Tuberculosis resistance-conferring mutations with fitness cost among HIV-positive individuals in Uganda.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is considered to be less transmissible due to the fitness cost associated with drug resistance-conferring mutations in essential genes. OBJECTIVE: To test the hypothesis that TB drug resistance-conferring mutations with fitness cost are more frequent among human immunodeficiency virus (HIV) positive than among HIV-negative patients. DESIGN: We analysed all strains from the two TB drug resistance surveys conducted in Uganda between 2008 and 2011. Strains phenotypically susceptible to rifampicin and/or isoniazid were assumed to be wild-type; in all other cases, we performed whole-genome sequencing. Mutations at the rpoB531 and katG315 codons were considered without fitness loss, whereas other rpoB codons and non-katG were considered with fitness loss. RESULTS: Of the 897 TB patients, 286 (32.1%) were HIV-positive. Mutations with fitness loss in HIV-positive and HIV-negative patients were respectively as follows: non-531 rpoB: 1.03% (n = 3), 0.71% (n = 4) (OR 1.46, 95%CI 0.58-3.68); non-katG: 0.40% (n = 1), 1.0% (n = 6) (OR 0.40, 95%CI 0.07-2.20); rpoB531: 1.49% (n = 4), 0.69% (n = 4) (OR 2.29, 95%CI 0.83-5.77); katG315: 3.86% (n = 11), 2.55% (n = 15) (OR 1.54, 95%CI 0.81-2.90). The odds of mutations with and without fitness cost were higher for patients with a history of previous anti-tuberculosis treatment. CONCLUSIONS: Our data do not support the hypothesis that resistance-conferring mutations with fitness cost are likely to be often present in HIV-positive individuals.

Cost and cost-effectiveness of tuberculosis treatment shortening: a model-based analysis.

BACKGROUND: Despite improvements in treatment success rates for tuberculosis (TB), current six-month regimen duration remains a challenge for many National TB Programmes, health systems, and patients. There is increasing investment in the development of shortened regimens with a number of candidates in phase 3 trials. METHODS: We developed an individual-based decision analytic model to assess the cost-effectiveness of a hypothetical four-month regimen for first-line treatment of TB, assuming non-inferiority to current regimens of six-month duration. The model was populated using extensive, empirically-collected data to estimate the economic impact on both health systems and patients of regimen shortening for first-line TB treatment in South Africa, Brazil, Bangladesh, and Tanzania. We explicitly considered 'real world' constraints such as sub-optimal guideline adherence. RESULTS: From a societal perspective, a shortened regimen, priced at USD1 per day, could be a cost-saving option in South Africa, Brazil, and Tanzania, but would not be cost-effective in Bangladesh when compared to one gross domestic product (GDP) per capita. Incorporating 'real world' constraints reduces cost-effectiveness. Patient-incurred costs could be reduced in all settings. From a health service perspective, increased drug costs need to be balanced against decreased delivery costs. The new regimen would remain a cost-effective option, when compared to each countries' GDP per capita, even if new drugs cost up to USD7.5 and USD53.8 per day in South Africa and Brazil; this threshold was above USD1 in Tanzania and under USD1 in Bangladesh. CONCLUSION: Reducing the duration of first-line TB treatment has the potential for substantial economic gains from a patient perspective. The potential economic gains for health services may also be important, but will be context-specific and dependent on the appropriate pricing of any new regimen.

Cost-effectiveness of the Xpert® MTB/RIF assay for tuberculosis diagnosis in Brazil.

INTRODUCTION: The Xpert® MTB/RIF assay is being implemented as a substitute for sputum smear microscopy (SSM) in many low and high tuberculosis (TB) burden countries, including Brazil, a country with low multidrug resistance and moderate human immunodeficiency virus co-infection rates. SETTING: Brazilian National TB Programme (NTP). OBJECTIVE AND DESIGN: We estimated the incremental cost-effectiveness ratio (ICER) of Xpert as a substitute for two SSM tests in the diagnosis of drug-susceptible TB. The costs for confirming each additional case and for avoiding treatment due to false-positive empirical diagnoses were estimated. RESULTS: The ICER was US$943 for each additional TB diagnosis and US$356 for each additional TB diagnosis with bacteriological confirmation, assuming 80% specificity of clinical diagnosis using both strategies. For every 100 000 patients with suspected TB, the NTP would spend an additional US$1.2 million per year to confirm 3344 more TB patients. The model was highly sensitive to specificity of clinical diagnosis after a negative test. CONCLUSION: Although the NTP has no threshold for cost-effectiveness, our model can provide support for decision makers in Brazil and other countries with a low prevalence of drug resistance among TB patients. Financial benefit can potentially be expected if physicians rely more on a negative Xpert result and empirical treatment is reduced.

A simplified cost-effectiveness model to guide decision-making for shortened anti-tuberculosis treatment regimens.

User-friendly models (UFMs) allow local decision makers to explore relationships and apply results from more detailed models of such outcomes as cost-effectiveness. When developing UFMs, modelers must decide which simplifications may be appropriate, enabling the UFM to retain accuracy while reducing complexity. We use the example of cost-effectiveness analysis (CEA) for novel shortened anti-tuberculosis treatment regimens across four settings to demonstrate how UFMs can allow decision makers to adapt published results to their local context. We simplified a complex model to produce a UFM that provides similar results, the ability to modify key parameter values, and receive customized results in seconds.

The potential of a multiplex high-throughput molecular assay for early detection of first and second line tuberculosis drug resistance mutations to improve infection control and reduce costs: a decision analytical modeling study.

BACKGROUND: Molecular resistance detection (MRD) of resistance to second-line anti-tuberculous drugs provides faster results than phenotypic tests, may shorten treatment and allow earlier separation among patients with and without second-line drug resistance. METHODS: In a decision-analytical model we simulated a cohort of patients diagnosed with TB in a setting where drug resistant TB is highly prevalent and requires initial hospitalization, to explore the potential benefits of a high-throughput MRD-assay for reducing potential nosocomial transmission of highly resistant strains, and total costs for diagnosis of drug resistance, treatment and hospitalization. In the base case scenario first-line drug resistance was diagnosed with WHO-endorsed molecular tests, and second-line drug resistance with culture and phenotypic methods. Three alternative scenarios were explored, each deploying high-throughput MRD allowing either detection of second-line mutations in cultured isolates, directly on sputum, or MRD with optimized markers. RESULTS: Compared to a base case scenario, deployment of high-throughput MRD reduced total costs by 17-21 %. The period during which nosocomial transmission may take place increased by 15 % compared to the base case if MRD had currently reported suboptimal sensitivity and required cultured isolates; increased by 7 % if direct sputum analysis were possible including in patients with smear-negative TB, and reduced by 24 % if the assay had improved markers, but was still performed on cultured isolates. Improved clinical sensitivity of the assay (additional markers) by more than 35 % would be needed to avoid compromising infection control. CONCLUSIONS: Further development of rapid second-line resistance testing should prioritize investment in optimizing markers above investments in a platform for direct analysis of sputum.

Impact and cost-effectiveness of current and future tuberculosis diagnostics: the contribution of modelling.

The landscape of diagnostic testing for tuberculosis (TB) is changing rapidly, and stakeholders need urgent guidance on how to develop, deploy and optimize TB diagnostics in a way that maximizes impact and makes best use of available resources. When decisions must be made with only incomplete or preliminary data available, modelling is a useful tool for providing such guidance. Following a meeting of modelers and other key stakeholders organized by the TB Modelling and Analysis Consortium, we propose a conceptual framework for positioning models of TB diagnostics. We use that framework to describe modelling priorities in four key areas: Xpert(®) MTB/RIF scale-up, target product profiles for novel assays, drug susceptibility testing to support new drug regimens, and the improvement of future TB diagnostic models. If we are to maximize the impact and cost-effectiveness of TB diagnostics, these modelling priorities should figure prominently as targets for future research.

Cost-effectiveness of rapid susceptibility testing against second-line drugs for tuberculosis.

BACKGROUND: Drug susceptibility testing (DST) against second-line tuberculosis drugs (SLDs) is essential for improving outcomes among multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) cases. OBJECTIVE: To evaluate the potential cost-effectiveness of rapid DST for SLDs. DESIGN: We constructed a decision analysis model of Xpert MTB/RIF-based TB diagnosis in East and South-East Asia to compare culture-based DST vs. a hypothetical rapid SLD DST system for specimens resistant to rifampin. Our primary outcomes were the effectiveness and incremental cost-effectiveness of a rapid SLD DST assay relative to culture-based DST. RESULTS: For rapid SLD DST to be more effective than culture-based DST, treating individuals with pre-XDR/XDR-TB with a standardized MDR-TB regimen while awaiting culture-based DST must incur at least 30% excess XDR-TB mortality (100% = treatment with first-line drugs); rapid SLD DST should attain an aggregate sensitivity and specificity for all pre-XDR/XDR mutations of 88% and 96%, respectively. The unit cost of the rapid SLD DST assay must approach that of culture to achieve common thresholds for cost-effectiveness in low-income countries. CONCLUSION: Rapid SLD DST has the potential to be cost-effective, but must meet stringent criteria for accuracy and costs, and requires that standardized second-line treatment for pre-XDR/XDR-TB incur substantial excess mortality before the return of culture results.

Making innovations accessible to the poor through implementation research.

Within countries, poorer populations have greater health needs and less access to good medical care than better-off populations. This is particularly true for tuberculosis (TB), the archetypal disease of poverty. Innovations also tend to become available to better-off populations well before they become available to those who need them the most. In a new era of innovations for TB diagnosis and treatment, it is increasingly important not only to be sure that these innovations can work in terms of accuracy and efficacy, but also that they will work, especially for the poor. We argue that after an innovation or a group of innovations has been endorsed, based on demonstrated accuracy and/or efficacy, introduction into routine practice should proceed through implementation by research. Cluster-randomised pragmatic trials are suited to this approach, and permit the prospective collection of evidence needed for full impact assessment according to a previously published framework. The novel approach of linking transmission modelling with operational modelling provides a methodology for expanding and enhancing the range of evidence, and can be used alongside evidence from pragmatic implementation trials. This evidence from routine practice should then be used to ensure that innovations in TB control are used for positive action for all, and particularly the poor.

Operational research for improved tuberculosis control: the scope, the needs and the way forward.

The promotion of research is one of the main components of the World Health Organizations Stop TB Strategy, which includes 'programme-based operational research (OR)' and 'research on introducing new tools into practice'. The importance of OR in improving tuberculosis (TB) control was recognised a long time ago, and historical OR studies have been instrumental in the development of major strategies for TB control. Although a growing number of OR projects are being conducted in the world today, little is known about their results or their likely impact on TB control programmes. As funding organisations increasingly recognise the need for OR, we propose a rational framework to conduct OR, which covers a spectrum from local setting-oriented to international policy guiding research, and determines the relevance, replicability and generalisability of the results. OR in TB control is aimed at 1) improving programme performance; 2) assessing the feasibility, effectiveness and impact of new strategies or interventions on TB control; and 3) collecting evidence to guide policy recommendations on specific interventions. This requires strengthened capacity to plan and conduct OR in low-income countries and appropriate support to conduct both nationally and internationally led OR projects. Suggestions are made for potential steps for improved purpose-driven OR, which may help to improve TB control locally and inform policy recommendations internationally.

Household expenditure and tuberculosis prevalence in VietNam: prediction by a set of household indicators.

OBJECTIVE: To study the association between TB and household expenditure in a nationwide TB prevalence survey in Viet Nam using nine household characteristics. METHOD: To assess the prevalence of TB in Viet Nam, a nationwide stratified cluster sample survey was conducted from 2006 to 2007. Nine household characteristics used in the second Viet Nam Living Standards Survey (VLSS) were scored per household. In the VLSS dataset, we regressed these nine characteristics against household expenditure per capita, and used the coefficients to predict household expenditure level (in quintiles) in our survey and assess its relation with TB prevalence. RESULTS: The prevalence of bacteriologically confirmed TB was 307 per 100,000 population in persons aged ≥ 15 years (95%CI 249-366). After adjustment for confounders, prevalence was found to be associated with household expenditure level: the rate was 2.5 times higher for those in the lowest household expenditure quintile (95%CI 1.6-3.9) than those in the highest quintile. CONCLUSION: With a set of nine household characteristics, we were able to predict household expenditure level fairly accurately. There was a significant association between TB prevalence rates and estimated household expenditure level, showing that TB is related to poverty in Viet Nam.

Inclusion of information on risk factors, socio-economic status and health seeking in a tuberculosis prevalence survey.

Data on socio-economic status, exposure to risk factors for tuberculosis (TB) and previous health-seeking for TB may be included in a TB prevalence survey to gain better knowledge about the distribution of TB in the population as well as a better understanding of what factors are driving the TB epidemic in a given setting. This article provides an overview of how such additional information may be collected. The article highlights the need to carefully consider the risk of jeopardising the quality of the overall survey by overburdening it with additional data collection, and concludes that additional time and resources for planning, training, logistics and supervision are required to safeguard quality. The article also discusses special considerations regarding sampling, sample size and data interpretation when including such information in a TB prevalence survey.

Organisation of a tuberculosis prevalence survey.

Measuring tuberculosis (TB) prevalence trends provides information on progress towards the Millennium Development Goals. The World Health Organization recently published guidelines on assessing TB prevalence through population-based surveys. The current manuscript describes in detail the organisation of the field activities in such a survey. These activities need to be embedded in a strong organisational framework where the steering committee has the overall responsibility and the survey coordinator the day-to-day supervision. Field activities need to be tailored to the community, with respect to both time and place and direct involvement of community members. Frequent and well-described monitoring procedures need to be in place to be able to identify systematic and non-systematic errors at the earliest opportunity.

Tuberculosis prevalence surveys: rationale and cost.

This article is the first of the educational series 'Assessing tuberculosis (TB) prevalence through population-based surveys'. The series will give overall guidance in conducting cross-sectional surveys of pulmonary TB (PTB) disease. TB prevalence surveys are most valuable in areas where notification data obtained through routine surveillance are of unproven accuracy or incomplete, and in areas with an estimated prevalence of bacteriologically confirmed TB of more than 100 per 100,000 population. To embark on a TB prevalence survey requires commitment from the national TB programme, compliance in the study population, plus availability of trained staff and financial resources. The primary objective of TB prevalence surveys is to determine the prevalence of PTB in the general population aged >or=15 years. Limitations of TB prevalence surveys are their inability to assess regional or geographic differences in prevalence of TB, estimate the burden of childhood TB or estimate the prevalence of extra-pulmonary TB. The cost of a prevalence survey is typically US$ 4-15 per person surveyed, and up to US$ 25 per person with radiographic screening. A survey of 50,000 people, of limited precision, would typically cost US$ 200,000-1,250,000.

Tuberculosis epidemiology in six provinces of Vietnam after the introduction of the DOTS strategy.

SETTING: Six provinces in Vietnam where the DOTS strategy was introduced in 1989. OBJECTIVE: To assess the impact of improved tuberculosis (TB) control on TB epidemiology in Vietnam. METHODS: Data from the surveillance system in the period 1990-2003 were analysed to assess trends of notification rates and the mean ages of notified cases. Data from repeated tuberculin surveys in the period 1986-2002 were estimated to assess the prevalence of TB infection, the annual risk of infection and its trend using various cut-off points in those with and without bacille Calmette-Guérin (BCG) scar. RESULTS: Age-standardised notification rates in the period 1996-2003 declined significantly, by 2.6% to 5.9% per year, in five provinces. However, in four provinces notification rates in the age group 15-24 years increased significantly, by 4.5% to 13.6% per year, during this period. The mean age of newly diagnosed patients with smear-positive TB increased up to 1995 but decreased thereafter. The annual risk of TB infection showed a significant annual decrease (4.9% per year) in one province in surveys performed between 1986 and 1997, and in two provinces (6.6% and 4.7%) in surveys conducted between 1993 and 2002. CONCLUSION: These data suggest limited impact to date of the DOTS strategy in Vietnam.

[Large-scale outbreak investigation for tuberculosis in Zeist]. / Grootschalig contactonderzoek op tuberculose in Zeist.

Recently a large-scale outbreak investigation was held among customers of a supermarket in the Dutch town of Zeist after an employee was diagnosed with smear-positive pulmonary tuberculosis. About 14,000 people had a tuberculin skin test and an additional 6,000 had a chest X-ray. About 400 positive skin tests and 8 cases of active tuberculosis have been reported so far. Investigation of contacts of infectious tuberculosis cases is an important tool in tuberculosis control in low-prevalence countries. It includes chest X-ray examination for active pulmonary tuberculosis after or instead of tuberculin skin testing, and identifying contacts with latent tuberculosis infection followed by preventive treatment. Investigation of household and other close contacts is highly effective. This may not be true for sporadic contacts who are likely to have a low risk of infection, such as in this investigation, where the prevalence of recent infections estimated from reported data is only 3%. The benefits of detecting these cases must be weighed against the costs of such large-scale operations and the probability of false-positive skin test results.

Testing for anti-circumsporozoite and anti-blood-stage antibodies for epidemiologic assessment of Plasmodium falciparum infection in travelers.

The purpose of this investigation was to assess the role of serology for establishing incidences of Plasmodium falciparum malaria and of exposure to P. falciparum in epidemiologic studies of travelers using chemoprophylaxis. The design was a prospective cohort study involving 548 short-term Dutch travelers to areas endemic for P. falciparum malaria. Sera were collected before departure and, together with the medical history, 2-6 weeks after return. All sera were tested for anti-circumsporozoite (CS) antibodies by an R32tet32-ELISA; sera of subjects reporting febrile illness during travel or after return or with anti-CS responses were tested for anti-blood-stage antibodies by an indirect fluorescence antibody test (IFAT). Five subjects (0.9%) reported P. falciparum malaria confirmed by thick blood smear examination (documented cases) and six (1.0%) reported treatment for malaria without a documented diagnosis (presumptive cases). Conversions in the IFAT were detected in six subjects, including all five documented cases and one presumptive case. Anti-CS antibodies were detected in seven subjects (1.3%), including three documented cases and four of 442 subjects with no history of fever or malaria treatment (0.9%). Incidence rates per 1,000 person-months of travel (95% confidence interval) of infection with P. falciparum, whether or not suppressed by chemoprophylaxis, were 16.9 (8-31) for all destinations and 91.6 (33-200) for West Africa. In epidemiologic studies of P. falciparum malaria in travelers, testing for antibodies to blood stages can increase the sensitivity and specificity of case detection; testing for antibodies to sporozoites may be useful for the assessment of exposure to P. falciparum in travelers using chemoprophylaxis, but the sensitivity is limited.