Appendix B1
Report from the National Institute of Allergy and Infectious Diseases (NIAID) Workshop

On March 1 and 2, 2010, during the 2 days before the workshop summarized in this volume, NIAID held the United States–Southern Africa Joint Research Forum on Tuberculosis in Pretoria, South Africa. The purpose of the workshop was to discuss research on TB that is taking place in southern Africa, to identify opportunities for collaboration within both South Africa and its neighboring countries, and to explore opportunities for collaboration between southern African countries and the United States. The highlights of that workshop were presented during the proceedings of the Institute of Medicine (IOM)–Academy of Science of South Africa (ASSAf) workshop by Valerie Mizrahi of the National Health Laboratory Service and University of Witwatersrand and Barbara Laughon of the National Institutes of Health, and are summarized below.

THE INCIDENCE OF DRUG-RESISTANT TB

  • HIV is a key driver of the TB epidemic in southern Africa, bringing about a six-fold increase in incidence in South Africa, Lesotho, and Swaziland.

  • There is a large burden of undiagnosed TB in the community.

  • The same epidemiological model cannot be used for TB and HIV epidemics in different countries.

1

This Appendix B summarizes the presentation made by Valerie Mizrahi of the National Health Laboratory Service and University of Witwatersrand and Barbara Laughon of the National Institutes of Health.



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Appendix B 1 Report from the National Institute of Allergy and Infectious Diseases (NIAID) Workshop On March 1 and 2, 2010, during the 2 days before the workshop sum- marized in this volume, NIAID held the United States−Southern Africa Joint Research Forum on Tuberculosis in Pretoria, South Africa. The purpose of the workshop was to discuss research on TB that is taking place in south- ern Africa, to identify opportunities for collaboration within both South Africa and its neighboring countries, and to explore opportunities for col- laboration between southern African countries and the United States. The highlights of that workshop were presented during the proceedings of the Institute of Medicine (IOM)−Academy of Science of South Africa (ASSAf) workshop by Valerie Mizrahi of the National Health Laboratory Service and University of Witwatersrand and Barbara Laughon of the National Institutes of Health, and are summarized below. THE INCIDENCE OF DRUG-RESISTANT TB • HIV is a key driver of the TB epidemic in southern Africa, bringing about a six-fold increase in incidence in South Africa, Lesotho, and Swaziland. • There is a large burden of undiagnosed TB in the community. • The same epidemiological model cannot be used for TB and HIV epidemics in different countries. 1 This Appendix B summarizes the presentation made by Valerie Mizrahi of the National Health Laboratory Service and University of Witwatersrand and Barbara Laughon of the National Institutes of Health. 103

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104 DRUG-RESISTANT TUBERCULOSIS IN SOUTHERN AFRICA THE TRANSMISSION OF DRUG-RESISTANT TB AND INFECTION CONTROL • Most TB disease, both drug-sensitive and drug-resistant, is recently transmitted via social interactions away from the house- hold. Thus, there is a need to understand the adult and childhood social networks in South African townships that contribute to TB transmission. • Surrogate biomarkers are essential for public health interventions. • Transmission and infection need to be studied intensively. • A TB control program must be able to rapidly identify cases and commence therapy. • Operational research and implementation science are needed to enhance feasible and available infection control strategies and sup- port the development and testing of new approaches. THE MOLECULAR EPIDEMIOLOGY OF DRUG-RESISTANT TB • Strains of TB are more diverse than previously appreciated. • The immense amount of variation occurring between strains sug- gests that purifying selection is reduced in Mycobacterium tuber- culosis (M.tb.). • Strain variation is extensive within individual study sites and across regions, with the University of Stellenbosch group reporting more than 150 strains per square kilometer in the study areas. • The population structure of M.tb. is highly variable, with a domi- nance of Beijing genotype (both typical and atypical) being uncov- ered in some study areas and playing a major role in driving drug resistance in South Africa. Intriguingly, Beijing strain has not (yet) been observed in Zambia, and the KZN strain predominates in XDR TB cases in that area. • DNA sequence data are highly informative and will soon be the standard for molecular epidemiology. • Although genetic and molecular epidemiology is powerful, it has been studied only in some areas of the region. DIAGNOSING DRUG-RESISTANT TB • While new diagnostics could detect 400,000 cases each year, the realities of using new versus current diagnostics need to be taken into account.

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105 APPENDIX B • Novel diagnostics being evaluated in Africa, all of which have various advantages and disadvantages, include — Light emitting diode (LED) microscopy — GeneXpert — Line probe assay (LPA) — Urine lipoarabinomannan (LPA) immunochromatographic (ICT) strip test — Interferon-gamma release assay (IGRA) — Microscopic observation drug susceptibility (MODS) • Key questions beyond the performance characteristics of a new diagnostic involve delivery, roll-out, and scale-up, as well as the impact on patient outcomes, program performance, the burden of disease, and global TB control. • The experience of the National Health Laboratory Service in mov- ing from validation of new technology to roll-out of the LPA was illuminating. Fitting the LPA into an algorithm for TB diagnosis and the development of an algorithm for early detection of MDR TB involved several challenges: — the plan to roll out the LPA to an additional 20 laboratories by December 2010; — requirements for laboratory space, equipment, staff recruit- ment training, the implementation of the assay, and review of its success; — preparation for the roll-out of GeneXpert to four additional laboratories later in 2010; and — human resource limitations particular to South Africa, some of which relate to policy. • the GeneXpert M.tb./Rifampicin test is being evaluated in five countries with differing HIV and MDR TB status. • The search for TB antigens is under way for a proof-of-concept test. • The Foundation for Innovative New Diagnostics has 20 trial sites for TB diagnostics in Africa. • The establishment of more laboratories and the development of proof-of-concept tests should not be viewed as mutually exclusive. • Molecular diagnostic technology is moving toward being less com- plex and more robust, with the potential for a proof-of-concept diagnostic in 2015.

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106 DRUG-RESISTANT TUBERCULOSIS IN SOUTHERN AFRICA THE TREATMENT OF DRUG-RESISTANT TB • Many drug-resistant TB cases are untreatable with existing or available antibiotics. • New drug regimens are needed now to treat drug-resistant TB. In particular, combination therapy is needed with new classes of drugs and novel mechanisms of action. • Better tolerability, less toxicity, and shorter treatment courses are needed. • Three to four new drugs need to be developed against which resis- tance is not established. • The number of new drugs that have novel targets and mechanisms of action is not adequate. More basic research is needed to increase the number of compounds entering the pipeline. In particular, there are gaps in candidates with preclinical safety. • Going from discovery to the launch of a successful drug takes 10 to 15 years. Five to 10 new entities generally need to enter human trials to yield one drug that will be safe, sufficiently effective, and affordable to be used for TB treatment. The estimated cost of a new entity is $1−$1.5 billion. Most of the drugs are being developed by public−private partnerships and by philanthropic organizations. • There is a huge R&D funding gap. More funds are needed to facili- tate preclinical development, to build capacity at trial sites, to per- form clinical trials, and to provide enabling infrastructure. • In terms of pharmacology and pharmacokinetics, there is a need to optimize dosing in neglected subpopulations, such as children and pregnant women. This goal can be facilitated by new technology. • Surrogate markers to monitor response to therapy quantitatively are critically needed. Large cohorts are required to validate bio- marker studies of treatment efficacy, relapse, and latent TB infec- tion and should be built into drug trials. • The pulmonary route of delivery is underexplored. Preliminary work suggests that the formulation of TB drugs and vaccines as spray-dried powders using large porous particles for inhaled deliv- ery holds promise in the future. • Directly Observed Treatment Short Course (DOTS) coverage is reasonably good in the African region but is clearly inadequate to curb the epidemic. • The Malawi Public Health system offers lessons in best practice. • Botswana has close-to-universal access to antiretrovirals and IPTG (isopropyl-β-D-thio-galactoside), which may be a reason for the slight reduction in the case rate there. An important message from

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107 APPENDIX B the latest Botswana study is that there is no evidence for isoniazid preventive therapy fueling isoniazid resistance. • An African regional collaboration is essential in order to: — establish a clinical trials network for TB treatment and preven- tion regimens, — establish more registration-qualified clinical sites with adequate laboratories for future Phase III efficacy trials, and — establish regulatory agencies to harmonize and improve approval processes so that studies can be started more quickly. • Regional collaboration also could make possible a “20 communities study” of regional epidemiology, including molecular epidemiology. • A working group on new drugs is making information available on the website www.newtbdrugs.org. VACCINES FOR TB • The goal is for a new vaccine to be developed by 2016, with 20 candidates in Phase 1 by 2015 and 9 in Phase II by 2018. These are ambitious targets. • Highlights of the work done on immune responses induced by new vaccines include — Novel boost vaccines induce T cells in distinct patterns. — Differences in response may reflect an interaction with the innate immune system. — Candidates differ in terms of local and systemic side effects. — Patterns of immune activation may differ in infants and adults. • Some points concerning biomarkers of protection were: — Cytokine expression does not correlate with protection. — Soluble IFNg levels do not correlate with protection. — T cell expression of cytotoxic markers may delineate protection. — Models based on combinations of markers may have value as biomarkers in the future. — Unbiased approaches to biomarker discovery (such as gene expression profiles) need to be pursued. • In terms of clinical preparedness for new vaccines, challenges include — costs, site development, a lack of immunological correlates of protection, TB diagnoses in children, and the need for clinical end points for determining efficacy; and — key issues regarding the regulatory environment. • Important issues involving efficacy trials in HIV-infected and -exposed adults against TB include — whether vaccines are safe and immunogenic, and — the size of the sample required to achieve an efficacy outcome.

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108 DRUG-RESISTANT TUBERCULOSIS IN SOUTHERN AFRICA • Sustained commitment and extensive collaboration are required within and between developed and developing countries. DRUG-RESISTANT TB IN CHILDREN • TB in children has been neglected; it is underreported and extremely difficult to diagnose, and has a limited evidence base on which to base treatment decisions. • Diagnostics need to be child friendly, cost-effective, and operation- ally feasible. Application in pediatric TB should be considered in the development of any new diagnostics as early as possible. • New tools for clinical management, epidemiology, and surveillance are urgently needed, as is an end point for Phase III trials. • Extra-short-course therapy is needed for less severe forms of TB in children, but needs confirmation. • The value of targeted screening in high-risk populations needs to be explored. • The degree of exposure needs to be assessed as a possible predictor of infection, persistent infection, or disease. • Additional pharmacokinetic studies are needed in children. • An Extrapulmonary TB Trials Consortium needs to be created. CONCLUSIONS AND POLICY DISCUSSION • Rapid and accurate drug sensitivity testing should be a prerequisite for the commencement of therapy, given the amplifying role of drugs in the evolution of resistant strains. • The South African government should collaborate in the develop- ment of capacity and infrastructure. There is only one supranational TB reference laboratory in the region, and there is insufficient capac- ity to cope in the regional laboratories. In addition, the capacity to conduct clinical trials is very limited. • Lessons can be learned from the HIV field, where major National Institutes of Health (NIH) grants for research have been linked with development and capacity development grants. Synergy between research grants and capacity development is necessary.