Charalambos Sismanidis

Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007-2010

OBJECTIVE To present a global update of drug-resistant tuberculosis (TB) and explore trends in 1994-2010. METHODS Data on drug resistance among new and previously treated TB patients, as reported by countries to the World Health Organization, were analysed. Such data are collected through surveys of a representative sample of TB patients or surveillance systems based on routine drug susceptibility testing. Associations between multidrug-resistant TB (MDR-TB) and human immunodeficiency virus (HIV) infection and sex were explored through logistic regression. FINDINGS In 2007-2010, 80 countries and 8 territories reported surveillance data. MDR-TB among new and previously treated cases was highest in the Russian Federation (Murmansk oblast, 28.9%) and the Republic of Moldova (65.1%), respectively. In three former Soviet Union countries and South Africa, more than 10% of the cases of MDR-TB were extensively drug-resistant. Globally, in 1994 to 2010 multidrug resistance was observed in 3.4% (95% confidence interval, CI: 1.9-5.0) of all new TB cases and in 19.8% (95% CI: 14.4-25.1) of previously treated TB cases. No overall associations between MDR-TB and HIV infection (odds ratio, OR: 1.4; 95% CI: 0.7-3.0) or sex (OR: 1.1; 95% CI: 0.8-1.4) were found. Between 1994 and 2010, MDR-TB rates in the general population increased in Botswana, Peru, the Republic of Korea and declined in Estonia, Latvia and the United States of America. CONCLUSION The highest global rates of MDR-TB ever reported were documented in 2009 and 2010. Trends in MDR-TB are still unclear in most settings. Better surveillance or survey data are required, especially from Africa and India.

A Four-Month Gatifloxacin-Containing Regimen for Treating Tuberculosis

BACKGROUND Shortening the course of treatment for tuberculosis would be a major improvement for case management and disease control. This phase 3 trial assessed the efficacy and safety of a 4-month gatifloxacin-containing regimen for treating rifampin-sensitive pulmonary tuberculosis. METHODS We conducted a noninferiority, randomized, open-label, controlled trial involving patients 18 to 65 years of age with smear-positive, rifampin-sensitive, newly diagnosed pulmonary tuberculosis in five sub-Saharan African countries. A standard 6-month regimen that included ethambutol during the 2-month intensive phase was compared with a 4-month regimen in which gatifloxacin (400 mg per day) was substituted for ethambutol during the intensive phase and was continued, along with rifampin and isoniazid, during the continuation phase. The primary efficacy end point was an unfavorable outcome (treatment failure, recurrence, or death or study dropout during treatment) measured 24 months after the end of treatment, with a noninferiority margin of 6 percentage points, adjusted for country. RESULTS A total of 1836 patients were assigned to the 4-month regimen (experimental group) or the standard regimen (control group). Baseline characteristics were well balanced between the groups. At 24 months after the end of treatment, the adjusted difference in the risk of an unfavorable outcome (experimental group [21.0%] minus control group [17.2%]) in the modified intention-to-treat population (1356 patients) was 3.5 percentage points (95% confidence interval, -0.7 to 7.7). There was heterogeneity across countries (P=0.02 for interaction, with differences in the rate of an unfavorable outcome ranging from -5.4 percentage points in Guinea to 12.3 percentage points in Senegal) and in baseline cavitary status (P=0.04 for interaction) and body-mass index (P=0.10 for interaction). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%). There was no evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen. CONCLUSIONS Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.).

Improvement of tuberculosis case detection and reduction of discrepancies between men and women by simple sputum-submission instructions: a pragmatic randomised controlled trial

BACKGROUND In several settings, women with suspected tuberculosis are less likely to test smear positive than are men. Submission of poor-quality sputum specimens by women might be one reason for the difference between the sexes. We did a pragmatic randomised controlled trial to assess the effect of sputum-submission instructions on female patients. METHODS 1494 women and 1561 men with suspected tuberculosis attending the Federal Tuberculosis Centre in Rawalpindi, Pakistan, were randomly assigned between May and July, 2005 either to receive sputum-submission guidance before specimen submission or to submit specimens without specific guidance, according to prevailing practice. Of enrolled patients, 133 (4%) declined to participate. The primary outcome measure was the proportion of instructed and non-instructed women testing smear positive. Intention-to-treat analysis was undertaken on the basis of treatment allocation. This study is registered with the International Standard Randomised Controlled Trial number 34123170. FINDINGS Instructed women were more likely to test smear positive than were controls (Risk ratio 1.63 [95% CI 1.19-2.22]). Instructions were associated with a higher rate of smear-positive case detection (58 [8%] in controls vs 95 [13%] in the intervention group; p=0.002), a decrease in spot-saliva submission (p=0.003), and an increase in the number of women returning with an early-morning specimen (p=0.02). In men, instructions did not have a significant effect on the proportion testing smear positive or specimen quality. INTERPRETATION In the Federal Tuberculosis Centre in Rawalpindi, lower smear positivity in women than in men was mainly a function of poor-quality specimen submission. Smear positivity in women was increased substantially by provision of brief instructions. Sputum-submission guidance might be a highly cost-effective intervention to improve smear-positive case detection and reduce the disparity between the sexes in tuberculosis control in low-income countries.

Risk factors for house-entry by malaria vectors in a rural town and satellite villages in The Gambia

BackgroundIn the pre-intervention year of a randomized controlled trial investigating the protective effects of house screening against malaria-transmitting vectors, a multi-factorial risk factor analysis study was used to identify factors that influence mosquito house entry.MethodsMosquitoes were sampled using CDC light traps in 976 houses, each on one night, in Farafenni town and surrounding villages during the malaria-transmission season in The Gambia. Catches from individual houses were both (a) left unadjusted and (b) adjusted relative to the number of mosquitoes caught in four sentinel houses that were operated nightly throughout the period, to allow for night-to-night variation. Houses were characterized by location, architecture, human occupancy and their mosquito control activities, and the number and type of domestic animals within the compound.Results106,536 mosquitoes were caught, of which 55% were Anopheles gambiae sensu lato, the major malaria vectors in the region. There were seven fold higher numbers of An. gambiae s.l. in the villages (geometric mean per trap night = 43.7, 95% confidence intervals, CIs = 39.5–48.4) than in Farafenni town (6.3, 5.7–7.2) and significant variation between residential blocks (p < 0.001). A negative binomial multivariate model performed equally well using unadjusted or adjusted trap data. Using the unadjusted data the presence of nuisance mosquitoes was reduced if the house was located in the town (odds ratio, OR = 0.11, 95% CIs = 0.09–0.13), the eaves were closed (OR = 0.71, 0.60–0.85), a horse was tethered near the house (OR = 0.77, 0.73–0.82), and churai, a local incense, was burned in the room at night (OR = 0.56, 0.47–0.66). Mosquito numbers increased per additional person in the house (OR = 1.04, 1.02–1.06) or trapping room (OR = 1.19, 1.13–1.25) and when the walls were made of mud blocks compared with concrete (OR = 1.44, 1.10–1.87).ConclusionThis study demonstrates that the risk of malaria transmission is greatest in rural areas, where large numbers of people sleep in houses made of mud blocks, where the eaves are open, horses are not tethered nearby and where churai is not burnt at night. These factors need to be considered in the design and analysis of intervention studies designed to reduce malaria transmission in The Gambia and other parts of sub-Saharan Africa.

Prevalence of Tuberculosis, HIV and Respiratory Symptoms in Two Zambian Communities: Implications for Tuberculosis Control in the Era of HIV

Background The Stop TB Partnership target for tuberculosis is to have reduced the prevalence of tuberculosis by 50% comparing 2015 to 1990. This target is challenging as few prevalence surveys have been conducted, especially in high burden tuberculosis and HIV countries. Current tuberculosis control strategies in high HIV prevalent settings are therefore based on limited epidemiological evidence and more evidence is needed from community-based surveys to inform improved policy formulation. Methods and Findings 8044 adults were sampled from 2 sub-districts (wards) in Lusaka province, Zambia. Questionnaires were used to screen for symptoms, respiratory samples were obtained for culture and oral secretions collected for HIV testing. 79 individuals were found to have Mycobacterium tuberculosis in their sputum, giving an adjusted overall prevalence of tuberculosis of 870/100,000 (95% CI 570–1160/100,000). The adjusted overall prevalence of HIV was 28.61% (95% CI 26.04–31.19). HIV- infection was significantly associated with prevalent tuberculosis (Adj OR 2.3, 95% CI 1.42–3.74) and the population attributable fraction of HIV for prevalent tuberculosis was 36%. Symptoms such as prolonged cough (adj OR 12.72, 95% CI 7.05–22.94) and fever (Adj OR 2.04, 95%CI 1.23–3.39), were associated with prevalent tuberculosis, but 8 (10%) individuals with prevalent tuberculosis denied having any symptoms at all and only 34 (43%) would have been classified as a TB suspect by current guidelines. Conclusions Undiagnosed tuberculosis is a challenge for tuberculosis control and new approaches are needed if we are to reach international targets. Epidemiological studies can inform screening algorithms for both detection and prevention of active tuberculosis.

Global Epidemiology of Tuberculosis

Despite the availability of effective chemotherapy, tuberculosis (TB) killed 1.3 million people in 2012. Alongside HIV, it remains a top cause of death from an infectious disease. Global targets for reductions in the epidemiological burden of TB have been set for 2015 and 2050 within the context of the Millennium Development Goals (MDGs) and by the Stop TB Partnership. Achieving these targets is the focus of national and international efforts in TB control, and showing whether or not they are achieved is of major importance to guide future and sustainable investments. This article provides a short overview of sources of data to estimate TB disease burden; presents estimates of TB incidence, prevalence, and mortality in 2012 and an assessment of progress toward the 2015 targets for reductions in these indicators based on trends since 1990 and projections up to 2015; analyzes trends in TB notifications and in the implementation of the Stop TB Strategy; and considers prospects for elimination of TB after 2015.

Lives saved by tuberculosis control and prospects for achieving the 2015 global target for reducing tuberculosis mortality

OBJECTIVE To assess whether the global target of halving tuberculosis (TB) mortality between 1990 and 2015 can be achieved and to conduct the first global assessment of the lives saved by the DOTS/Stop TB Strategy of the World Health Organization (WHO). METHODS Mortality from TB since 1990 was estimated for 213 countries using established methods endorsed by WHO. Mortality trends were estimated separately for people with and without human immunodeficiency virus (HIV) infection in accordance with the International classification of diseases. Lives saved by the DOTS/Stop TB Strategy were estimated with respect to the performance of TB control in 1995, the year that DOTS was introduced. FINDINGS TB mortality among HIV-negative (HIV-) people fell from 30 to 20 per 100,000 population (36%) between 1990 and 2009 and could be halved by 2015. The overall decline (when including HIV-positive [HIV+] people, who comprise 12% of all TB cases) was 19%. Between 1995 and 2009, 49 million TB patients were treated under the DOTS/Stop TB Strategy. This saved 4.6-6.3 million lives, including those of 0.23-0.28 million children and 1.4-1.7 million women of childbearing age. A further 1 million lives could be saved annually by 2015. CONCLUSION Improvements in TB care and control since 1995 have greatly reduced TB mortality, saved millions of lives and brought within reach the global target of halving TB deaths by 2015 relative to 1990. Intensified efforts to reduce deaths among HIV+ TB cases are needed, especially in sub-Saharan Africa.

Global burden of drug-resistant tuberculosis in children: a mathematical modelling study

BACKGROUND After infection with Mycobacterium tuberculosis, children are at an increased risk of progression to tuberculosis disease; a condition that can be challenging to diagnose. New estimation approaches for children have highlighted the gap between incidence and notifications of M tuberculosis, and suggest there are more cases of isoniazid-resistant and multidrug-resistant (MDR) disease than are identified. No work has yet quantified the burden of drug-resistant infection, or accounted for other types of drug resistance or sampling uncertainty. METHODS We combined a mathematical model of tuberculosis in children with an analysis of drug-resistance patterns to produce country-level, regional, and global estimates of drug-resistant infection and disease. We determined drug resistance using data from the Global Project on Antituberculosis Drug Resistance Surveillance at WHO, from surveys and surveillance reported between 1988 and 2014. We combined 1000 sampled proportions for each country from a Bayesian approach with 10 000 sampled country estimates of tuberculosis disease incidence and M tuberculosis infection prevalence. We estimated the proportions of tuberculosis cases at a country level with isoniazid monoresistance, rifampicin monoresistance, multidrug resistance (MDR), fluoroquinolone-resistant multidrug resistance, second-line injectable-resistant multidrug resistance, and extensive multidrug resistance with resistance to both a fluoroquinolone and a second-line injectable (XDR). FINDINGS We estimated that 850 000 children developed tuberculosis in 2014; 58 000 with isoniazid-monoresistant tuberculosis, 25 000 with MDR tuberculosis, and 1200 with XDR tuberculosis. We estimate 67 million children are infected with M tuberculosis; 5 million with isoniazid monoresistance, 2 million with MDR, and 100 000 with XDR. Africa and southeast Asia have the highest numbers of children with tuberculosis, but the WHO Eastern Mediterranean region, European region, and Western Pacific region also contribute substantially to the burden of drug-resistant tuberculosis because of their much higher proportions of resistance. INTERPRETATION Far more drug-resistant tuberculosis occurs in children than is diagnosed, and there is a large pool of drug-resistant infection. This finding has implications for approaches to empirical treatment and preventive therapy in some regions of the world. FUNDING UNITAID.

Prevention, Diagnosis, and Treatment of Tuberculosis in Children and Mothers: Evidence for Action for Maternal, Neonatal, and Child Health Services

Tuberculosis affected an estimated 8.8 million people and caused 1.4 million deaths globally in 2010, including a half-million women and at least 64 000 children. It also results in nearly 10 million cumulative orphans due to parental deaths. Moreover, it causes 6%-15% of all maternal mortality, which increases to 15%-34% if only indirect causes are considered. Increasingly, more women with tuberculosis are notified than men in settings with a high prevalence of human immunodeficiency virus (HIV), and maternal tuberculosis increases the vertical transmission of HIV. Tuberculosis prevention, diagnosis, and treatment services should be included as key interventions in the integrated management of pregnancy and child health. Tuberculosis screening using a simple clinical algorithm that relies on the absence of current cough, fever, weight loss, and night sweats should be used to identify eligible pregnant women living with HIV for isoniazid preventive therapy or for further investigation for tuberculosis disease as part of services for prevention of vertical HIV transmission. While implementing these simple, low-cost, effective interventions as part of maternal, neonatal, and child health services, the unmet basic and operational tuberculosis research needs of children, pregnant, and breastfeeding women should be addressed. National policy makers, program managers, and international stakeholders (eg, United Nations bodies, donors, and implementers) working on maternal, neonatal, and child health, especially in HIV-prevalent settings, should give due attention and include tuberculosis prevention, diagnosis, and treatment services as part of their core functions and address the public health impacts of tuberculosis in their programs and services.

Multidrug-resistant tuberculosis in children: evidence from global surveillance

Multidrug-resistant tuberculosis (MDR-TB) can affect persons of any age, but it remains unknown whether children are more or less likely than adults to have MDR-TB. Representative drug resistance surveillance data reported to the World Health Organization between 1994 and 2011 were analysed to test the association between MDR-TB and age group (children aged <15 years versus adults aged ≥15 years), using odds ratios derived by logistic regression with robust standard errors. Of 85 countries with data from nationwide surveys or surveillance systems, 35 reported at least one paediatric MDR-TB case. Aggregated data on age and drug susceptibility testing for 323 046 tuberculosis cases notified in these 35 countries were analysed. Odds ratios for MDR-TB in children compared to adults varied widely between countries. In Germany, Namibia, South Africa, the UK and the USA, MDR-TB was positively associated with age <15 years. In the remaining countries no association was established. Despite the limitations intrinsic to the use of surveillance data and to the challenges of diagnosing childhood tuberculosis, our analysis suggests that proportions of MDR-TB in children and adults are similar in many settings. Of particular concern is the association found between age <15 years and MDR-TB in southern African countries with high HIV prevalence. Surveillance data from 35 countries suggest that proportions of MDR-TB in children are not lower than those in adults http://ow.ly/kPgPH