Helen Cox

Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

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.

Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis

BACKGROUND Current anti-tuberculosis therapeutics are not sufficiently effective against drug-resistant tuberculosis (DR-TB), and there is a need for new drugs and therapeutic approaches. It has been proposed that repurposing clofazimine for DR-TB treatment might be one way to increase therapeutic options. METHODS We conducted a systematic review of studies reporting on the efficacy and safety of clofazimine as part of combination therapy for DR-TB. Six databases and six conference abstract sites were searched from inception until April 2012. All studies involving the use of clofazimine in the treatment of DR-TB were included. RESULTS Twelve studies, comprising 3489 patients across 10 countries, were included in this review. Treatment success ranged from 16.5% (95% CI 2.7%-38.7%) to 87.8% (95% CI 76.8%-95.6%), with an overall pooled proportion of 61.96% achieving treatment success (95% CI 52.79%-71.12%) (τ(2) 0.07). Mortality, treatment interruptions, defaulting and adverse events were all in line with DR-TB treatment outcomes overall. The most commonly reported adverse events were gastrointestinal disturbances and skin pigmentation. CONCLUSIONS The available evidence to date suggests that clofazimine could be considered as an additional therapeutic option in the treatment of DR-TB. The optimal dose of clofazimine and duration of use require further investigation.

Wind-Driven Roof Turbines: A Novel Way to Improve Ventilation for TB Infection Control in Health Facilities

Objective Tuberculosis transmission in healthcare facilities contributes significantly to the TB epidemic, particularly in high HIV settings. Although improving ventilation may reduce transmission, there is a lack of evidence to support low-cost practical interventions. We assessed the efficacy of wind-driven roof turbines to achieve recommended ventilation rates, compared to current recommended practices for natural ventilation (opening windows), in primary care clinic rooms in Khayelitsha, South Africa. Methods Room ventilation was assessed (CO2 gas tracer technique) in 4 rooms where roof turbines and air-intake grates were installed, across three scenarios: turbine, grate and window closed, only window open, and only turbine and grate open, with concurrent wind speed measurement. 332 measurements were conducted over 24 months. Findings For all 4 rooms combined, median air changes per hour (ACH) increased with wind speed quartiles across all scenarios. Higher median ACH were recorded with open roof turbines and grates, compared to open windows across all wind speed quartiles. Ventilation with open turbine and grate exceeded WHO-recommended levels (60 Litres/second/patient) for 95% or more of measurements in 3 of the 4 rooms; 47% in the remaining room, where wind speeds were lower and a smaller diameter turbine was installed. Conclusion High room ventilation rates, meeting recommended thresholds, may be achieved using wind-driven roof turbines and grates, even at low wind speeds. Roof turbines and air-intake grates are not easily closed by staff, allowing continued ventilation through colder periods. This simple, low-cost technology represents an important addition to our tools for TB infection control.

Effect of multidrug resistance on global tuberculosis control.

In their Seminar on tuberculosis Thomas Frieden and colleagues (Sept 13 p 887) note that to tackle the current epidemic affecting many resource-poor settings emphasis needs to be placed on effective global control of the disease. It is important to add discussion on the extent to which high rates of drug-resistant forms of tuberculosis now emerging in many resource-poor regions of the world are jeopardising pre-existing tuberculosis control measures. If we are to have any hope of stemming the global pandemic emphasis needs to be placed on the freeing up of resources globally to address drug resistance and to bring treatment options to infected patients. (excerpt)

Decentralisation of multidrug-resistant-tuberculosis care and management.

Multidrug-resistant (MDR) tuberculosis is an important medical and public health challenge, affl icting an estimated 500 000 new patients each year. Recent progress in the development of new molecular diagnostic techniques and the fi rst new antituberculosis drug registration in almost 40 years provide reasons for optimism, but still, globally, less than 10% of individuals with MDR-tuberculosis receive treatment of known quality. Country data for detection and enrolment onto treatment reported to WHO over the past 3 years paint a varied picture of progress. Some high burden countries report steady increases in the numbers of patients treated over the past 3 years, notably India, Russia, and South Africa. However, less than a quarter of the countries providing complete data showed a linear increase in case detection, and less than half showed a year-on-year increase in the numbers of patients enrolled onto treatment. No country that treated more than 500 patients achieved a treatment success rate of greater than 55%. There has been progress in places, but not nearly enough. Impediments towards universal access to MDRtuberculosis treatment are many, ranging from insuffi cient donor funding to poor laboratory diagnostic capacity and health system challenges, including the need to encourage ambulatory care models. This last point is crucial, because although advances in diagnostics and improved treatment regimens will go a long way to improving access, the models of care in which such technologies are delivered will strongly aff ect patient access and retention in care. Historically, MDR-tuberculosis treatment has been provided through small, individualised programmes with specialist clinical support. Such models of care might work where patient numbers are small, but in settings like South Africa and Russia, which both detected more than 10 000 cases in 2011 alone, specialised, centralised programmes are unlikely to meet the need. Moreover, larger MDR-tuberculosis treatment programmes are associated with poorer rates of retention in care. Increased eff orts in global tuberculosis control have resulted in strong basic tuberculosis programmes in many settings that have developed local systems for supporting patients on treatment for tuberculosis and ensuring adherence. Integration of MDR-tuberculosis care and management into routine tuberculosis programmes in such settings is feasible and allows patients with MDR-resistant tuberculosis to receive treatment close to where they live. There is increasing evidence from several large-scale MDR-tuberculosis programmes of improved access to care and management through decentralisation, without compromising treatment outcomes, including programmes that have task shifted initiation of MDR-tuberculosis treatment to trained nurses. Decentralisation has been a crucial strategy for expanding access to treatment for HIV and has been associated with better patient outcomes than with hospital-managed care, mainly due to improved retention; there is a broad consensus that to improve early health-seeking behaviour, promote adherence to medication, and minimise defaulting, HIV care is best provided as close as possible to the patient’s home and community. These lessons for patient support are clearly applicable to MDR-tuberculosis because default rates from care commonly exceed 20%. One concern about decentralising MDR-tuberculosis care is the potential increased risk of community transmission, but in most high-burden settings, the MDR-tuberculosis epidemic is driven primarily by direct transmission of MDR-tuberculosis strains. The low proportion of estimated cases that are treated appropriately means that most transmission is occurring among undiagnosed and untreated cases. Therefore, eff orts to reduce transmission should be directed at diagnosing and treating as many cases as possible and as early as possible. After decades of neglect, much needed improvements in diagnostics and therapeutics are becoming available. However, their impact will be small without parallel eff orts to improve the service delivery model. Decentralisation is likely to off er the best opportunity for early initiation of treatment at the scale required, Published Online June 4, 2013 http://dx.doi.org/10.1016/ S1473-3099(13)70151-8

XDR tuberculosis can be cured with aggressive treatment

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Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method

Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection. We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference. Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34–0.42) for all patients and 0.33 (0.25–0.42) for HIV-co-infected patients. Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests. Monthly culture monitoring is crucial to earlier detection of treatment failure in MDR-TB patients http://ow.ly/w2MI301mK8M

To treat or not to treat? Implementation of DOTS in Central Asia

Limiting today’s study found in an earlier smaller series of cases of directly observed treatment short course (DOTS) expansion and restricting DOTS to only new cases does not offer hope for a rapid and longlasting solution to the ongoing tuberculosis epidemic in this region. There is an urgent need for context-specific discussion around these issues a need already acknowledged by WHO leading to an improved strategy to tackle tuberculosis in areas with high levels of multidrug-resistant disease. This strategy should include appropriate individualised treatment regimens for retreatment cases in this context. Conflicting opinions from experts a lack of clarity in many areas of the DOTS protocol and limited international discussion over the practical considerations of treating a disease that is set to kill 30 million people in the next decade leaves those working on the ground unsure of the best way to assist the populations at risk. (excerpt)