence estimates indicate more than 16 million cases of active disease. Eighty per cent of all incident cases of TB are found in 22 countries and more than half of the cases occur in five populous south-east Asian countries. Ten of the 15 countries with the highest per capita rates of smear-positive disease are located in Africa. The prevalence of TB/HIV coinfection world-wide is estimated at 0.18%; some 656,000 new TB cases were coinfected with HIV in 2003. An estimated 1.7 million people die of TB each year. The global case-fatality rate is 23%, but exceeds 50% in some African countries with high HIV burden.32 A number of questions in relation to the timing of diagnosis and its potential impact on TB transmission remain. At present, it remains unclear how early TB diagnosis needs to occur in order to prevent transmission in different patient populations such as people living with HIV/AIDS, infants and pregnant women. For comprehensive TB and HIV prevention, care and support, there is a compelling need for research on specific elements of the interaction between HIV infection and TB, along with a better understanding of the epidemiology of coinfection, including a definition on the timing of development of TB after HIV infection, and the effect of comorbidity on TB susceptibility.

CHALLENGES AND OPPORTUNITIES Increasing the quality of surveillance data will provide a more accurate picture of the epidemic, and illuminate the global impact of TB control efforts. There is a clear need to improve case notification reliability; however, it is recognized that, given current diagnostic limitations, certain active cases, notably smear-negative disease, will remain difficult to identify even in ideal circumstances. Accurate estimates of the TB burden in selected countries can be obtained from special surveys of the prevalence of disease and infection. Unfortunately, good surveys are scarce and there are not enough resources to obtain survey information on a global scale. In addition, countries where the rates of HIV/TB coinfection are high or TB incidence rates are in decline make survey information hard to interpret. An additional and promising element in TB epidemiology would be the ability to disaggregate data from national TB programmes. The further implementation of computerized databases at the district level promises to provide TB notification data that allow a closer, more detailed look at relevant local and district-level micro-epidemiology – including data on poor, vulnerable and hard-to-reach populations.

nutrition, coinfections (such as HIV/AIDS) and migration from or to higher risk communities. In addition, patients suffering from TB are less able to work and to generate income for themselves and their dependants. These factors pose significant additional economic hardships on patients and households, with a disproportionate impact on the poor, further limiting their access to care.36–39 Research questions which arise include the following:











What kind of financing schemes, including partnerships between the private and public sectors, can enhance development of technology, and patients’ access to TB diagnosis and treatment (Fig. 73.5)? What type of social and economic incentives for patients and DOTS workers can improve case-finding and adherence to therapy? How can health providers outside of the public health sector, including private practitioners and traditional healers, contribute to case detection and access to care? How can health providers outside of the public health sector, including private practitioners and traditional healers, contribute to clinical management?

EFFECTS OF GENDER ON DISEASE RISK, DISEASE SEVERITY AND CASE DETECTION Both women and men face gender-specific barriers to TB diagnosis and care. These barriers, which vary in different settings, require thorough assessment and evaluation to identify interventions that can reduce these barriers. Poor women with TB also tend to suffer from fear of rejection by their families and their community. It has been shown that the stigma of TB is often more pronounced among women than men. While men usually worry more about loss of wages and capacity for work, women worry most about social rejection – from husbands, in-laws and the community in general – if they have TB. Women in many countries must overcome several barriers before they can access healthcare. Where they undertake multiple roles in reproduction, production and childcare, they may be left with less time to reach diagnostic and curative services than men. Women may be given less priority for health needs and generally have less decision-making power over

Public sector

Private sector

• Needs-driven • Altruism • Partnership

• Financing • Market-driven • Manufacture • Product focus and distribution • IP management • Goal-directed R&D • Rigid targets/ milestones • Complex project • Marketing

1900

1950

Public–private partnership • Industry model • Needs-driven • Partnership

2000

Fig. 73.5 Evolution of technology development for diseases prevalent in

CROSS-CUTTING ISSUES IMPACT OF POVERTY ON TUBERCULOSIS While TB is not exclusively a disease of the poor, the association between poverty and TB is well established and widespread. Impoverished communities and social groups are at higher risk of infection with M. tuberculosis than are the general population because of overcrowded living or working conditions, poor

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developing countries. Poor understanding and perceived inaccessibility of TB-related treatment and diagnostics markets have limited private sector investment, and, thus, market forces have not delivered speedy development of new drugs or technologies. This shortcoming has inspired the growth of public–private partnerships, which are likely to change the way health products are developed and delivered to developing countries. Such partnerships, whilst driven by health needs in the global public interest, also benefit from a focused milestone-driven approach, intellectual property (IP) management and the manufacturing and distribution capacity of the commercial sector. R&D, research and development.

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the use of household resources. Research questions which arise include the following:











How do malnutrition and other comorbidities (such as malaria and HIV) relate to women’s and girls’ susceptibility to TB? In populations where women need to access healthcare accompanied by a man, what interventions would improve health-seeking for women? How can provider delays for women, men and children be reduced? What are the gender-specific barriers to TB diagnosis and care in different settings and how can they be translated into appropriate gender-sensitive interventions?

MULTIDRUG-RESISTANT TUBERCULOSIS MDR-TB is considered an important threat to TB control. Combating resistance is through application and strengthening of DOTS and appropriate treatment of resistant cases, DOTS-Plus. Globally, MDR-TB remains a locally severe problem. A three-pronged strategy for control of MDR-TB has been proposed by the Global Plan to STOP TB:1 1. widespread implementation of short-course chemotherapy; 2. improved resistance testing and surveillance; and 3. careful introduction of second-line drugs following proper evaluation, cost-effectiveness and feasibility. Research areas identified by the DOTS-Plus Working Group include: 1. ideal management of MDR-TB; 2. economic evaluation of DOTS-Plus; 3. transmissibility and fitness of MDR-TB strains; 4. effect of HIV epidemic on MDR-TB epidemic; 5. quality assurance of drug sensitivity testing on second-line agents; 6. resistance criteria for second-line drugs; 7. development of an early warning system for drug resistance; and 8. assessment of management strategies of MDR contacts and special populations, e.g. pregnant women, HIV-infected patients and children.

EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS On 1 September 2006 the WHO announced that a deadly new strain of extensively resistant M. tuberculosis had been detected in Tugela Ferry, a town in Kwazulu Natal, South Africa. It was resistant to rifampicin and isoniazid plus three other second-line agents. XDRTB is defined as MDR-TB (resistant to rifampicin and isoniazid) plus resistance to any fluoroquinolone, and to at least one of the following drugs: kanamycin, amikacin or capreomycin. XDR-TB is a serious threat to TB control, raising concerns of TB epidemics with severely restricted treatment options. Of 55 cases of XDR-TB 44 were tested for HIV and all of them were HIV-infected. The median survival time from sputum collection was 16 days! By December 2006, more than 500 cases were reported in South Africa.40 Treatment-related outcomes in high HIV prevalence settings such as South Africa may be poorer than in other settings.41 This now poses a very serious global threat and reflects a failure of the health system. Many research questions arise apart from those mentioned earlier under MDR-TB:




What is the extent of the problem? What factors fuelled the outbreak? Was the use of anti-TB drugs appropriate?












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Is DOTS applied effectively in the system? What is the micro- and macro-epidemiology of XDR-TB in South Africa, the region and the globe? What can be done to contain the spread of XDR-TB? How can the spread be monitored? What control measures can be instituted? What treatment regimens can be developed and used effectively? Should patients be forced to have supervised treatment?

ETHICAL ISSUES IN TUBERCULOSIS RESEARCH As the research community now moves away from ‘colonial parachute research’ and the concept of equal partnerships arises, focus is now on ethical issues governing these developed country partnerships. Performing the clinical trials of new drugs or interventions in Africa that if found effective, will not be affordable by countries in which research is performed highlights the ethical issues surrounding current clinical trials. A number of TB and TB/HIV research programme activities, especially in developing countries in the recent past, have fostered the discussion around research ethics and helped to establish bioethics as an integral part of health research in resource-limited settings. The WHO-TDR helped to set up a global Strategic Initiative for Developing Capacity in Ethical Review (SIDCER), ensuring that appropriate and competent ethics committees are established in countries where research is carried out. Already under SIDCER, six regional forums and more than 15 national forums have been established. Guidelines for ethics committees that review biomedical research were developed by WHO-TDR (in 2000) and widely distributed. Guidelines were later established on surveying and evaluating ethical review practices. Guidelines on data and safety monitoring boards are now being finalized through coordination with local government to ensure political endorsement. Training of local ethics committee staff in developing countries has become a high priority and should be vigorously pursued. Audit and follow-up of ethics committee decisions and outcome of trials with subsequent actions on making the product available at affordable prices should be a priority.

CONCLUSIONS Remarkable progress has been made over the past decade in TB research, especially in the fields of drug/immunotherapy development, newer diagnostics and vaccine development. These achievements are a result of collaborative efforts between public and private organizations that have combined scientific and clinical knowledge with further developments in TB research. The battle is not won yet (as evidenced by high mortality rates from TB, the MDR-TB problem and recent reports of XDR-TB) and will require further close cooperation and investment by all concerned to develop, evaluate and introduce more effective interventions, which will lead to TB control world-wide.

ACKNOWLEDGEMENTS The authors thank the WHO/TDR Tuberculosis Diagnostics Economic Working Group (Jane Cunningham and Mark Perkins) and TDR (Nina Mattock) for permission to use figures displayed in this chapter (adapted from Diagnostics for Tuberculosis: Global Demand and Market Potential; Gevena: WHO and TDR).

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