Lucica Ditiu

Drug-resistant tuberculosis: time for visionary political leadership

Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans.

Drug-Resistant Tuberculosis--Current dilemmas, unanswered questions, challenges, and priority needs

Tuberculosis was declared a global emergency by the World Health Organization (WHO) in 1993. Following the declaration and the promotion in 1995 of directly observed treatment short course (DOTS), a cost-effective strategy to contain the tuberculosis epidemic, nearly 7 million lives have been saved compared with the pre-DOTS era, high cure rates have been achieved in most countries worldwide, and the global incidence of tuberculosis has been in a slow decline since the early 2000s. However, the emergence and spread of multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, and more recently, totally drug-resistant tuberculosis pose a threat to global tuberculosis control. Multidrug-resistant tuberculosis is a man-made problem. Laboratory facilities for drug susceptibility testing are inadequate in most tuberculosis-endemic countries, especially in Africa; thus diagnosis is missed, routine surveillance is not implemented, and the actual numbers of global drug-resistant tuberculosis cases have yet to be estimated. This exposes an ominous situation and reveals an urgent need for commitment by national programs to health system improvement because the response to MDR tuberculosis requires strong health services in general. Multidrug-resistant tuberculosis and XDR tuberculosis greatly complicate patient management within resource-poor national tuberculosis programs, reducing treatment efficacy and increasing the cost of treatment to the extent that it could bankrupt healthcare financing in tuberculosis-endemic areas. Why, despite nearly 20 years of WHO-promoted activity and >12 years of MDR tuberculosis-specific activity, has the country response to the drug-resistant tuberculosis epidemic been so ineffectual? The current dilemmas, unanswered questions, operational issues, challenges, and priority needs for global drug resistance screening and surveillance, improved treatment regimens, and management of outcomes and prevention of DR tuberculosis are discussed.

Results from early programmatic implementation of Xpert MTB/RIF testing in nine countries

BackgroundThe Xpert MTB/RIF assay has garnered significant interest as a sensitive and rapid diagnostic tool to improve detection of sensitive and drug resistant tuberculosis. However, most existing literature has described the performance of MTB/RIF testing only in study conditions; little information is available on its use in routine case finding. TB REACH is a multi-country initiative focusing on innovative ways to improve case notification.MethodsWe selected a convenience sample of nine TB REACH projects for inclusion to cover a range of implementers, regions and approaches. Standard quarterly reports and machine data from the first 12 months of MTB/RIF implementation in each project were utilized to analyze patient yields, rifampicin resistance, and failed tests. Data was collected from September 2011 to March 2013. A questionnaire was implemented and semi-structured interviews with project staff were conducted to gather information on user experiences and challenges.ResultsAll projects used MTB/RIF testing for people with suspected TB, as opposed to testing for drug resistance among already diagnosed patients. The projects placed 65 machines (196 modules) in a variety of facilities and employed numerous case-finding strategies and testing algorithms. The projects consumed 47,973 MTB/RIF tests. Of valid tests, 7,195 (16.8%) were positive for MTB. A total of 982 rifampicin resistant results were found (13.6% of positive tests). Of all tests conducted, 10.6% failed. The need for continuous power supply was noted by all projects and most used locally procured solutions. There was considerable heterogeneity in how results were reported and recorded, reflecting the lack of standardized guidance in some countries.ConclusionsThe findings of this study begin to fill the gaps among guidelines, research findings, and real-world implementation of MTB/RIF testing. Testing with Xpert MTB/RIF detected a large number of people with TB that routine services failed to detect. The study demonstrates the versatility and impact of the technology, but also outlines various surmountable barriers to implementation. The study is not representative of all early implementer experiences with MTB/RIF testing but rather provides an overview of the shared issues as well as the many different approaches to programmatic MTB/RIF implementation.

Active case finding of tuberculosis in Europe: a Tuberculosis Network European Trials Group (TBNET) survey

Tuberculosis control depends on successful case finding and treatment of individuals infected with Mycobacterium tuberculosis. Passive case finding is widely practised: the present study aims to ascertain the consensus and possible improvements in active case finding across Europe. Recommendations from national guidelines were collected from 50 countries of the World Health Organization European region using a standard questionnaire. Contacts are universally screened for active tuberculosis and latent tuberculosis infection (LTBI). Most countries (>70%) screen those with HIV infection, prisoners and in-patient contacts. Screening of immigrants is related to their contribution to national rates of tuberculosis. Only 25 (50%) out of 50 advise a request for symptoms in their guidelines. A total of 36 (72%) out of 50 countries recommend sputum examination for those with a persistent cough; 13 countries do not, even if the chest radiograph suggests tuberculosis. Nearly all countries (49 out of 50) use tuberculin skin testing (TST); 27 (54%) out of 50 countries also perform chest radiography irrespective of the TST result. Interpretation of the TST varies widely. All countries use 6–9 months of isoniazid for treatment of LTBI, with an estimated median (range) uptake of 55% (5–92.5%). Symptoms and sputum examination could be used more widely when screening for active tuberculosis. Treatment of latent tuberculosis infection might be better focused by targeted use of interferon-γ release assays.

Zoonotic tuberculosis in human beings caused by Mycobacterium bovis—a call for action

Mycobacterium tuberculosis is recognised as the primary cause of human tuberculosis worldwide. However, substantial evidence suggests that the burden of Mycobacterium bovis, the cause of bovine tuberculosis, might be underestimated in human beings as the cause of zoonotic tuberculosis. In 2013, results from a systematic review and meta-analysis of global zoonotic tuberculosis showed that the same challenges and concerns expressed 15 years ago remain valid. These challenges faced by people with zoonotic tuberculosis might not be proportional to the scientific attention and resources allocated in recent years to other diseases. The burden of zoonotic tuberculosis in people needs important reassessment, especially in areas where bovine tuberculosis is endemic and where people live in conditions that favour direct contact with infected animals or animal products. As countries move towards detecting the 3 million tuberculosis cases estimated to be missed annually, and in view of WHOs end TB strategy endorsed by the health authorities of WHO Member States in 2014 to achieve a world free of tuberculosis by 2035, we call on all tuberculosis stakeholders to act to accurately diagnose and treat tuberculosis caused by M bovis in human beings.

Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models.

Summary Background The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements. Methods 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy. Findings Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31–62%) and a 72% reduction in mortality (range 64–82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis. Interpretation Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level. Funding Bill and Melinda Gates Foundation

Cost-effectiveness and resource implications of aggressive action on tuberculosis in China, India, and South Africa: a combined analysis of nine models.

BACKGROUND The post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa. METHODS We examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016-35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice. FINDINGS Incremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective. INTERPRETATION Expansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary. FUNDING Bill & Melinda Gates Foundation.

Setting new targets in the fight against tuberculosis

To the Editor: A recent article published by Nature Medicine (19, 115, 2013) on future, post-2015 global targets for tuberculosis (commonly called TB) control mentioned the potential of clashing among experts who were about to convene in Geneva in early February at the behest of the World Health Organization (WHO). In the article, particular emphasis was put on the possibility of a target of 50% reduction in death from this disease by 2025 as compared to 2015 levels. This target was one among several proposed and debated during the November 2012 Union World Conference on Lung Health in Kuala Lumpur, Malaysia. The idea of a 50% target did not receive strong support by some experts as it was considered insufficiently ambitious to stimulate proper mobilization of resources and action by countries and international institutions. The WHO and the Stop TB Partnership decided, therefore, to call a consultation in Geneva as part of a series that focuses on the development of the post-2015 global tuberculosis strategy and targets for member states to consider at the 2014 World Health Assembly. The WHO workshop participants who met on 7 and 8 February shared, above all, the aspirational goal of “zero TB deaths, zero TB disease and zero suffering.” There was broad agreement on a proposed set of interim targets for the year 2025 on the path of meeting this goal. The first proposed interim target is to reduce tuberculosis deaths by 75% by 2025 compared with 2015, which would mean a decrease from a projected 1.2 million tuberculosis deaths in 2015 to 300,000 in 2025, thus saving millions of human lives. The second proposed interim target, which is closely related to and a determinant of the first one, is to reduce the tuberculosis incidence rate by 40% in the same timeframe. In addition, a bold 2025 target linked to universal health coverage, to reach “zero catastrophic expenditure for families affected by TB by 2025,” was proposed. To achieve these targets, a rapid acceleration in the reduction of tuberculosis incidence and mortality will be necessary, through implementation of several key interventions. These include much increased commitment and financing for rapid scale-up of available diagnostic and treatment measures, accelerated adoption of the newest and most effective technological advances to endemic settings, and progress in pursuing universal health coverage and social protection mechanisms coupled with economic development and poverty reduction. The participants also agreed that further dramatic progress is possible after 2025 if massive new investments are made now for the development of new tools such as innovative point-of-care diagnostics, much shorter and more effective treatment regimens and a potent vaccine that is readily available in countries where tuberculosis is endemic. The current Stop TB Partnership target date for tuberculosis elimination is 2050. But further work will be necessary to determine targets for 2030 and 2040 that might take the world to full tuberculosis elimination earlier. Further scientific and strategic meetings will be held to build consensus for—and ensure full commitment to—a new vision for tuberculosis control and elimination by a wide array of stakeholders. This vision will also be at the core of the Stop TB Partnership’s next global plan to eliminate tuberculosis.

Reversing the tuberculosis upwards trend: a success story in Romania

At present, no published evidence is available on the effectiveness of the DOTS (directly observed treatment, short-course) strategy in reducing the incidence of tuberculosis (TB) within a country in the European “hot spots”. The present study aimed to demonstrate the effectiveness of the strategy implementation in reversing the epidemiological TB trend in Romania based on programmatic data analysis. Key programme indicators were analysed from 1998 to 2007, and included DOTS coverage, case-detection rate, treatment success and overall incidence of notified cases. Internationally agreed definitions were used. The key programme indicators began declining and the World Health Assembly targets were reached (79% case-detection of new sputum-smear positive cases and 85.5% success rate in new culture-positive TB cases), 7 yrs after initiation of the DOTS expansion. The success story in Romania suggests that other middle-income, high-incidence countries (i.e. those belonging to the former Soviet Union) might be able to reach the World Health Assembly Targets and curb the burden of tuberculosis.

Tuberculosis in BRICS: challenges and opportunities for leadership within the post-2015 agenda.

Tuberculosis is a disease of poverty that claims the lives of over a million people annually.1 Globally, tuberculosis is concentrated in low- to middle-income countries. The five countries – Brazil, the Russian Federation, India, China and South Africa – that make up the BRICS group account for 46% of all incident cases of tuberculosis and 40% of all tuberculosis-related mortality. China and India alone account for almost 40% of the estimated global burden of tuberculosis and a similar proportion of all cases notified to the World Health Organization (WHO). South Africa accounts for 30% of the estimated global number of incident cases of tuberculosis–human immunodeficiency virus (HIV) coinfection. In terms of multidrug-resistant tuberculosis (MDR-TB), China, India and the Russian Federation together account for more than half – 56% – of the estimated global burden. Brazil alone accounts for about a third of the western hemisphere’s estimated burdens of tuberculosis and MDR-TB.1 Global efforts to control tuberculosis have had considerable success. These efforts have resulted in substantial progress towards halving tuberculosis prevalence and mortality between 1990 and 2015 (current targets of the Stop TB Partnership) and halting and reversing the incidence of tuberculosis by 2015 (Millennium Development Goal 6c). Despite this progress, about three million people developing tuberculosis are missed by national notification systems each year, only a small fraction of MDR-TB cases are being treated and the poor and vulnerable continue to suffer disproportionally.1 It is time to look at the enormous challenges that will have to be faced in the post-2015 agenda and the expanded leadership role that BRICS can – and should – play in the fight against tuberculosis. The five BRICS countries were grouped together because they were all fast-growing economies but they also have another similarity: they each harbour more tuberculosis cases than any other country or territory in their respective WHO region. In terms of tuberculosis, each also has different weaknesses and challenges to confront. South Africa has a staggering burden of tuberculosis–HIV coinfection. Brazil and the Russian Federation are trying to eradicate intense foci of tuberculosis among some of their most vulnerable subgroups including homeless people, prisoners, people who use drugs and indigenous populations. China is now faced with the challenge of urgently scaling up access to treatment for MDR-TB. India has more missed cases than any other country and it is difficult to assess the quality of tuberculosis care provided in the country’s very active and diverse private sector. Despite these multiple challenges, the five BRICS countries are often considered to be regional and global leaders in the fight against tuberculosis. They provide models of care and are working together to strengthen efforts that may well be instrumental in setting and achieving future global tuberculosis targets. Several examples show how these countries have addressed local challenges on a large scale, delivered important evidence for improving tuberculosis prevention and care and provided critical political support for new tuberculosis-related initiatives and policy advances. In China – after years of poor tuberculosis notification – the government scaled up access to directly observed treatment and now sees a higher proportion of the estimated notifications (89%) than any other high-burden country. The engagement of hospitals in tuberculosis care has also produced major gains. Following problems with the surveillance of severe acute respiratory syndrome in 2003, the surveillance of all communicable diseases was improved and notification of tuberculosis cases became mandatory. Surveillance of tuberculosis is now based on a nationwide network of more than 3000 facilities that are linked in real time. This network has increased the annual number of notifications and improved the quality of the surveillance data.2 India has also recently developed a web-based national notification, banned the use of inaccurate serological tests and made tuberculosis notification mandatory.3 Although Brazil has a thriving private health-care sector, all of the country’s tuberculosis patients receive treatment free of charge, with publicly-provided drugs. This initiative should slow the development of drug resistance because it should reduce the use of substandard drugs and the risk of incomplete treatment. Improving tuberculosis care will require more research and the large-scale assessment of novel interventions. Several of the BRICS countries have been involved in trials of diagnostic tests, vaccines and new drugs. For example, South Africa has played a leading role in the introduction of Xpert MTB/RIF – a rapid molecular test. It was the first country to scale up the use of this test for initial diagnosis. In 2012, this scale-up, which had strong ministerial support, led to more people being diagnosed with MDR-TB than the number of cases that WHO estimated would occur in the country. Brazil and India have also taken leading roles in the large-scale programmatic implementation of new rapid diagnostic tests.4 In addition, China and India are developing “fast-follower” diagnostic technologies to drive down costs and improve access.1 Improving vulnerable populations’ access to quality tuberculosis care is vital in the world’s attempts to reach the three million missing cases of tuberculosis each year. Brazil already has a strong political commitment to reduce social inequalities in health by implementing large-scale social protection schemes. Brazil’s national tuberculosis programme works to enhance community participation, in the Stop TB Partnership.5 By working across the various ministries that handle health and the penal sector – to introduce tuberculosis screening and improve the general conditions, infection control and tuberculosis treatment in prisons – the Russian Federation reduced tuberculosis prevalence in its prisons.6 Over the last decade, the Russian Federation has also achieved major reductions in tuberculosis incidence, prevalence and mortality.1 As the result of India’s recent implementation of a plan to expand drug susceptibility testing, the annual number of people initiating treatment for MDR-TB in 2012 was fourfold higher than for 2011.3 Since the introduction of WHO’s DOTS/Stop TB Strategy, political commitment has formed the bedrock of all successful programmes of tuberculosis control – including those in BRICS. The Ministers of Health of Lesotho, South Africa and Swaziland led the development of the first Heads of State declaration on tuberculosis; the South African Development Community’s statement on tuberculosis in the mining sector. This declaration resulted in major progress in the planning, financing and implementation of multisectoral interventions against mining-associated tuberculosis in southern Africa. All five BRICS countries are providing large levels of domestic funding for tuberculosis care. The Russian Federation, for example, invests the equivalent of more than a billion United States dollars per year in such control. India produces large amounts of anti-tuberculosis medications that are either used domestically or exported. India’s pharmaceutical industry could play a leading role in lowering the cost of treatment of MDR-TB. China, India, the Russian Federation and, particularly, Brazil and South Africa played major roles in shaping WHO’s new post-2015 TB strategy that was initially approved by WHO’s Executive Board in early 2014. It is clear that, in the control of both tuberculosis and HIV, more opportunities exist for enhanced collaboration within BRICS. Senior officials from BRICS gathered in Paris in October 2013 to discuss tuberculosis and HIV. These officials agreed to work towards decreasing the price of drugs and diagnostics and to support research on several key topics: improving service delivery for tuberculosis and HIV, developing and improving electronic information systems and improving the health of individuals who migrate within or between countries. The officials also agreed to support greater collaboration – between BRICS – on economic analyses and modelling, to optimize the allocation of health resources and to maximize efficiency and effectiveness and promote the sustainability of investments. These discussions on tuberculosis and HIV were reported to BRICS’ ministers of health when they met in Cape Town in November 2013. The Ministers agreed that tuberculosis and HIV should be prioritized as areas of work. The senior officials who met in Paris have now been asked to develop an appropriate roadmap of activities to be undertaken and to report progress to the next meeting of BRICS’ ministers of health. BRICS have made progress in tuberculosis control and treatment thanks to high levels of political commitment, the availability of domestic resources, the use of each country’s capacities and strengths and good levels of collaboration between all relevant ministries and other partners. Since these countries bear much of the global burden posed by tuberculosis, it is not surprising that they have taken leading roles in the fight against tuberculosis. To accelerate the progress, each of the BRICS countries needs to continue to innovate, to provide data on the scaling up of new approaches, and to ensure that future global tuberculosis strategies and plans promote bold efforts and set ambitious – but achievable – post-2015 targets.