Mario Raviglione

WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

Global Surveillance for Antituberculosis-Drug Resistance, 1994–1997

BACKGROUND Drug-resistant tuberculosis threatens efforts to control the disease. This report describes the prevalence of resistance to four first-line drugs in 35 countries participating in the World Health Organization-International Union against Tuberculosis and Lung Disease Global Project on Anti-Tuberculosis Drug Resistance Surveillance between 1994 and 1997. METHODS The data are from cross-sectional surveys and surveillance reports. Participating countries followed guidelines to ensure the use of representative samples, accurate histories of treatment, standardized laboratory methods, and common definitions. A network of reference laboratories provided quality assurance. The median number of patients studied in each country or region was 555 (range, 59 to 14,344). RESULTS Among patients with no prior treatment, a median of 9.9 percent of Mycobacterium tuberculosis strains were resistant to at least one drug (range, 2 to 41 percent); resistance to isoniazid (7.3 percent) or streptomycin (6.5 percent) was more common than resistance to rifampin (1.8 percent) or ethambutol (1.0 percent). The prevalence of primary multidrug resistance was 1.4 percent (range, 0 to 14.4 percent). Among patients with histories of treatment for one month or more [corrected], the prevalence of resistance to any of the four drugs was 36.0 percent (range, 5.3 to 100 percent), and the prevalence of multidrug resistance was 13 percent (range, 0 to 54 percent). The overall prevalences were 12.6 percent for resistance to any of the four drugs [corrected] (range, 2.3 to 42.4 percent) and 2.2 percent for multidrug resistance (range, 0 to 22.1 percent). Particularly high prevalences of multidrug resistance were found in the former Soviet Union, Asia, the Dominican Republic, and Argentina. CONCLUSIONS Resistance to antituberculosis drugs was found in all 35 countries and regions surveyed, suggesting that it is a global problem.

Global trends in resistance to antituberculosis drugs.

Background Data on global trends in resistance to antituberculosis drugs are lacking. Methods We expanded the survey conducted by the World Health Organization and the International Union against Tuberculosis and Lung Disease to assess trends in resistance to antituberculosis drugs in countries on six continents. We obtained data using standard protocols from ongoing surveillance or from surveys of representative samples of all patients with tuberculosis. The standard sampling techniques distinguished between new and previously treated patients, and laboratory performance was checked by means of an international program of quality assurance. Results Between 1996 and 1999, patients in 58 geographic sites were surveyed; 28 sites provided data for at least two years. For patients with newly diagnosed tuberculosis, the frequency of resistance to at least one antituberculosis drug ranged from 1.7 percent in Uruguay to 36.9 percent in Estonia (median, 10.7 percent). The prevalence increased in Estonia, from 28....

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.

International Standards for Tuberculosis Care

Part of the reason for failing to bring about a more rapid reduction in tuberculosis incidence worldwide is the lack of effective involvement of all practitioners-public and private-in the provision of high quality tuberculosis care. While health-care providers who are part of national tuberculosis programmes have been trained and are expected to have adopted proper diagnosis, treatment, and public-health practices, the same is not likely to be true for non-programme providers. Studies of the performance of the private sector conducted in several different parts of the world suggest that poor quality care is common. The basic principles of care for people with, or suspected of having, tuberculosis are the same worldwide: a diagnosis should be established promptly; standardised treatment regimens should be used with appropriate treatment support and supervision; response to treatment should be monitored; and essential public-health responsibilities must be carried out. Prompt and accurate diagnosis, and effective treatment are essential for good patient care and tuberculosis control. All providers who undertake evaluation and treatment of patients with tuberculosis must recognise that not only are they delivering care to an individual, but they are also assuming an important public-health function. The International Standards for Tuberculosis Care (ISTC) describe a widely endorsed level of care that all practitioners should seek to achieve in managing individuals who have, or are suspected of having, tuberculosis. The document is intended to engage all care providers in delivering high quality care for patients of all ages, including those with smear-positive, smear-negative, and extra-pulmonary tuberculosis, tuberculosis caused by drug-resistant Mycobacterium tuberculosis complex, and tuberculosis combined with HIV infection.

Epidemiology of antituberculosis drug resistance 2002–07: an updated analysis of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance

BACKGROUND The Global Project on Anti-Tuberculosis Drug Resistance has been gathering data since 1994. This study provides the latest data on the extent of drug resistance worldwide. METHODS Data for drug susceptibility were gathered from 90 726 patients in 83 countries and territories between 2002 and 2007. Standardised collection of results enabled comparison both between and within countries. Where possible, data for HIV status and resistance to second-line drugs were also obtained. Laboratory data were quality assured by the Supranational Tuberculosis Reference Laboratory Network. FINDINGS The median prevalence of resistance to any drug in new cases of tuberculosis was 11.1% (IQR 7.0-22.3). The prevalence of multidrug resistance in new tuberculosis cases ranged from 0% in eight countries to 7% in two provinces in China, 11.1% in Northern Mariana Islands (although reporting only two cases), and between 6.8% and 22.3% in nine countries of the former Soviet Union, including 19.4% in Moldova and 22.3% in Baku, Azerbaijan (median for countries surveyed 1.6%, IQR 0.6-3.9). Trend analysis showed that between 1994 and 2007, the prevalence of multidrug-resistant (MDR) tuberculosis in new cases increased substantially in South Korea and in Tomsk Oblast and Orel Oblast, Russia, but was stable in Estonia and Latvia. The prevalence of MDR tuberculosis in all tuberculosis cases decreased in Hong Kong and the USA. 37 countries and territories reported representative data on extensively drug-resistant (XDR) tuberculosis. Five countries, all from the former Soviet Union, reported 25 cases or more of XDR tuberculosis each, with prevalence among MDR-tuberculosis cases ranging between 6.6% and 23.7%. INTERPRETATION MDR tuberculosis remains a threat to tuberculosis control in provinces in China and countries of the former Soviet Union. Data on drug resistance are unavailable in many countries, especially in Africa, emphasising the need to develop easier methods for surveillance of resistance in tuberculosis. FUNDING Global Project: United States Agency for International Development and Eli Lilly and Company. Drug resistance surveys: national tuberculosis programmes, the Government of the Netherlands, the Global Fund to Fight AIDS, Tuberculosis and Malaria, Japan International Cooperation Agency, and Kreditanstalt für Wiederaufbau.

WHO's new Stop TB Strategy

Government commitment diagnosis through microscopy standardised and supervised treatment uninterrupted drug supply and regular monitoring which together constitute DOTS--the WHO recommended tuberculosis control strategy--are all essential for controlling tuberculosis. DOTS has helped make remarkable progress in global control of the disease over the past decade. The gain is evident: nearly 20 million patients have been cured of tuberculosis. However global statistics suggest that DOTS alone is not sufficient to achieve the 2015 tuberculosis-related Millennium Development Goals (MDG) and the Stop TB Partnership targets. The need for a new strategy that builds on and goes beyond DOTS has also been recognised by the Second Ad-hoc Committee on the Global TB Epidemic and the 2005 World Health Assembly. (excerpt)

HIV-associated tuberculosis in developing countries: epidemiology and strategies for prevention

The association between tuberculosis and HIV presents an immediate and grave public health and socioeconomic threat, particularly in the developing world. In early 1992 WHO estimated that approximately 4 million people had been infected with both Mycobacterium tuberculosis and HIV since the beginning of the pandemic; 95% of them were in developing countries. The association between tuberculosis and HIV is evident from the high incidence of tuberculosis, estimated at 5-8% per year, among HIV-infected persons, the high HIV seroprevalence among patients with tuberculosis, the high occurrence of tuberculosis among AIDS patients, and the coincidence of increased tuberculosis notifications with the spreading of the HIV epidemic in several African countries. The impact of the two epidemics on resource-poor countries has ominous social and medical implications, and the already overstretched health services now have to face a tremendously increasing tuberculosis problem. HIV infection worsens the tuberculosis situation by increasing reactivation of latent tuberculosis infection in dually infected persons as well as by favouring rapid progression of new infections in the HIV-infected. This also results in an increase of the risk of infection and a subsequent increase of cases in the general population. In order to respond to this urgent problem, the highest priority must be given to strengthening tuberculosis control programmes in the countries where they are poorly developed and where the prevalence of HIV and tuberculosis infections is high. Besides improving the cure rate by early diagnosis and prompt treatment of patients with tuberculosis, two major strategies that need consideration include BCG vaccination and preventive chemotherapy among HIV-infected individuals. The latter strategy is considered as the most critical intervention that would help to limit the expected increase in clinical tuberculosis from the pool of HIV and tuberculosis coinfected individuals. However, a number of issues need to be addressed urgently and before such an intervention can be implemented in the developing countries.

Epidemiology of antituberculosis drug resistance (the Global Project on Anti-tuberculosis Drug Resistance Surveillance): an updated analysis.

BACKGROUND The burden of tuberculosis is compounded by drug-resistant forms of the disease. This study aimed to analyse data on antituberculosis drug resistance gathered by the WHO and International Union Against Tuberculosis and Lung Disease Global Project on Anti-tuberculosis Drug Resistance Surveillance. METHODS Data on drug susceptibility testing for four antituberculosis drugs--isoniazid, rifampicin, ethambutol, and streptomycin--were gathered in the third round of the Global Project (1999-2002) from surveys or ongoing surveillance in 79 countries or geographical settings. These data were combined with those from the first two rounds of the project and analyses were done. Countries that participated followed a standardised set of guidelines to ensure comparability both between and within countries. FINDINGS The median prevalence of resistance to any of the four antituberculosis drugs in new cases of tuberculosis identified in 76 countries or geographical settings was 10.2% (range 0.0-57.1). The median prevalence of multidrug resistance in new cases was 1.0% (range 0.0-14.2). Kazakhstan, Tomsk Oblast (Russia), Karakalpakstan (Uzbekistan), Estonia, Israel, the Chinese provinces Liaoning and Henan, Lithuania, and Latvia reported prevalence of multidrug resistance above 6.5%. Trend analysis showed a significant increase in the prevalence of multidrug resistance in new cases in Tomsk Oblast (p<0.0001). Hong Kong (p=0.01) and the USA (p=0.0002) reported significant decreasing trends in multidrug resistance in new cases of tuberculosis. INTERPRETATION Multidrug resistance represents a serious challenge for tuberculosis control in countries of the former Soviet Union and in some provinces of China. Gaps in coverage of the Global Project are substantial, and baseline information is urgently required from several countries with high tuberculosis burden to develop appropriate control interventions.

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