Lancet Series Showcases Challenges, Promise in the Fight Against TB

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The Lancet launched a  series of articles on the global tuberculosis epidemic, which claims 1.8 million lives every year. The Lancet articles note that TB is a leading cause of death in people in the most economically productive age-groups. The series highlights scale up of treatment and diagnoses, drug-resistant TB, and HIV/TB co-infection, as well as the huge funding gap for TB control and research and development, with many countries struggling to deliver basic diagnostic and treatment services.

The authors of one lead article conclude: “Acceleration of the present decline towards TB elimination will need invigorated actions in four broad areas: continued scale-up of early diagnosis and proper treatment in line with the Stop TB Strategy; development and enforcement of bold health-system policies; establishment of links with the  broader development agenda; and promotion and intensification of research.”

With the unveiling of this series, we spoke today with Zhenkun Ma, Ph.D., Chief Scientific Officer for the TB Alliance, who authored this article focused on TB drug development and the promise of new medicines to greatly improve TB treatment.

Q: You point to the results of a modeling study that suggests the combination of a 2-month treatment regimen that cures 95% of MDR tuberculosis, a better TB diagnostic tool, and a joint pre-exposure and post-exposure TB vaccine could potentially reduce the incidence of this disease by 71% by 2050. But that seems like a very tall order. How realistic is it that we can achieve those goals and what will it take to get there?

A: I think it’s very feasible. We have a very strong pipeline. On the drugs front, the goal of achieving a 95 percent cure rate for drug-resistant TB with new drugs is very doable. Right now, there are 10 drugs in clinical development, and the majority—six new drugs—belong to novel drug classes with new modes of action, new mechanisms. Bacterium has never seen these compounds before. They work differently from old drugs and are able to overcome drug-resistant forms of TB.

Four of the drugs in the pipeline are currently being used to treat other bacterial infections. We are in the process of figuring out how to best use these to treat TB. Because of these developments, I think it’s very feasible to achieve significant reductions in TB incidence.

Q: One problem you highlight is inadequate clinical trial capacity to test new regimens for TB treatment. Can you elaborate on that? Why isn’t there enough capacity, how inadequate is it, and what will it take to get to full capacity?

A: TB has its worst impact on developing countries. The places you have TB patients, generally, do not have the capacity to conduct modern clinical trials. Most parts of Africa, for example, simply don’t have the laboratory capacity required to support registration trials. And the places we are able to conduct registration trials, you simply don’t have enough patients with TB. So that’s the challenge and the disconnect. Funding is really the key to support capacity building and clinical capacity strengthening.

Q: What research is currently underway to improve pediatric treatment of TB?

A: Pediatric TB has largely been ignored. It’s a major challenge because it’s hard to do. We don’t have very good diagnostic tools. It will take a lot of research work to figure out how best to detect TB and monitor the efficacy of treatments in children. However, we are committed to developing drugs that can be used for all patient populations.

Q: The funding shortfall for TB research is huge. It has long been a neglected disease. What do you think it will take to change that?

A: Clearly the funding gap is huge. MSF recently reported there is a 75 percent gap in the funds needed for TB research and development. A lot of people think TB is simply not a problem anymore. The Lancet articles are a great opportunity to point out that TB is still a devastating global problem, with 2 million people dying from TB and more than 9 million new cases of TB occurring each year. This is really a massive global problem and requires people to pay more attention and invest more resources. We need all the stakeholders to allocate more resources to support TB drug development.

For more info, here’s a link to the Lancet press office and below is the Lancet press release on the Series, which has descriptions and links for each article:

 

 

EMBARGO: 1830H (New York time) Tuesday 18 May 2010

  • TUBERCULOSIS: 6 MILLION LIVES SAVED SO FAR BUT THE DISEASE STILL CAUSES 1.8 MILLION DEATHS WORLDWIDE EVERY YEAR
  • MULTIDRUG-RESISTANT FORMS OF TB COULD BECOME DOMINANT STRAINS WITHOUT SIGNIFICANT INVESTMENT
  • FREQUENT HIV TESTING, AND EARLY START OF ANTIRETROVIRAL TREATMENT IN THOSE WITH HIV, WOULD GIVE SHORT- AND LONG-TERM DECLINES IN TB INCIDENCE
  • COMBINED EFFECT OF NEW DRUGS, VACCINES, BIOMARKERS AND DIAGNOSTICS COULD REDUCE TB INCIDENCE BY 94% BY 2050
  • STRENGTHEN THE HEALTH SYSTEM, STRENGTHEN THE TB RESPONSE
  • TB CAN NO LONGER BE THE NEGLECTED SISTER OF HIV AND MALARIA, PLUS THE LAUNCH OF THE LANCET TB OBSERVATORY
  • COMMENTS WITH THE SERIES: TB AND WOMEN; AGE AND TB, MIGRATION AND TB, AND COMMUNITY RESPONSE TO TB

 

TUBERCULOSIS: 6 MILLION LIVES SAVED SO FAR BUT THE DISEASE STILL CAUSES 1.8 MILLION DEATHS WORLDWIDE EVERY YEAR

During the period 1995-2008, 36 million people were cured from tuberculosis (TB) and up to 6 million lives were saved compared to the performance of TB control programmes at the start of the DOTS* era in 1995. However, with 1·8 million estimated deaths every year, tuberculosis (TB) still takes a huge toll, especially for the world’s poorest people. It is a leading cause of death in people in the most economically productive age-groups. There were around 11 million active cases of TB in 2008, with 95% of cases in low- and middle-income countries. In the first paper in The Lancet Series on Tuberculosis, Dr Mario Raviglione and Dr Knut Lönnroth, Stop TB Department, WHO, Geneva, Switzerland, and colleagues look at the global burden of TB and what needs to be done to eliminate it by 2050.

Available drugs can cure most cases of TB, and such intervention is highly cost-effective, leading to economic gains up to ten times what is spent on treatment. Rapid expansion of the standardised approach to TB diagnosis and treatment that is recommended by WHO (the Stop TB strategy**) has allowed more than 36 million people to be cured between 1995 and 2008, averting up to six million deaths.  TB/HIV collaboration has improved recently, but further rapid improvements are needed. Quality controlled management of multidrug-resistant (MDR) TB is improving, albeit very slowly.

Part of Millennium Development Goal 6—to halt and begin to reverse TB incidence by 2015—is estimated to have been reached in 2004 globally. Global incidence was estimated at 139 cases per 100,000 population in 2008, down from 143 in the apparent peak year of 2004. However, the decline is less than 1% per year.  With present efforts, the targets to halve prevalence and death rates by 2015, compared with 1990 rates, will probably be met in most regions, but might not be met worldwide. And the long-term elimination target, to reduce incidence to less than one case per million by 2050, will not be reached with existing technologies and approaches.

22 countries*** contain 80% of the world’s cases of TB, including Brazil, China, Russia, India, Burma, South Africa and Zimbabwe.  Encouragingly, all these 22 countries are implementing standardized diagnosis, treatment and management of TB i.e. the DOTS component of the Stop TB Strategy. The global case detection rate improved six-fold between 1995 and 2008, but is still at 61%—thus 39% of active TB cases remain undetected every year by national TB programmes.  To speed up the decline in TB burden, case detection rates need to be improved substantially, and cases must be identified much earlier. Synergy with additional interventions (for other diseases) should be explored, including interventions to prevent TB.

HIV and TB co-infection is a major problem, especially in Africa. But of around 1.4 million people estimated to be co-infected, only 357,000 (less than 25%) were identified in 2008. Intensified case detection approaches are needed, linked to general health-system strengthening, ensuring universal access to high-quality early diagnosis, treatment, and care for all forms of this disease, including people infected with HIV and those affected by multidrug-resistant TB. The authors say that a rapid and simple point-of-care test would improve early case detection substantially. While whole-population screening might not be cost effective, it might be in high-risk subpopulations such as health-care workers, prisoners, drug addicts, homeless people, slum dwellers, refugees, migrants, displaced populations, people affected by mental illness or other high-risk groups.

Preventive therapy with the isoniazid should be scaled up. Additional prevention efforts include development of more effective vaccines, or reducing risk factors for TB, as well as their underlying social determinants.  HIV increases the risk of TB by more than 20 times. Undernutrition, smoking, diabetes and alcohol misuse can all increase this risk by 2-3 times. The paper estimates the relative threat of each of these risk factors (population-attributable fractions). For instance, in Russia, where alcohol abuse is rife, up to a third of active TB cases could be due to alcoholism. But in South Africa and Zimbabwe, up to two thirds of TB cases are thought to be caused by HIV co-infection. Around a further third of Russian TB cases are linked to smoking, while in China and India, up to 20% of cases are linked to smoking.

Funding for TB control in high-burden countries more than doubled between 2002 and 2009. Nevertheless, large funding gaps remain. The funding shortfall expected in these countries in 2010 is US$0·5 billion, and in all countries the deficit in 2010 compared with the Global Plan to Stop TB is $2·1 billion. Many countries are struggling to sustain basic diagnostic and treatment services.

The authors conclude: “Acceleration of the present decline towards TB elimination will need invigorated actions in four broad areas: continued scale-up of early diagnosis and proper treatment in line with the Stop TB Strategy; development and enforcement of bold health-system policies; establishment of links with the  broader development agenda; and promotion and intensification of research.”

Dr Mario Raviglione, Stop TB Department, WHO, Geneva, Switzerland. T) +41 22 791 2663 E) raviglionem@who.int

Dr Knut Lönnroth, Stop TB Department, WHO, Geneva, Switzerland. T) +41 22 791 1628 E) lonnrothk@who.int

Glenn Thomas, Senior Communications Adviser, WHO Stop TB Department. T) +41 79 509 0677 E) thomasg@who.int

For full Series paper 1, see: http://press.thelancet.com/tbsp1.pdf

Note to editors: *DOTS is the package of essential interventions in TB control including: political commitment, diagnosis through bacteriology, standardized and supervised treatment, an effective drug supply system, and monitoring and evaluation of performance

**Stop TB Strategy: see page 15 of Series paper 1

***22 countries: Afghanistan, Bangladesh, Burma, Cambodia, China, DR Congo, Ethiopia, India, Indonesia, Kenya, Mozambique, Nigeria, Pakistan, Philippines, Russia, South Africa, Thailand, Uganda, Tanzania, Vietnam, Zimbabwe

MULTIDRUG-RESISTANT FORMS OF TB COULD BECOME DOMINANT STRAINS WITHOUT SIGNIFICANT INVESTMENT

An estimated 440 000 cases of multidrug-resistant tuberculosis (MDR TB) occurred worldwide in 2008 (3·6% of all TB cases that year), but only 7% of these cases were identified and treated. Extensively drug-resistant TB (XDR TB) has also been reported in most countries and is even more difficult to treat than MDR TB. Without significant investment in technology and capacity for prevention, diagnosis and treatment, MDR TB threatens to become the dominant strain of TB over the next few decades. The issues are discussed in the second paper in The Lancet Series on Tuberculosis, written by Dr Neel R Gandhi, Albert Einstein College of Medicine and Montefiore Medical Center, Yeshiva University, New York, USA, and Dr Paul Nunn, Stop TB Department of the World Health Organization, Geneva, Switzerland, and colleagues.

Drug-resistant TB poses a major threat to existing TB control programmes since it is associated with substantially lower cure rates and higher mortality rates than drug-susceptible TB disease.  Additionally, MDR TB treatment is less effective, requiring 24 months of treatment rather than the usual 6 months, and far more costly (US$3,500 average drug costs per patient vs around US$20).  Thus, even though there are fewer cases of drug-resistant TB, the cost and complexity of their management place a significantly greater burden on the health system than do drug-susceptible TB cases.

MDR TB was traditionally believed to develop as a result of improper treatment in patients with drug-susceptible TB, allowing for selection of drug-resistant TB strains. TB drug resistance, however, can also be transmitted from people with MDR or XDR TB, giving rise to drug-resistant TB disease in people with no previous exposure to TB drugs. Estimates suggest transmission of drug resistance now accounts for more than half of global MDR TB cases; although improper treatment of drug-susceptible TB also continues to play a major role in the development of new cases of drug resistance.  Efforts to prevent MDR TB cases have been severely limited by a failure to implement infection control programmes in most low- and middle-income countries, together with insufficient financial and human resources, laboratory capacity and access to second-line TB drugs.

Although MDR and XDR TB exist on every continent, the true extent of the epidemic remains unknown.  Drug resistance surveys have been carried out in only 59% of countries, and of these data, 20% were collected before 2003 and are outdated.  India and China together carry nearly 50% of the global MDR TB burden, followed by Russia (9%). The trend of whether drug resistance is increasing or decreasing worldwide is also unknown, since more than one drug-resistance survey has been completed in only 59 (31%) countries. Some countries have shown that epidemics of MDR TB can be reversed by use of technologies which already available.  In these countries (Estonia, Hong Kong [Special Administrative Region], Latvia, Lithuania, Russia [Orel and Tomsk regions], Singapore, and the USA) the incidence of MDR TB is known to be decreasing. But in Botswana, Peru, South Korea, the incidence of MDR TB has been rising, leading to concerns that the same may be true in other developing countries where trend data are not available. Alarmingly, in Botswana, all cases of tuberculosis are increasing in incidence, and MDR TB is increasing even faster.

Treatment success rates in MDR TB can be as high as 83%, and 60% in patients with XDR TB, in treatment programmes that function optimally and have low rates of HIV co-infection. MDR TB and XDR TB patients should be treated with four to six drugs to which their strains are known or likely to be susceptible.  In order to achieve these high levels of treatment success on a broad scale, however, health systems and national TB programmes will need to recruit and train sufficient health workers and ensure that drug-resistant TB treatment is provided by accredited physicians with experience in managing MDR and XDR TB cases. Additionally, major improvements in laboratory capacity, infection control, and treatment regimens for both drug-susceptible and drug-resistant disease will be needed, together with a massive scale-up in diagnosis and treatment of MDR and XDR TB, to prevent drug-resistant strains becoming the dominant form of tuberculosis.

New diagnostic tests and drugs may become available during the next decade and would help control of MDR and XDR TB. However, they must be made available in resource-limited settings which are hit hardest by this epidemic.  Moreover, the authors say, we must “ensure that these new drugs are not exposed to the weak health systems and irrational drug practices that are currently giving rise to resistance.”

They conclude: “Unless countries invest substantially in management of MDR TB, the possibility remains that MDR strains could become the dominant form of TB. Moreover, the future possibility of strains that are totally resistant to all anti-tuberculosis drugs is not inconceivable…Equally important, especially in the highest-burden countries of India, China, and Russia, will be a commitment to tuberculosis control including improvements in national policies and health systems that remove financial barriers to treatment, encourage rational drug use, and create the settings necessary to manage MDR TB on a national scale.”

Dr Neel R Gandhi, Albert Einstein College of Medicine and Montefiore Medical Center, Yeshiva University, New York, USA. T) +1 718-944-3865 E) neelgandhi@alumni.williams.edu

Dr Paul Nunn, Stop TB Department, WHO, Geneva, Switzerland. T) +41 22 791 2963 E) nunnp@who.int

Glenn Thomas, Senior Communications Adviser, WHO Stop TB Department. T) +41 79 509 0677 E) thomasg@who.int

For full Series paper 2, see: http://press.thelancet.com/tbsp2.pdf

For an Article and Comment published Online First on XDR-TB in South Africa: LINK TO BE ADDED (same embargo) see: (NOTE THIS WILL NOT FORM PART OF THE PRESS RELEASE/PRESS CONFERENCE AND IS FOR JOURNALISTS’ REFERENCE ONLY) http://press.thelancet.com/xdrtbsa.pdf

FREQUENT HIV TESTING, AND EARLY START OF ANTIRETROVIRAL TREATMENT IN THOSE WITH HIV, WOULD GIVE SHORT- AND LONG-TERM DECLINES IN TB INCIDENCE

The epidemic of HIV-associated tuberculosis continues to rage, particularly in southern Africa. Urgent assessment of frequent testing for HIV and early start of antiretroviral treatment (ART) should result in short-term and long-term declines in TB incidence through individual immune reconstitution and reduced HIV transmission. The issues surrounding the burden of co-infection are discussed in the third paper in The Lancet Series on Tuberculosis, written by Professor Anthony Harries, International Union Against Tuberculosis and Lung Disease, Paris, France, and colleagues.
The authors say: “Many people with HIV infection start ART too late, especially in Africa, and have already developed TB by the time that they present to health services for care. Rigorous implementation of recent international guidelines to ensure early start of ART could prevent some of these failed opportunities.”

Implementation of the 3Is policy (Intensified tuberculosis case finding, Infection control, and Isoniazid preventive therapy) for prevention of HIV-associated TB, combined with earlier start of ART, will reduce the burden of TB in people with HIV infection and provide a safe clinical environment for delivery of ART. Some progress is being made in provision of HIV care to HIV-infected patients with TB, but too few receive co-trimoxazole prophylaxis and ART. Among the suggestions to improve this situation are starting all HIV-infected TB patients on ART, irrespective of CD4 cell count; decentralising ART to health centres where TB care is decentralised; bringing HIV services to TB clinics so that patients can obtain antituberculosis drugs, co-trimoxazole prophylaxis, and ART from the same health facility; and  in settings of high HIV prevalence, an HIV clinician can be deputed to the TB clinic to provide HIV services and ART. The authors say: “Early HIV diagnosis and treatment, the 3Is, and a comprehensive package of HIV care, in association with directly observed therapy, short-course (DOTS) for TB, form the basis of prevention and control of HIV-associated TB.”

 

The Global Plan to Stop TB estimated that US$6·7 billion would be needed during 2006–15 to fully implement collaborative TB and HIV activities. The authors say: “With the continuing economic downturn and restricted financial support by donor countries for achievement of universal access in the immediate future, intensified advocacy is needed to ensure equitable and adequate financing to address this epidemic. Notably, short-term costs might be set to increase because of the movement towards early start of ART with drugs that are more durable and tolerable, but also more expensive.”

They conclude: “From the perspective of TB control, a sound theoretical base supports much earlier start of ART, which could additionally reduce mortality from HIV/AIDS. Moreover, isoniazid preventive therapy could further reduce TB incidence for those on ART. Worldwide, more than a third of the burden of HIV and almost half of the burden of HIV-associated TB is concentrated in southern Africa—affected countries should examine such innovative strategies with urgency. Without imaginative use of available and potential strategies, the epidemic of

HIV-associated TB will continue long term, robbing countries of years of productive and useful citizens’ life.”

In a Comment with the Series, Dr Tedros Adhanom Ghebreyesus, Minister of Health for Ethopia, and colleagues list five urgent actions needed for effective and integrated services for TB and HIV: bold national leadership, health-system restructuring, decentralised care, investment in new tools and better use of existing ones, and global leadership from donors, countries of the global south, and key health agencies. They point out the key role of the Global Fund, WHO, UNAIDS, and the Stop TB Partnership in these efforts, concluding: “In collaboration with countries, these collective efforts will contribute to an ambitious but achievable objective: virtual elimination of tuberculosis deaths in people with HIV infection and ridding the world of needless suffering from tuberculosis/HIV.”

Professor Anthony Harries, International Union Against Tuberculosis and Lung Disease, Paris, France. T) (Mon 17/Tues 18 May +44 (0) 1962 714 297 / +44 (0) 7818030315) E) adharries@theunion.org

 

Dr Tedros Adhanom Ghebreyesus, Minister of Health for Ethopia. E) moh.vmo@ethionet.et

 

For full Series paper 3, see: http://press.thelancet.com/tbsp3.pdf

 

For full Comment see link to Comment secton at end of release

 

COMBINED EFFECT OF NEW DRUGS, VACCINES, BIOMARKERS AND DIAGNOSTICS COULD REDUCE TB INCIDENCE BY 94% BY 2050

Papers four, five and six in The Lancet Series on Tuberculosis look at effect of drugs, vaccines, biomarkers and diagnostics—with estimates that the combined effect of all four could reduce TB incidence by 94% by 2050.

The fourth paper looks at developments in diagnostics and biomarkers.  There remains a desperate need for a more accurate, cheap point-of-care test applicable in TB and HIV endemic areas; and more investment is needed in biomarkers which could be predictors of whether someone is more likely be cured from TB by treatment or relapse, and their potential immunity conferred by a future vaccine. The biomarkers aspects of the paper are covered by Professor Alimuddin Zumla, University College, London, and colleagues; while the diagnostics issues are covered by Dr Mark Perkins, Foundation for Innovative New Diagnostics, Geneva, Switzerland, and colleagues.

The authors say: “Tuberculosis case detection remains difficult, partly because of inaccurate diagnostic methods. Investments have yielded some progress in development of new diagnostics, although the existing pipeline is limited for tests for sputum-smear-negative cases, childhood tuberculosis, and accurate prediction of reactivation of latent

tuberculosis.”

The biomarker nearest qualification is 2-month culture conversion as a predictor of relapse. This gives an indication how quickly the mycobacterium which causes TB is cleared from sputum by treatment. Mycobacteria not cleared from sputum after months of treatment may indicate drug-resistant TB, patient non-compliance with taking drugs, or that a longer period of treatment could be required.

The authors say that several diagnostics and diagnostic strategies have been endorsed by WHO and are being introduced into clinical use and national TB programmes. In 2009, data were published on the first automated molecular test for tuberculosis, the Xpert MTB/RIF. This assay avoids many pitfalls of conventional nucleic acid amplification tests (safety, contamination, ease of use, etc), can be done by staff with little training, and can be used for case detection or MDR TB screening. They add that clinical and field studies are needed to assess whether programmatic introduction of new diagnostics contributes to improved individual patient outcomes and a measurable beneficial public health effect.

The authors conclude: “Despite new, sensitive, automated molecular platforms for detection of tuberculosis and drug resistance, a simple, inexpensive point-of-care test is still not available. The effect of any new tests will depend on the method and extent of their introduction, the strength of the laboratories, and the degree to which access to appropriate therapy follows access to diagnosis. Translation of scientific progress in biomarkers and diagnostics into clinical and public health programmes is possible—with political commitment, increased funding, and engagement of all stakeholders.”

The fifth paper discusses new drugs in development, and says that ten compounds have progressed into the clinical development pipeline, including six new compounds specifically developed for tuberculosis. This paper is written by Dr Zhenkun Ma, Global Alliance for TB Drug Development, New York, USA, and colleagues.

The authors say: “Despite this progress, the global TB drug pipeline is insufficient to address the unmet needs for treatment. Additional and sustainable funding is needed to further improve the pipeline… The main challenges in the development of new treatments are the needs for novel drug regimens, new trial designs, studies in paediatric populations, increased clinical trial capacity, clear regulatory guidelines, and biomarkers for prediction of the long-term outcome.” Ensuring new drugs are used responsibly, with drug selection and patient adherence correctly managed, is also essential to prevent resistance to new regimens developing rapidly.

The funding shortfall to support TB drug research and development is 75%, according to a new report by Médecins Sans Frontières.  The authors say: “Development of new drugs for TB is lengthy, expensive, and risky, and the expected revenues are too small to justify commercial investment… New financing and market incentive mechanisms are needed to encourage pharmaceutical and biotechnology companies to invest in drug discovery and development, particularly in late-stage clinical trials.”
They conclude: “To eliminate TB as a public health concern by 2050, all responsible parties need to work together to strengthen the global anti-tuberculosis drug pipeline and support the development of new antituberculosis drug regimens.”

The sixth paper looks at TB vaccine development and is written by Prof Stefan H E Kaufmann, Max Planck Institute for Infection Biology, Berlin, Germany, and colleagues.  They say: “New vaccines are urgently needed if we want to reach the goal of substantially reducing the incidence of TB by 2050. Despite a steady increase in funding over the past decade, there is still a striking financial shortfall for vaccine research and development for TB… The present BCG vaccination regimen protects newborn babies (not adults) against severe TB… Protection induced by BCG vaccination against adolescent and adult TB, the most prevalent form of the disease, is insufficient.”

Despite this shortfall, 11 vaccine candidates have entered clinical trials: most are pre-exposure vaccines and will most likely prevent TB disease. They are intended to either replace BCG  or to be given after BCG as boosters (either protein adjuvant formulations or recombinant viral carriers). The authors add that post-exposure vaccines are also required and, ultimately, vaccines are needed that either prevent infection or achieve sterile eradication. They say vaccine trial sites with appropriate infrastructure are urgently needed.

The authors conclude: “The most recent prediction calculates a reduction in TB incidence of 39–52% by 2050 as a result of new pre-exposure vaccines; a reduction in incidence of 10–27% from new drugs that shorten duration of treatment and are effective against drug-resistant strains; and an additional reduction of 13–42% from new measures allowing reliable and fast diagnosis of TB. Combined, these three new measures could reduce TB incidence by up to 71%. Incidence could be further reduced by up to 94% by mass vaccination campaigns, new post-exposure vaccines, and drugs for latent infection.”

Professor Alimuddin Zumla, University College, London. T) +44-207-6799311 E) a.zumla@ucl.ac.uk

Dr Mark Perkins, Foundation for Innovative New Diagnostics, Geneva, Switzerland. T) +41 22-7100590 E) mark.perkins@finddiagnostics.org

 

For Dr Zhenkun Ma, Global Alliance for TB Drug Development, New York, USA, please contact Joanna Breitstein T) +1 646 616-8633 / +1 917-361-0683 E) zhenkun.ma@tballiance.org / joanna.breitstein@tballiance.org

Prof Stefan H E Kaufmann, Max Planck Institute for Infection Biology, Berlin, Germany. T) +49-30-28460-500 extension 502 / +49-170-56 272 47 (but e-mail preferred) E) kaufmann@mpiib-berlin.mpg

 

For Series paper 4 see: http://press.thelancet.com/tbsp4.pdf

 

For Series paper 5 see: http://press.thelancet.com/tbsp5.pdf

 

For Series paper 6 see: http://press.thelancet.com/tbsp6.pdf

 

STRENGTHEN THE HEALTH SYSTEM, STRENGTHEN THE TB RESPONSE

The seventh paper in the Lancet Series on Tuberculosis shows how health system bottlenecks are impeding global efforts to control tuberculosis. Rapid introduction of suboptimum health system reforms have undermined tuberculosis control in many settings. Whereas, strengthening of TB control and concurrent financing and service access innovations have been associated with improved performance.  It is written by Professor Rifat Atun, Global Fund to Fight AIDS, Tuberculosis and Malaria, Geneva, Switzerland, and Imperial College London, UK, and colleagues from WHO, Tanzania and Cambodia.

The authors say: “National tuberculosis programmes have been instrumental in global efforts to control tuberculosis. But bottlenecks in health systems related to financing, the workforce, and supply chain management have hampered progress towards national targets and Millennium Development Goals, despite increases in external funding. Rapidly introduced health-system reforms and suboptimum system designs have adversely affected national efforts to control tuberculosis in Africa, Latin America, and eastern Europe. Early and full case detection is a major challenge, and frequency of treatment success is low in many African and eastern European countries.”

But there have been positive examples from a number of countries. Bangladesh, Cambodia, India, Tanzania, Thailand, and Vietnam, show innovative solutions for disease control and system design to address bottlenecks in health systems. Bangladesh has fostered involvement of non-governmental organisations in tuberculosis control to scale up services. Tanzania has expanded access by including tuberculosis services into primary care and using private sector and community health worker capacity, while Thailand expanded tuberculosis services by including them within its universal health coverage plan. The authors say: “Tuberculosis services have been integrated into primary health care, and are functioning with good outcomes. Participation of non-governmental organisations and the private sector has [been critical for] expanded access.”

The authors point out that each country will require a solution specific to its own TB epidemic, with the national health system and the partners involved. But they show that the evidence on these solutions, which the countries can draw on, remains appallingly weak. They say: “No one size fits all. These highly varied responses need to be documented and compared to develop evidence-based policies and practice.”

They say: “Despite increased financing for disease control, weak health systems are impeding global efforts to achieve tuberculosis targets and other health MDGs,” adding*: “To target the complex and dynamic nature of the tuberculosis epidemic, the overlapping HIV epidemic, and emerging drug resistance, we need radical innovations to strengthen health systems and disease control. More of the same just won’t do.”

They conclude: “Evidence to support which strategies will and will not work in specific

contexts remains weak… As efforts to strengthen health systems are intensified to reach MDGs and address threats to health security, such as tuberculosis and HIV, this evidence

will prove crucial,” adding*: “But, we are far from understanding what works in different contexts.”

Professor Rifat Atun, Global Fund to Fight AIDS, Tuberculosis and Malaria, Geneva, Switzerland, and Imperial College London, UK. T) please complete telephone number E) Rifat.Atun@theglobalfund.org / r.atun@imperial.ac.uk

 

Diana Weil, Coordinator, Policy & Strategy, Stop TB Department, WHO. T) +41-22-791-3072 E) weild@who.int

 

For full Series paper 7, see: http://press.thelancet.com/tbsp7.pdf

Note to editors: *asterixed part of quote is direct from authors and not found in text of the paper

 

TB CAN NO LONGER BE THE NEGLECTED SISTER OF HIV AND MALARIA, PLUS THE LAUNCH OF THE LANCET TB OBSERVATORY

In the eighth and final paper on the Lancet Series on Tuberculosis, a call to action is made to a wide range of sectors to assist scale-up TB service delivery, research and control. The launch of The Lancet TB Observatory, which will monitor progress on key indicators on an ongoing basis, is also announced. Its multiple contributors, lead by all three series editors (Professor Ben Marais, Stellenbosch University, South Africa; Dr Mario Raviglione, Stop TB Department, WHO; and Professor Alimuddin Zumla University College, London) offer a critical assessment of the status quo and clear guidance on the best way forward.

Since the introduction of standard control practices in 1995, 36 million people have been cured and about 6 million deaths averted. Despite this piece of good news, control and elimination of the global TB epidemic remain elusive and many challenges remain.  The authors say: “However, substantial scientific advances and innovative solutions are urgently needed together with creative new strategies. Strong international and national political commitment is essential. Urgent action is needed by national governments to fund their own programmes, and for the G8 countries and other donor governments and organisations to support governmental and non-governmental efforts.”

UN agencies, the private sector, professional societies, and human rights groups—as well as communities and individuals directly affected by TB—are all called upon to take action. Urgent action is required to realise both the relevant Millennium Development Goals (MDG 6) and the ambitious targets of the Stop TB Partnership.  The partnership’s Global Plan to Stop TB aims to reduce the global burden of tuberculosis (prevalence and death rates) by 50% relative to the global burden in 1990 (prevalence lower than 150 per 100 000, and deaths fewer than 15 per 100 000 per year); and, by 2050,eliminate TB as a health threat (defined as global incidence of less than one case of tuberculosis per million population per year).

Of the 9 epidemiological sub-regions 6 have already halved the prevalence rate and 4 the mortality rate compared to 1990 levels, with all others on course to do so before 2015, apart from Africa where it appears highly unlikely that these goals will be met (current prevalence rate in Africa 400-500 per 100 000/year, mortality rate 40-50 per 100 000 per year). Improved diagnosis, treatment and prevention are important, but tuberculosis presents as much a developmental crisis as a health crisis.  More funds are required to advance research agendas and improve service delivery, but local ownership of the problem coupled with sustainable funding models and improved efficiency are equally important.

In funding terms, the authors state that TB can no longer be the neglected sister of HIV and malaria, and massive increases in financial commitment, from governments and donors, are needed across the board. They say: “Despite TB killing nearly as many people as HIV/AIDS (about 4500 per day), there has not been a similar increase in funding for TB control and research. For instance, research funds provided by the US National Institutes of Health (the second top donor in the world for TB research) represent roughly a 15th of what is invested in HIV research by the same agency.”

The authors also note that the UN MDG Summit to be held in New York on Sept 20–22, 2010, will be an excellent opportunity to ensure that the global community assesses the progress towards achievement of the MDG (and Stop TB Partnership) targets related to TB control. Although the main target of halting and beginning to reverse global TB incidence might have been achieved already in 2004, the yearly reduction is minimum and is offset by population increases. Some 700,000 women, most of reproductive age, and tens of thousands of children die each year from TB.

To monitor progress, The Lancet, in collaboration with the Stop TB Partnership, WHO, the Global Fund to Fight AIDS, Tuberculosis, and Malaria, and the leading experts participating in this Series, is launching a new initiative The Lancet TB Observatory, which will assess and monitor progress in control of and research into tuberculosis, assess domestic and global financing, regularly disseminate information, and advocate for intensified efforts with stakeholders at all levels. The remit of the observatory would be:

  • Establish a website that details objectives, outputs, and links with the main TB websites
  • Publish quarterly website updates on these objectives
  • Publish a yearly update in a report in The Lancet updating progress
  • Develop a blog for open discussion on the website
  • Hold meetings every 1-2 years to discuss progress and continue innovation to boost progress
  • Publish progress reports in a mini-series in The Lancet every 3 years that address the main themes
  • Publish an editorial for the UN Millennium Development Goal Summit in September, 2010, to summarise the situation and issue a call to action

The authors conclude*: “In a sense TB can be regarded as an indicator disease that reflects poverty and global health disparities.  There has never been a greater need for health and political leaders to join hands in a concerted effort to find sustainable solutions, pursuing bold new policies that are adequately funded and supported to achieve ultimate tuberculosis eradication.”

In a Comment with the Series, Lancet Editor-in-Chief Dr Richard Horton and Executive Editor Dr Pamela Das say: “Although epidemiological data and funding flows are routinely collected by WHO and others, there is no formal mechanism to assess this information critically and independently. Nor is there any means to hold the various stakeholders in tuberculosis control to account. The Lancet TB Observatory, an internal and inclusive collection of tuberculosis scientists and physicians, will serve that function.”

Professor Ben Marais, Stellenbosch University, Tygerberg, South Africa. T) E) bjmarais@sun.ac.za

 

Dr Mario Raviglione, Stop TB Department, WHO, Geneva, Switzerland. T) +41 22 791 2663 E) raviglionem@who.int

 

Professor Alimuddin Zumla, University College, London. T) +44-207-6799311 E) a.zumla@ucl.ac.uk

 

Glenn Thomas, Senior Communications Adviser, WHO Stop TB Department. T) +41 79 509 0677 E) thomasg@who.int

 

Lancet Press Office T) +44 (0) 20 7424 4949 E) pressoffice@lancet.com / tony.kirby@lancet.com

 

For full Series paper 8, see: http://press.thelancet.com/tbsp8.pdf

 

*Note to editors: Quote direct from authors and cannot be found in paper

 

COMMENTS WITH THE SERIES: INCLUDING AGE AND TB, MIGRATION AND TB, AND COMMUNITY RESPONSE TO TB

 

For full versions of all Comments, please see: http://press.thelancet.com/tbscomments.pdf

In the first Comment with The Lancet Series on Tuberculosis, Lancet Editor-in-Chief Dr Richard Horton and Executive Editor Dr Pamela Das say that, Despite the inclusion of tuberculosis in the Millennium Development Goals (MDGs), tackling this infection as a wider development problem has hardly begun. One difficulty is that the central development issue for tuberculosis is its complex intersection with poverty. They say:  “Efforts to control TB should therefore include more than just ministries of health. Policy and practice must also include ministries responsible for finance, housing, social development, and education. Indeed, our Series concludes that treatment-related actions will be insufficient to reach global goals. There is an urgent need to assess interventions for social and economic determinants, such as malnutrition, alcohol use, poor housing, indoor air pollution, and poverty.”

Lancet Press Office T) +44 (0) 20 7424 4949 E) pressoffice@lancet.com / tony.kirby@lancet.com

For second Comment, see earlier release on HIV/TB co-infection.

The third Comment looks at the interaction of age and immunity with TB, and is written by Dr Peter R Donald, Stellenbosch University, Tygerberg, South Africa, and colleagues. They point out risk of TB disease after infection with Mycobacterium tuberculosis is highest at ages four years and younger, followed by the period of lowest risk between 5-10 years. During adolescence, risk rises sharply again to a second peak at ages 20-30 years. The authors say: “Age-related differences in disease risk are accompanied by differences in the response to infection and clinical features of disease.”

Such information is crucial to aid development of vaccines, as well as the age at which they should be administered. The authors conclude: “The dynamic interaction of age and immunity, as well as its influence on pathogen evolution, needs to be considered in the development of future vaccination strategies.”

Dr Peter R Donald, Stellenbosch University, Tygerberg, South Africa. T) +27 (0)82 6035355 / +27 (0) 21 9389592/  +27 (0) 21 5541686 E) prd@sun.ac.za

The fourth Comment looks at TB in women and children, and is written by Professor Ben Marais, Stellenbosch University, Tygerberg, South Africa and colleagues. They say: “Globally, 700 000 women die from TB every year; this disease kills more women than do all causes of maternal mortality combined. Case-fatality rates seem to be higher in women than in men, and women are more often diagnosed with extrapulmonary tuberculosis.” They add that children younger than 15 years contribute 15–20% of the global TB disease burden, with incidence rates about half those reported in adults; and highlight the need for child-friendly formulations and child dose-ranging studies of TB drugs.

They conclude: “Women and children have unique susceptibilities and might encounter substantial barriers to access appropriate care. Subgroups that require particular consideration include HIV-infected pregnant women, socially or culturally marginalised individuals, and very young or immunocompromised children. Young children are particularly susceptible, and every effort should be made to prevent exposure to tuberculosis and to provide preventive treatment should exposure occur.”

Professor Ben Marais, Stellenbosch University, Tygerberg, South Africa. E-mail contact preferred. E) bjmarais@sun.ac.za

The fifth Comment looks at the role of the community in TB response, and is written by Paula Akugizibwe, AIDS and Rights Alliance for Southern Africa, Cape Town, South Africa and  Bobby Ramakant, Stop TB Citizen News Service, Indira Nagar, Lucknow, India. They say: “In many countries, especially where tuberculosis is fuelled by HIV, government healthcare providers have been outstripped of their ability to cope with the levels of service delivery needed to meet targets. Therefore advance on the implementation of tuberculosis programmes needs broader community engagement.”

The authors note “the persistence of the historically coercive model of tuberculosis control, a model that inherently disenfranchises patients and can lead to violation of rights, alienation of patients, and reinforcement of stigma, thus undermining the improved outcomes that the model ostensibly aims to achieve” and conclude: “The mindset of top-down TB control urgently needs to be scrutinised and challenged at all levels of health leadership. We need a much more progressive model to harness and optimise the effect of community participation, without which our collective potential to overcome this community disease cannot be realised.”

Paula Akugizibwe, AIDS and Rights Alliance for Southern Africa, Cape Town, South Africa. T) +27 83 642 0817 E) paula@arasa.info

The final Comment looks at migration and TB, and is written by Dr Henry M Blumberg, Emory University, Atlanta, USA, and colleagues. They say that nearly 1 billion—or one of seven—people are migrants. An estimated 740 million are internal migrants and 200 million are international migrants, with most (130 million) moving from one developing country to another and 70 million moving from a developing to a developed country. The authors say: “Migrants are disproportionately affected by TB, a reflection of the high rate of disease in their country of origin due to poverty and made worse by limited health-care and public health infrastructure. Migration has significantly affected the epidemiology of TB in high-income countries in Europe, USA, and Canada, which have a low incidence of TB but where most cases now occur in migrants (ie, foreign-born individuals); most cases of multidrug-resistant TB are imported as well.”
They conclude: “Unfortunately, governmental public policies towards migrants have been antagonistic to TB control efforts by furthering stigma and marginalisation… Each country should first ensure that, everywhere, all patients with tuberculosis have easy access to diagnosis and treatment free of charge, and that undocumented migrants are not deported until completion of treatment, as stated by the International Union Against Tuberculosis and Lung Disease… In view of globalisation and migration, the mantra, ‘tuberculosis anywhere is tuberculosis everywhere’ rings true.”

Dr Henry M Blumberg, Emory University, Atlanta, USA. T) +1 404-727-399 E) henry.m.blumberg@emory.edu

 

 

 

 

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