Olivia Oxlade

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.

Initial Drug Resistance and Tuberculosis Treatment Outcomes: Systematic Review and Meta-analysis

Context Identifying strategies to optimize tuberculosis treatment outcomes is important in light of the increasing occurrence of drug-resistant tuberculosis. Contribution This systematic review of 22 trials and 7 cohort studies involved 14333 new tuberculosis cases. Findings showed that poor outcomes were associated with initial drug resistance and that treatment was not based on susceptibility testing. Estimated rates of failure or relapse were 35% to 40% for patients who received rifampin for 2 months and 20% for those who received rifampin for 6 months. Implication These findings suggest that poor outcomes can be anticipated in settings that, because of limited resources, do not do susceptibility testing before initiation of tuberculosis treatment. The Editors Resistance to antituberculosis drugs was first described soon after the introduction of streptomycin (1) and is currently one of the most important threats to global tuberculosis control (2). In 2004, the World Health Organization estimated that among patients who had never received treatment before (new cases), the prevalence of drug resistance to any of the standard first-line tuberculosis drugs ranged from less than 5% to more than 30% in different countries (3). The World Health Organization also estimated that more than 240000 cases of multidrug-resistant tuberculosis (defined as resistance to at least isoniazid and rifampin) occurred, which represented 2.7% of all new cases. An additional 181000 cases of multidrug-resistant tuberculosis occurred among previously treated patients (representing 18.5% of re-treatment cases) (4). The threat of drug resistance has been underscored by recent reports of extensively drug-resistant strains (5). Drug-resistant strains cause much higher rates of mortality, failure, and relapse (6), and treatment is more toxic, expensive, and lengthy (7). In addition to the ongoing HIV epidemic, the emergence of multidrug-resistant and extensively drug-resistant tuberculosis underscores the importance of preventing drug resistance (8, 9), especially in settings without the resources to do drug-sensitivity testing or purchase the second-line drugs for treatment. Selecting a strategy to prevent drug resistance should be based on strong evidence, such as the results a systematic review can provide. Therefore, we planned a systematic review and meta-analysis (if appropriate) among previously untreated patients (new cases) with active pulmonary tuberculosis to determine the association among tuberculosis treatment outcomes (failure, relapse, and acquired drug resistance) and initial drug resistance (that is, before treatment); duration of rifampin therapy; use of pyrazinamide; use of streptomycin; and the number of drugs used in therapy. Methods Data Sources We searched PubMed, EMBASE, and the Cochrane Central Database of Clinical Trials for original articles and reviews from 1965 to June 2007. Our keywords included tuberculosis or TB and treatment or therapy and resistance or MDR-TB or sensitivity or susceptibility. We limited the search to studies published in English for treatment of active disease caused by Mycobacterium tuberculosis in humans. We searched reference lists of identified original articles and reviews for other relevant articles. We did not include abstracts, chapters of books, conference proceedings, or correspondence. Study Selection We reviewed cohort studies or randomized, controlled trials (RCTs) that reported treatment outcomes of failure or relapse. In selected studies, all patients had active pulmonary disease, without previous treatment, that was confirmed by mycobacterial culture. Drug-susceptibility testing was done in all patients before treatment and among all failures or relapses by using standard methods (10, 11). Treatment was standardized (not individualized), was directly supervised or observed, and included isoniazid and rifampin. We reported the number of patients starting treatment and developing treatment outcomes by each treatment regimen and initial drug-susceptibility testing pattern. We excluded studies or groups that included rifapentine or rifabutine therapy, nondrug therapy (for example, vaccines), or therapies that would be considered inadequate by current standards (1214). Two investigators independently conducted the electronic search. The selection of articles for review was done in 3 stages: titles alone, then abstracts, and then full-text articles. Disagreements about study selection were resolved by consensus. Data Extraction and Quality Assessment We reviewed selected studies by using standardized forms to abstract data about study design; treatment regimens; pretreatment drug-susceptibility testing; supervision of treatment; use of fixed-dose combinations; funding source; and numbers of patients who started treatment, defaulted, died, had treatment failure, were lost to follow-up, or had relapse. Two independent reviewers extracted the data, and disagreements were resolved by consensus. We selected only high-quality studies for diagnosis, treatment, and outcome assessment. Studies were considered high quality if they lost fewer than 10% of patients during treatment, fewer than 10% during follow-up of 30 months or less, or fewer than 20% of patients during follow-up of 30 to 60 months. Randomized, controlled trials were considered high quality if they were double-blind and concealed allocation by using central randomization or numbered opaque, sealed envelopes; sealed envelopes from a closed bag; numbered or coded bottles or containers; or drugs prepared by a central pharmacy. Data Synthesis and Analysis In accordance with the World Health Organizations definitions for tuberculosis control (15), treatment failure was defined as cultures that were consistently positive or positive and required treatment after 5 months of treatment. Relapse was defined as recurrence of positive cultures that required therapy after apparent cure. Initial drug resistance was defined as pretreatment resistance and categorized as pan-sensitive, single drug resistance (resistance to 1 first-line antituberculosis drug other than rifampin), or polydrug resistance (resistance to 2 drugs). If patients with initial rifampin resistance (and multidrug resistance) were identified in the report, they were excluded from analysis. Acquired drug resistance was defined as new resistance to 1 or more of the tuberculosis drugs received among patients with treatment failure and those with relapse. Patients treated in different groups of the same RCT were analyzed as separate cohorts if the regimens differed in initial drug resistance, duration of rifampin, use of pyrazinamide or streptomycin, or number of drugs in the initial or continuation phase. The initial phase was defined as the initial period when more drugs were usedtypically the first 1 to 3 months. The continuation phase was the remainder of therapy, when the number of drugs was reduced. For each cohort, we calculated cumulative incidence (and 95% CIs) of failure, relapse, and acquired drug resistance. We used forest plots to summarize these results. A random-effects meta-analysis was done by using the DerSimonianLaird method (Meta-Disc software, version 1.2, Madrid, Spain [16]), with studies weighted by total sample size to pool incidence of all outcomes (17). We corrected for overdispersion to account for variability among studies. To account for heterogeneity, we did subgroup analyses and stratified study results by predefined covariates of interest. We assessed heterogeneity by using the chi-square test (statistical significance was set at P < 0.05) and evaluated the presence of a statistically significant degree of variability among studies. Role of the Funding Source The authors were supported in part by the Canadian Institutes of Health Research and the Fonds de la recherche en sant du Qubec. The funding sources had no direct role in the design and conduct of the study or in the decision to submit the manuscript for publication. Results Qualitative Assessment of Studies We identified 645 citations through the electronic database search. Figure 1 summarizes the results of these searches, appraisals, and reasons for exclusion of studies. In brief, 44 of 145 full-text articles were reviewed and selected (22 RCTs and 7 cohort studies). We identified 39 articles describing 25 studies from the PubMed search, then an additional 3 articles describing 2 studies from the Cochrane database search and 2 further articles by using EMBASE. Failure and relapse were reported in 28 and 25 studies, respectively. Only 1 study received operating funds from a pharmaceutical company. Figure 1. Summary of literature search and study selection. MDR TB = multidrug-resistant tuberculosis. Appendix Table 1 summarizes cohort studies, and Appendix Table 2 summarizes the RCTs. Half of the trials were initiated from 1969 to 1979, compared with only 3 trials and 6 cohorts initiated since 1990. Because of the study selection criteria, all studies were considered to be of high quality in terms of diagnostic criteria, treatment administration, and outcome assessment. Of the studies assessing relapse, 23 (91%) were considered high quality because the dropout rate during follow-up was less than 10%. Half the studies reported methods of randomization, and all were considered adequate. Only 9% of studies were double-blind because of differences between groups in number of drugs, use of streptomycin, different lengths, or different frequency of administration. Only 5 studies included known HIV-positive patients, for a total of 712 HIV-infected patients in our review. Compared with those in RCTs, relapse rates in the cohort studies were the same, whereas rates of treatment failure and acquired drug resistance were somewhat higher (although not statistically significant). Appendix Table 1. Methods and Quality Assessment of Cohort Studies Appendix Table 2. Methods and Quality Assessment o

Fatores associados ao atraso no diagnóstico da tuberculose pulmonar no estado do Rio de Janeiro

OBJECTIVE: To estimate the total time elapsed between symptom onset and diagnosis of pulmonary tuberculosis (patient delay plus health care system delay), analyzing the factors associated with delayed diagnosis in the state of Rio de Janeiro, Brazil. METHODS: We conducted a questionnaire-based survey involving 218 pulmonary tuberculosis patients treated for two months at 20 health care clinics and 3 hospitals in eight cities within the state of Rio de Janeiro. We collected socioeconomic and demographic data, as well as data regarding the health care system and the medical history of the patients. RESULTS: The median time elapsed from the onset of symptoms to diagnosis was 68 days (interquartile range [IQR]: 35-119 days). The median patient delay (time from symptom onset to initial medical visit) was 30 days (IQR: 15-60 days), and the median health care system delay (time from initial medical visit to diagnosis) was 21 days (IQR: 8-47 days). A cut-off point of 21 days was adopted. The factors independently associated with patient delay were female gender, cough, and unemployment [adjusted OR (95% CI) = 2.7 (1.3-5.6); 11.6 (2.3-58.8); and 2.0 (1.0-3.8), respectively], whereas only female gender was independently associated with health care system delay (OR= 3.2; 95% CI: 1.7-6.0). CONCLUSIONS: Delayed diagnosis of pulmonary tuberculosis remains a problem in Rio de Janeiro, increasing the risk of transmission and mortality, that risk being greater for women and the socioeconomically disadvantaged. Patients might not recognize the significance of chronic cough as a health problem. Tuberculosis education programs targeting women might improve this situation.

Tuberculosis in pregnancy: an estimate of the global burden of disease

BACKGROUND The estimated number of maternal deaths in 2013 worldwide was 289 000, a 45% reduction from 1990. Non-obstetric causes such as infectious diseases including tuberculosis now account for 28% of maternal deaths. In 2013, 3·3 million cases of tuberculosis were estimated to occur in women globally. During pregnancy, tuberculosis is associated with poor outcomes, including increased mortality in both the neonate and the pregnant woman. The aim of our study was to estimate the burden of tuberculosis disease among pregnant women, and to describe how maternal care services could be used as a platform to improve case detection. METHODS We used publicly accessible country-level estimates of the total population, distribution of the total population by age and sex, crude birth rate, estimated prevalence of active tuberculosis, and case notification data by age and sex to estimate the number of pregnant women with active tuberculosis for 217 countries. We then used indicators of health system access and tuberculosis diagnostic test performance obtained from published literature to determine how many of these cases could ultimately be detected. FINDINGS We estimated that 216 500 (95% uncertainty range 192 100-247 000) active tuberculosis cases existed in pregnant women globally in 2011. The greatest burdens were in the WHO African region with 89 400 cases and the WHO South East Asian region with 67 500 cases in pregnant women. Chest radiography or Xpert RIF/MTB, delivered through maternal care services, were estimated to detect as many as 114 100 and 120 300 tuberculosis cases, respectively.

Cost-effectiveness of novel vaccines for tuberculosis control: a decision analysis study

BackgroundThe development of a successful new tuberculosis (TB) vaccine would circumvent many limitations of current diagnostic and treatment practices. However, vaccine development is complex and costly. We aimed to assess the potential cost effectiveness of novel vaccines for TB control in a sub-Saharan African country - Zambia - relative to the existing strategy of directly observed treatment, short course (DOTS) and current level of bacille Calmette-Guérin (BCG) vaccination coverage.MethodsWe conducted a decision analysis model-based simulation from the societal perspective, with a 3% discount rate and all costs expressed in 2007 US dollars. Health outcomes and costs were projected over a 30-year period, for persons born in Zambia (population 11,478,000 in 2005) in year 1. Initial development costs for single vaccination and prime-boost strategies were prorated to the Zambian share (0.398%) of global BCG vaccine coverage for newborns. Main outcome measures were TB-related morbidity, mortality, and costs over a range of potential scenarios for vaccine efficacy.ResultsRelative to the status quo strategy, a BCG replacement vaccine administered at birth, with 70% efficacy in preventing rapid progression to TB disease after initial infection, is estimated to avert 932 TB cases and 422 TB-related deaths (prevention of 199 cases/100,000 vaccinated, and 90 deaths/100,000 vaccinated). This would result in estimated net savings of

Impact of DOTS expansion on tuberculosis related outcomes and costs in Haiti

3.6 million over 30 years for 468,073 Zambians born in year 1 of the simulation. The addition of a booster at age 10 results in estimated savings of

Fluoroquinolone Therapy for the Prevention of Multidrug-Resistant Tuberculosis in Contacts. A Cost-Effectiveness Analysis

5.6 million compared to the status quo, averting 1,863 TB cases and 1,011 TB-related deaths (prevention of 398 cases/100,000 vaccinated, and of 216 deaths/100,000 vaccinated). With vaccination at birth alone, net savings would be realized within 1 year, whereas the prime-boost strategy would require an additional 5 years to realize savings, reflecting a greater initial development cost.ConclusionsInvestment in an improved TB vaccine is predicted to result in considerable cost savings, as well as a reduction in TB morbidity and TB-related mortality, when added to existing control strategies. For a vaccine with waning efficacy, a prime-boost strategy is more cost-effective in the long term.

The impact and cost-effectiveness of strategies to detect drug-resistant tuberculosis

BackgroundImplementation of the World Health Organizations DOTS strategy (Directly Observed Treatment Short-course therapy) can result in significant reduction in tuberculosis incidence. We estimated potential costs and benefits of DOTS expansion in Haiti from the government, and societal perspectives.MethodsUsing decision analysis incorporating multiple Markov processes (Markov modelling), we compared expected tuberculosis morbidity, mortality and costs in Haiti with DOTS expansion to reach all of the country, and achieve WHO benchmarks, or if the current situation did not change. Probabilities of tuberculosis related outcomes were derived from the published literature. Government health expenditures, patient and family costs were measured in direct surveys in Haiti and expressed in 2003 US

Developing a tuberculosis transmission model that accounts for changes in population health.

.ResultsStarting in 2003, DOTS expansion in Haiti is anticipated to cost

Comparing cost-effectiveness of standardised tuberculosis treatments given varying drug resistance

4.2 million and result in 63,080 fewer tuberculosis cases, 53,120 fewer tuberculosis deaths, and net societal savings of