Safety and availability of clofazimine in the treatment of multidrug and extensively drug-resistant tuberculosis: analysis of published guidance and meta-analysis of cohort studies.

OBJECTIVES: Given the spread of multidrug-resistant tuberculosis (MDR-TB), new therapies are urgently needed, including the repurposing of existing drugs. We aimed to assess key considerations for the clinical and programmatic use of clofazimine (Cfz), a riminophenazine with antimycobacterial activity currently used to treat leprosy. DESIGN: Fixed and random effects meta-analysis of cohort studies and systematic review. SETTING: Electronic and manual searches were combined. INCLUSION CRITERIA: Observational studies on treatment of multidrug-resistant and extremely drug-resistant tuberculosis with Cfz or a Cfz-containing regimen, and published guidance and documents relating to cost and availability were eligible. RESULTS: 5 observational studies enrolled 861 patients, of which 602 received Cfz. The pooled proportion of adverse drug reactions requiring discontinuation of Cfz treatment was 0.1% (95% CI (0.0 to 0.6%)), and the median frequency of all adverse events was 5.1%. Cfz showed in vitro efficacy against Mycobacterium tuberculosis, and Cfz-containing regimens may have had a useful role in the treatment of patients with drug-resistant strains and who had limited alternative treatment options. However, Cfz uptake remains insufficient to meet global needs; there is only one internationally quality-assured manufacturer, which produces a limited quantity of the drug prioritised for treatment of leprosy, the only indication for which the drug is registered. CONCLUSIONS: While the data were limited, Cfz was associated with a risk for adverse drug reactions comparable to that of first-line TB treatment, which could be reasonably managed under programmatic conditions. However, low market availability and high cost are important barriers to access to Cfz for patients with MDR-TB.

Challenges and controversies in defining totally drug-resistant tuberculosis.

In March 2012, in response to reports of tuberculosis (TB) resistant to all anti-TB drugs, the World Health Organization convened an expert consultation that identified issues to be resolved before defining a new category of highly drug-resistant TB. Proposed definitions are ambiguous, and extensive drug resistance is encompassed by the already defined extensively drug-resistant (XDR) TB. There is no evidence that proposed totally resistant TB differs from strains encompassed by XDR TB. Susceptibility tests for several drugs are poorly reproducible. Few laboratories can test all drugs, and there is no consensus list of all anti-TB drugs. Many drugs are used off-label for highly drug resistant TB, and new drugs formulated to combat resistant strains would render the proposed category obsolete. Labeling TB strains as totally drug resistant might lead providers to think infected patients are untreatable. These challenges must be addressed before defining a new category for highly drug-resistant TB.

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.

Viewpoint TB diagnostics: what does the world really need?

Stagnant tuberculosis (TB) case detection and rising TB drug resistance are in part the result of historically neglected laboratory services, slow technology transfer, and a lack of new TB diagnostic tools. The last decade has, however, seen the diagnostic pipeline grow rapidly, with research and investment prompted by concerns about the global spread of drug resistance and transmission in human immunodeficiency virus (HIV) settings. The drawbacks of conventional microbiological methods for TB diagnosis and resistance detection have largely been overcome by modern molecular technologies; however, the much needed point-of-care TB test will remain elusive if expectations stay unrealistic and research and funding strategies are not changed. Development of new technologies, better use of existing tools, and adequate treatment capacity to care for the increasing numbers of cases that will be diagnosed with scale-up of TB diagnostics all need to be addressed simultaneously.

Drug-Resistant tuberculosis, KwaZulu-Natal, South Africa, 2001-2007.

In Africa, incidence and prevalence of drug-resistant tuberculosis have been assumed to be low. However, investigation after a 2005 outbreak of extensively drug-resistant tuberculosis in KwaZulu-Natal Province, South Africa, found that the incidence rate for multidrug-resistant tuberculosis in KwaZulu-Natal was among the highest globally and would be higher if case-finding efforts were intensified.

Tuberculosis among health care workers.

To assess the annual risk for latent tuberculosis infection (LTBI) among health care workers (HCWs), the incidence rate ratio for tuberculosis (TB) among HCWs worldwide, and the population-attributable fraction of TB to exposure of HCWs in their work settings, we reviewed the literature. Stratified pooled estimates for the LTBI rate for countries with low (<50 cases/100,000 population), intermediate (50-100/100,000 population), and high (>100/100,000 population) TB incidence were 3.8% (95% confidence interval [CI] 3.0%-4.6%), 6.9% (95% CI 3.4%-10.3%), and 8.4% (95% CI 2.7%-14.0%), respectively. For TB, estimated incident rate ratios were 2.4 (95% CI 1.2-3.6), 2.4 (95% CI 1.0-3.8), and 3.7 (95% CI 2.9-4.5), respectively. Median estimated population-attributable fraction for TB was as high as 0.4%. HCWs are at higher than average risk for TB. Sound TB infection control measures should be implemented in all health care facilities with patients suspected of having infectious TB.

Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis.

Although progress has been made to reduce global incidence of drug-susceptible tuberculosis, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis during the past decade threatens to undermine these advances. However, countries are responding far too slowly. Of the estimated 440,000 cases of MDR tuberculosis that occurred in 2008, only 7% were identified and reported to WHO. Of these cases, only a fifth were treated according to WHO standards. Although treatment of MDR and XDR tuberculosis is possible with currently available diagnostic techniques and drugs, the treatment course is substantially more costly and laborious than for drug-susceptible tuberculosis, with higher rates of treatment failure and mortality. Nonetheless, a few countries provide examples of how existing technologies can be used to reverse the epidemic of MDR tuberculosis within a decade. Major improvements in laboratory capacity, infection control, performance of tuberculosis control programmes, 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 tuberculosis to prevent drug-resistant strains from becoming the dominant form of tuberculosis. New diagnostic tests and drugs are likely to become available during the next few years and should accelerate control of MDR and XDR tuberculosis. 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 infrastructure necessary to manage MDR tuberculosis on a national scale.

HIV infection-associated tuberculosis: the epidemiology and the response.

Of the 33.2 million persons infected with human immunodeficiency virus (HIV), one-third are estimated to also be infected with Mycobacterium tuberculosis. In 2008, there were an estimated 1.4 million new cases of tuberculosis (TB) among persons with HIV infection, and TB accounted for 26% of AIDS-related deaths. The relative risk of TB among HIV-infected persons, compared with that among HIV-uninfected persons, ranges from 20- and 37-fold, depending on the state of the HIV epidemic. In 2008, 1.4 million patients with TB were tested globally for HIV, and 81 countries tested more than half of their patients with TB for HIV. Only 4% of all persons infected with HIV were screened for TB in the same year. Decentralization of HIV treatment services and strengthening of its integration with TB services are essential. Use of the highly decentralized TB services as an entry point to rapidly expand access to antiretroviral therapy and methods for prevention of HIV infection must be pursued aggressively.

Tuberculosis incidence in prisons: a systematic review.

BACKGROUND: Transmission of tuberculosis (TB) in prisons has been reported worldwide to be much higher than that reported for the corresponding general population. METHODS AND FINDINGS: A systematic review has been performed to assess the risk of incident latent tuberculosis infection (LTBI) and TB disease in prisons, as compared to the incidence in the corresponding local general population, and to estimate the fraction of TB in the general population attributable (PAF%) to transmission within prisons. Primary peer-reviewed studies have been searched to assess the incidence of LTBI and/or TB within prisons published until June 2010; both inmates and prison staff were considered. Studies, which were independently screened by two reviewers, were eligible for inclusion if they reported the incidence of LTBI and TB disease in prisons. Available data were collected from 23 studies out of 582 potentially relevant unique citations. Five studies from the US and one from Brazil were available to assess the incidence of LTBI in prisons, while 19 studies were available to assess the incidence of TB. The median estimated annual incidence rate ratio (IRR) for LTBI and TB were 26.4 (interquartile range [IQR]: 13.0-61.8) and 23.0 (IQR: 11.7-36.1), respectively. The median estimated fraction (PAF%) of tuberculosis in the general population attributable to the exposure in prisons for TB was 8.5% (IQR: 1.9%-17.9%) and 6.3% (IQR: 2.7%-17.2%) in high- and middle/low-income countries, respectively. CONCLUSIONS: The very high IRR and the substantial population attributable fraction show that much better TB control in prisons could potentially protect prisoners and staff from within-prison spread of TB and would significantly reduce the national burden of TB. Future studies should measure the impact of the conditions in prisons on TB transmission and assess the population attributable risk of prison-to-community spread. Please see later in the article for the Editors' Summary.

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.

HIV seroprevalence among new TB patients in the civilian and prisoner populations of Donetsk Oblast, Ukraine.

After the Russian Federation, Ukraine is the country of the Former Soviet Union experiencing the greatest epidemics of tuberculosis (TB) and HIV, although complete official data are not available. This study investigates the prevalence of HIV among new TB patients in the civilian and penitentiary populations of Donetsk Oblast. A cross-sectional survey was undertaken of 1507 new patients with TB (1351 civilians, 156 prisoners) between January and June 2006. The prevalence of HIV among patients with TB was 15.5% (95% confidence interval 13.7-17.6) and 23.7% (95% CI 17.3-31.2) in the civilian and penitentiary sectors, respectively. Reported injecting drug use was the strongest independent predictor for HIV infection, followed by young age (25-44 y). Being prisoners was also found a significant independent predictor for HIV infection (OR: 1.5, 95% CI 1.1-2.1). In conclusion, the prevalence of HIV in the TB population is the highest ever reported in Ukraine, almost 2 times higher than the World Health Organization estimates for 2005 (7.9%), and 3 percentage points higher than the official data reported. These findings call for urgent measures to control HIV and, consequently, HIV-related TB.

Opportunities and challenges for HIV care in overlapping HIV and TB epidemics.

Tuberculosis (TB) and the emerging multidrug-resistant TB epidemic represent major challenges to human immunodeficiency virus (HIV) care and treatment programs in resource-limited settings. Tuberculosis is a major cause of mortality among patients with HIV and poses a risk throughout the course of HIV disease, even after successful initiation of antiretroviral therapy (ART). Progress in the implementation of activities directed at reducing TB burden in the HIV population lags far behind global targets. HIV programs designed for longitudinal care are ideally suited to implement TB control measures and have no option but to address TB vigorously to save patient lives, to safeguard the massive investment in HIV treatment, and to curb the global TB burden. We propose a framework of strategic actions for HIV care programs to optimally integrate TB into their services. The core activities of this framework include intensified TB case finding, treatment of TB, isoniazid preventive treatment, infection control, administration of ART, TB recording and reporting, and joint efforts of HIV and TB programs at the national and local levels.

Tuberculosis and air travel: WHO guidance in the era of drug-resistant TB.

Air travel provides opportunities for infectious diseases to spread rapidly between countries and continents. There may be a potential risk of transmission during the flight, notably with airborne and droplet-borne respiratory infections. Seven episodes of potential transmission of TB infection during air travel reported in 1992--1994 caused widespread concern. Contact investigations revealed evidence of transmission of infection in two instances but active TB disease was not found in any of the infected individuals, or in subsequently published cases. In recent years, multidrug-resistant TB (MDR-TB) has become an increasingly important public health problem in many countries, exacerbated by the emergence of extensively drug-resistant TB (XDR-TB). The potential risk of transmission of particularly dangerous forms of TB requires renewed vigilance. The revised International Health Regulations (1995) include new provisions which are relevant to the transmission of TB on aircraft. WHO published a second edition of Tuberculosis and air travel: guidelines for prevention and control in 2006, providing updated information and specific guidance for passengers and crew, physicians, public health authorities and airline companies. Following several recent incidents involving MDR-TB and XDR-TB in airline passengers, the 2006 recommendations will be amplified in the light of experience gained and the evolving epidemiological situation.

Limitations on human rights: are they justifiable to reduce the burden of TB in the era of MDR- and XDR-TB?

Tuberculosis, in all its forms, poses a serious, demonstrable threat to the health of countless individuals as well as to health as a public good. MDR-TB and, in particular, the emergence of XDR-TB, have re-opened the debate on the importance, and nature, of treatment supervision for basic TB control and the management of drug-resistant TB. Enforcing compulsory measures regarding TB patients raises questions of respect for human rights. Yet, international law provides for rights-limiting principles, which would justify enforcing compulsory measures against TB patients who refuse to have diagnostic procedures or who refuse to be monitored and treated once disease is confirmed. This article analyzes under what circumstances compulsory measures for TB patients may be enforced under international law. Compulsory measures for TB patients may, in fact, be justified on legal grounds provided that these measures are foreseen in the law, that they are used as a last resort, and that safeguards are in place to protect affected individuals. The deadly nature of the disease, its epidemiology, the high case fatality rate, and the speed at which the disease leads to death when associated with HIV are proven.