Knut Lönnroth

Tuberculosis control and elimination 2010–50: cure, care, and social development

Rapid expansion of the standardised approach to tuberculosis diagnosis and treatment that is recommended by WHO allowed more than 36 million people to be cured between 1995 and 2008, averting up to 6 million deaths. Yet tuberculosis remains a severe global public health threat. There are more than 9 million new cases every year worldwide, and the incidence rate is falling at less than 1% per year. Although the overall target related to the Millennium Development Goals of halting and beginning to reverse the epidemic might have already been reached in 2004, the more important long-term elimination target set for 2050 will not be met with present strategies and instruments. Several key challenges persist. Many vulnerable people do not have access to affordable services of sufficient quality. Technologies for diagnosis, treatment, and prevention are old and inadequate. Multidrug-resistant tuberculosis is a serious threat in many settings. HIV/AIDS continues to fuel the tuberculosis epidemic, especially in Africa. Furthermore, other risk factors and underlying social determinants help to maintain tuberculosis in the community. Acceleration of the decline towards elimination of this disease will need invigorated actions in four broad areas: continued scale-up of early diagnosis and proper treatment for all forms of tuberculosis 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 towards innovations.

The impact of diabetes on tuberculosis treatment outcomes: A systematic review

BackgroundMultiple studies of tuberculosis treatment have indicated that patients with diabetes mellitus may experience poor outcomes.We performed a systematic review and meta-analysis to quantitatively summarize evidence for the impact of diabetes on tuberculosis outcomes.MethodsWe searched PubMed, EMBASE and the World Health Organization Regional Indexes from 1 January 1980 to 31 December 2010 and references of relevant articles for reports of observational studies that included people with diabetes treated for tuberculosis. We reviewed the full text of 742 papers and included 33 studies of which 9 reported culture conversion at two to three months, 12 reported the combined outcome of failure and death, 23 reported death, 4 reported death adjusted for age and other potential confounding factors, 5 reported relapse, and 4 reported drug resistant recurrent tuberculosis.ResultsDiabetes is associated with an increased risk of failure and death during tuberculosis treatment. Patients with diabetes have a risk ratio (RR) for the combined outcome of failure and death of 1.69 (95% CI, 1.36 to 2.12). The RR of death during tuberculosis treatment among the 23 unadjusted studies is 1.89 (95% CI, 1.52 to 2.36), and this increased to an effect estimate of 4.95 (95% CI, 2.69 to 9.10) among the 4 studies that adjusted for age and other potential confounding factors. Diabetes is also associated with an increased risk of relapse (RR, 3.89; 95% CI, 2.43 to 6.23). We did not find evidence for an increased risk of tuberculosis recurrence with drug resistant strains among people with diabetes. The studies assessing sputum culture conversion after two to three months of tuberculosis therapy were heterogeneous with relative risks that ranged from 0.79 to 3.25.ConclusionsDiabetes increases the risk of failure and death combined, death, and relapse among patients with tuberculosis. This study highlights a need for increased attention to treatment of tuberculosis in people with diabetes, which may include testing for suspected diabetes, improved glucose control, and increased clinical and therapeutic monitoring.

Towards tuberculosis elimination: an action framework for low-incidence countries

This paper describes an action framework for countries with low tuberculosis (TB) incidence (<100 TB cases per million population) that are striving for TB elimination. The framework sets out priority interventions required for these countries to progress first towards “pre-elimination” (<10 cases per million) and eventually the elimination of TB as a public health problem (less than one case per million). TB epidemiology in most low-incidence countries is characterised by a low rate of transmission in the general population, occasional outbreaks, a majority of TB cases generated from progression of latent TB infection (LTBI) rather than local transmission, concentration to certain vulnerable and hard-to-reach risk groups, and challenges posed by cross-border migration. Common health system challenges are that political commitment, funding, clinical expertise and general awareness of TB diminishes as TB incidence falls. The framework presents a tailored response to these challenges, grouped into eight priority action areas: 1) ensure political commitment, funding and stewardship for planning and essential services; 2) address the most vulnerable and hard-to-reach groups; 3) address special needs of migrants and cross-border issues; 4) undertake screening for active TB and LTBI in TB contacts and selected high-risk groups, and provide appropriate treatment; 5) optimise the prevention and care of drug-resistant TB; 6) ensure continued surveillance, programme monitoring and evaluation and case-based data management; 7) invest in research and new tools; and 8) support global TB prevention, care and control. The overall approach needs to be multisectorial, focusing on equitable access to high-quality diagnosis and care, and on addressing the social determinants of TB. Because of increasing globalisation and population mobility, the response needs to have both national and global dimensions. Action framework for countries with low tuberculosis incidence: a coherent approach for eliminating tuberculosis http://ow.ly/H03ZZ

Alcohol use as a risk factor for tuberculosis – a systematic review

BackgroundIt has long been evident that there is an association between alcohol use and risk of tuberculosis. It has not been established to what extent this association is confounded by social and other factors related to alcohol use. Nor has the strength of the association been established. The objective of this study was to systematically review the available evidence on the association between alcohol use and the risk of tuberculosis.MethodsBased on a systematic literature review, we identified 3 cohort and 18 case control studies. These were further categorized according to definition of exposure, type of tuberculosis used as study outcome, and confounders controlled for. Pooled effect sizes were obtained for each sub-category of studies.ResultsThe pooled relative risk across all studies that used an exposure cut-off level set at 40 g alcohol per day or above, or defined exposure as a clinical diagnosis of an alcohol use disorder, was 3.50 (95% CI: 2.01–5.93). After exclusion of small studies, because of suspected publication bias, the pooled relative risk was 2.94 (95% CI: 1.89–4.59). Subgroup analyses of studies that had controlled for various sets of confounders did not give significantly different results and did not explain the significant heterogeneity that was found across the studies.ConclusionThe risk of active tuberculosis is substantially elevated in people who drink more than 40 g alcohol per day, and/or have an alcohol use disorder. This may be due to both increased risk of infection related to specific social mixing patterns associated with alcohol use, as well as influence on the immune system of alcohol itself and of alcohol related conditions.

Trends in tuberculosis incidence and their determinants in 134 countries

OBJECTIVE To determine whether differences in national trends in tuberculosis incidence are attributable to the variable success of control programmes or to biological, social and economic factors. METHODS We used trends in case notifications as a measure of trends in incidence in 134 countries, from 1997 to 2006, and used regression analysis to explore the associations between these trends and 32 measures covering various aspects of development (1), the economy (6), the population (3), behavioural and biological risk factors (9), health services (6) and tuberculosis (TB) control (7). FINDINGS The TB incidence rate changed annually within a range of +/-10% over the study period in the 134 countries examined, and its average value declined in 93 countries. The rate was declining more quickly in countries that had a higher human development index, lower child mortality and access to improved sanitation. General development measures were also dominant explanatory variables within regions, though correlation with TB incidence trends varied geographically. The TB incidence rate was falling more quickly in countries with greater health expenditure (situated in central and eastern Europe and the eastern Mediterranean), high-income countries with lower immigration, and countries with lower child mortality and HIV infection rates (located in Latin America and the Caribbean). The intensity of TB control varied widely, and a possible causal link with TB incidence was found only in Latin America and the Caribbean, where the rate of detection of smear-positive cases showed a negative correlation with national incidence trends. CONCLUSION Although TB control programmes have averted millions of deaths, their effects on transmission and incidence rates are not yet widely detectable.

Scaling up interventions to achieve global tuberculosis control: progress and new developments

Tuberculosis is still one of the most important causes of death worldwide. The 2010 Lancet tuberculosis series provided a comprehensive overview of global control efforts and challenges. In this update we review recent progress. With improved control efforts, the world and most regions are on track to achieve the Millennium Development Goal of decreasing tuberculosis incidence by 2015, and the Stop TB Partnership target of halving 1990 mortality rates by 2015; the exception is Africa. Despite these advances, full scale-up of tuberculosis and HIV collaborative activities remains challenging and emerging drug-resistant tuberculosis is a major threat. Recognition of the effect that non-communicable diseases--such as smoking-related lung disease, diet-related diabetes mellitus, and alcohol and drug misuse--have on individual vulnerability, as well as the contribution of poor living conditions to community vulnerability, shows the need for multidisciplinary approaches. Several new diagnostic tests are being introduced in endemic countries and for the first time in 40 years a coordinated portfolio of promising new tuberculosis drugs exists. However, none of these advances offer easy solutions. Achievement of international tuberculosis control targets and maintenance of these gains needs optimum national health policies and services, with ongoing investment into new approaches and strategies. Despite growing funding in recent years, a serious shortfall persists. International and national financial uncertainty places gains at serious risk. Perseverance and renewed commitment are needed to achieve global control of tuberculosis, and ultimately, its elimination.

WHO's new end TB strategy.

On May 19, 2014, the 67th World Health Assembly (WHA) adopted WHO’s “Global strategy and targets for tuberculosis prevention, care and control after 2015”. This post-2015 global tuberculosis strategy, labelled the End TB Strategy, was shaped during the past 2 years. A wide range of stakeholders—from ministries of health and national tuberculosis programmes to technical and scientifi c institutions, fi nancial and development partners, civil society and health activists, non-governmental organisations, and the private sector—contributed to its development. The strategy has a vision of making the world free of tuberculosis, with zero deaths, disease, and suff ering due to the disease (see appendix p 1 for summary of the End TB Strategy). In 2013, 9 million people fell ill with tuberculosis and 1·5 million died; about a quarter of them were HIV positive. Poor and deprived groups also bore the brunt of the enormous socioeconomic burden imposed by the disease and deaths. Concerned by this persistent human suff ering due to tuberculosis, but encouraged by the progress achieved during the past two decades and recognising the need to mount a multisectoral response to eff ectively address the problem, the health ministers at the WHA approved WHO’s proposal to push the limit of ambition to “end the global tuberculosis epidemic” by 2035, marked by well defi ned milestones and targets set along the way. Ending the tuberculosis epidemic implies bringing the levels of tuberculosis in the whole world down to converge with those already attained by many rich countries: fewer than ten new tuberculosis cases occurring per 100 000 population per year amounting to 90% reduction in tuberculosis incidence and tuberculosis deaths reduced by 95%. The rich countries achieved remarkable reductions in the tuberculosis burden not only by delivering adequate tuberculosis services, but also by pursuing universal access to health care and social protection while rapidly improving nutrition and economic conditions. Ending the tuberculosis epidemic in high-incidence countries needs a similar approach that guarantees access to high-quality tuberculosis care and prevention to all while simul taneously addressing the social determinants of tuberculosis. To this eff ect, elimination of catastrophic costs that tuberculosis-aff ected families face is an important milestone to be achieved under the End TB Strategy well within the next decade. Importantly, though, achievement of universal access to currently available methods of tuberculosis care and prevention will not be enough to end the epidemic within two decades. Global investments and eff orts are also essential to develop improved methods to diagnose, treat, and prevent tuberculosis. Equal emphasis on achievement of universal access to tuberculosis care and prevention, addressing of weaknesses in health systems and social determinants of tuberculosis, and pursuing of research and innovation for improved approaches and strategies constitute the core of the End TB Strategy. The achievements of the past two decades provide the basis for further progress. The DOTS (directly observed treatment, short-course) strategy of 1995 expanded access to high-quality tuberculosis care. The Stop TB Strategy of 2006 widened its scope to address management of all forms of tuberculosis including HIV-associated and drug-resistant tuberculosis, through engagement of communities, involvement of all care providers, strengthening of health systems, and fostering of research. Subsequently, the tuberculosis-related Millennium Development Goal to “halt and begin to reverse the incidence of tuberculosis” was achieved; 37 million lives were saved between 2000 and 2013; and a new rapid molecular test to simultaneously diagnose tuberculosis and rifampicin resistance was developed and two novel drugs were introduced. These achievements notwithstanding, the enormity of the task ahead cannot be overemphasised. Overall, the current 2% annual reduction in the global tuberculosis incidence is too slow to achieve an end to the epidemic in the foreseeable future. Tuberculosis remains a top infectious killer of men and women. A third of estimated incident tuberculosis cases go un-notifi ed or undiagnosed and close to half a million multidrug-resistant cases emerge each year. HIV-associated tuberculosis aff ects more than a million people a year. An estimated 2 billion people with latent tuberculosis infection form a reservoir that sustains the global epidemic. Analyses of constraints to global tuberculosis control bring four major persisting barriers to the fore. First, weak health systems including the unregulated non-state sector prevent reaching the currently available methods of diagnosis and treatment to all sections of the populations and a lack of universal health coverage and social protection inhibit provision of comprehensive tuberculosis care and prevention without further impoverishment to those who need it most. Second, determinants such as poverty, under nutrition, migration, and ageing populations enhance vulnerability and maintain the cycle of infection and disease. The risk of tuberculosis is further enhanced by non-communicable health problems such as diabetes, harmful use of alcohol, and tobacco smoking. Third, the lack of optimum methods—a point-of-care test for rapid diagnosis of disease and latent infection; better and safer drug regimens to shorten treatment; and a vaccine to prevent Lancet 2015; 385: 1799–801

Global epidemiology of tuberculosis: prospects for control.

The burden of tuberculosis (TB) is now very slowly decreasing globally. However, the rate of decline is too slow to reach all the epidemiological impact targets set for 2015. The prospects for reaching the TB elimination target set for 2050 are even bleaker. Implementation of the World Health Organizations Stop TB Strategy is currently lagging behind the envisioned scale-up pace, particularly with regard to TB/HIV collaborative activities and management of drug resistant TB. To ensure long-term TB control there is, first, a need to ensure that all components of the Stop TB Strategy are scaled up according to plans, with special attention to improved access for the poor. However, this may not be enough. Recent analyses suggest that the impact of current efforts to reduce TB incidence is less than expected and that improved diagnostic and curative efforts need to be combined with additional preventive efforts. New and more effective vaccines and drugs for preventive treatment would revolutionize TB control. A stronger focus on prevention would also entail more concerted actions to limit the impact of TB risk factors, including HIV/AIDS, smoking, malnutrition, alcoholism, diabetes, crowded living conditions, and indoor air pollution, which may all contribute a considerable proportion of the global TB burden.

The association between alcohol use, alcohol use disorders and tuberculosis (TB). A systematic review.

BackgroundIn 2004, tuberculosis (TB) was responsible for 2.5% of global mortality (among men 3.1%; among women 1.8%) and 2.2% of global burden of disease (men 2.7%; women 1.7%). The present work portrays accumulated evidence on the association between alcohol consumption and TB with the aim to clarify the nature of the relationship.MethodsA systematic review of existing scientific data on the association between alcohol consumption and TB, and on studies relevant for clarification of causality was undertaken.ResultsThere is a strong association between heavy alcohol use/alcohol use disorders (AUD) and TB. A meta-analysis on the risk of TB for these factors yielded a pooled relative risk of 2.94 (95% CI: 1.89-4.59). Numerous studies show pathogenic impact of alcohol on the immune system causing susceptibility to TB among heavy drinkers. In addition, there are potential social pathways linking AUD and TB. Heavy alcohol use strongly influences both the incidence and the outcome of the disease and was found to be linked to altered pharmacokinetics of medicines used in treatment of TB, social marginalization and drift, higher rate of re-infection, higher rate of treatment defaults and development of drug-resistant forms of TB. Based on the available data, about 10% of the TB cases globally were estimated to be attributable to alcohol.ConclusionThe epidemiological and other evidence presented indicates that heavy alcohol use/AUD constitute a risk factor for incidence and re-infection of TB. Consequences for prevention and clinical interventions are discussed.

Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries

Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3–4 month isoniazid plus rifampicin; or 3–4 month rifampicin alone. Guidelines on LTBI for low TB incidence countries – essential element of the @WHO #EndTB strategy and TB elimination http://ow.ly/RW8xn