Realizing the "40 by 2022" Commitment from the United Nations High-Level Meeting on the Fight to End Tuberculosis: What Will It Take to Meet Rapid Diagnostic Testing Needs?

The potential gains from full adoption of World Health Organization (WHO)-recommended rapid diagnostics (WRDs) for tuberculosis (TB) are significant, but there is no current analysis of the additional investment needed to reach this goal. We sought to estimate the necessary investment in instruments, tests, and money, using Xpert MTB/RIF (Xpert), which detects Mycobacterium tuberculosis (MTB) and tests for resistance to rifampicin (RIF), as an example. An existing calculator for TB diagnostic needs was adapted to estimate the Xpert needs for a group of 24 countries with high TB burdens. This analysis assumed that countries will achieve the case-finding commitments agreed to at the recent United Nations High-Level Meeting on the Fight to End Tuberculosis, and that countries would adopt the WHO-recommended algorithm in which all people with signs and symptoms of TB receive an Xpert test. When compared to the current investments in these countries, this baseline model revealed that countries would require a 4-fold increase in the number of Xpert modules and a 6-fold increase in the number of Xpert test cartridges per year to meet their full testing needs. The incremental cost of the additional instruments for these countries would total approximately US$474 million, plus an incremental cost each year of cartridges of approximately $586 million, or a 5-fold increase over current investments. A sensitivity analysis revealed a variety of possible changes under alternative scenarios, but most of these changes either do not meet the global goals, are unrealistic, or would result in even greater investment needs. These findings suggest that a major investment is needed in WRD capacity to implement the recommended diagnostic algorithm for TB and reach the case-finding commitments by 2022.

Emergence of drug resistance in patients with tuberculosis cared for by the Indian health-care system: a dynamic modelling study.

BACKGROUND: India has the highest number of patients with tuberculosis and multidrug-resistant tuberculosis in the world. We used a transmission model to project the emergence of drug resistance in India due to incorrect tuberculosis management practices in multiple sectors, including public and private providers, chemists, and non-allopathic practitioners. METHODS: We constructed a dynamic Markov model to represent India's tuberculosis epidemic, including a probabilistic framework reflecting complex treatment-seeking pathways. Underlying drug resistance and the acquisition of drug resistance during treatment were included. India-specific epidemiological data, including tuberculosis management practices, were obtained from published literature. Outcomes, which included annual risk of infection, incidence of new disease, prevalence of untreated tuberculosis, and tuberculosis-related mortality, were stratified by underlying drug resistance, as well as by health sector to understand how each sector contributes to the emergence of drug resistance. FINDINGS: If tuberculosis management practices across sectors in India remain unchanged over the next 20 years, we estimated a 47% increase in the incidence of isoniazid resistance, a 152% increase in multidrug-resistant tuberculosis incidence, a 242% increase in prevalent untreated multidrug-resistant tuberculosis, and a 275% increase in the risk of multidrug-resistant tuberculosis infection. By 2032, an estimated 85% of multidrug-resistant tuberculosis will be primary multidrug-resistant tuberculosis compared with only 15% in 2012. The public sector contributed 87% of acquired multidrug-resistant tuberculosis, related to irregular adherence; the remainder came from the private sector, related to treatment non-completion. Chemists and non-allopathic practitioners do not treat with rifampicin, but because of the high rates of inappropriate isoniazid-containing regimens, and treatment non-adherence, this would generate isoniazid resistance. INTERPRETATION: We predict a gradual transformation from the current epidemic of drug-susceptible tuberculosis to a drug-resistant epidemic. Evidence-based strategies to improve provider practices and patient adherence across health sectors are urgently needed to prevent this. FUNDING: United States Agency for International Development and the Canadian Institutes for Health Research.

Rolling Out Xpert® MTB/RIF for TB Detection in HIV-Infected Populations:An Opportunity for Systems Strengthening.

BACKGROUND: To eliminate preventable deaths, disease and suffering due to tuberculosis (TB), improved diagnostic capacity is critical. The Cepheid Xpert® MTB/RIF assay is recommended by the World Health Organization as the initial diagnostic test for people with suspected HIV-associated TB. However, despite high expectations, its scale-up in real-world settings has faced challenges, often due to the systems that support it. OPPORTUNITIES FOR SYSTEM STRENGTHENING: In this commentary we discuss needs and opportunities for systems strengthening to support widespread scale-up of Xpert® MTB/RIF as they relate to each step within the TB diagnostic cascade, from finding presumptive patients, to collecting, transporting and testing sputum specimens, to reporting and receiving results, to initiating and monitoring treatment and, ultimately, to ensuring successful and timely treatment and cure. Investments in evidence-based interventions at each step along the cascade and within the system as a whole will augment not only the utility of Xpert® MTB/RIF, but also the successful implementation of future diagnostic tests. CONCLUSION: Xpert® MTB/RIF will only improve patient outcomes if optimally implemented within the context of strong TB programs and systems. Roll-out of this technology to people living with HIV and others in resource-limited settings offers the opportunity to leverage current TB and HIV laboratory, diagnostic and programmatic investments, while also addressing challenges and strengthening coordination between laboratory systems, laboratory-program interfaces, and TB-HIV program interfaces. If successful, the benefits of this tool could extend beyond progress towards global End TB Strategy goals, to improve system-wide capacity for global disease detection and control.

GeneXpert for TB diagnosis: planned and purposeful implementation.

Xpert MTB/RIF is a major advance for TB diagnostics, especially for multidrug-resistant (MDR) TB and HIV-associated TB. But implementation concerns including cost, technical support requirements, and challenging demands of providing second-line TB drugs for diagnosed MDR-TB cases call for gradual, careful introduction based on country circumstances.

Opportunities and challenges for cost-efficient implementation of new point-of-care diagnostics for HIV and tuberculosis.

Stakeholders agree that supporting high-quality diagnostics is essential if we are to continue to make strides in the fight against human immunodeficiency virus (HIV) and tuberculosis. Despite the need to strengthen existing laboratory infrastructure, which includes expanding and developing new laboratories, there are clear diagnostic needs where conventional laboratory support is insufficient. Regarding HIV, rapid point-of-care (POC) testing for initial HIV diagnosis has been successful, but several needs remain. For tuberculosis, several new diagnostic tests have recently been endorsed by the World Health Organization, but a POC test remains elusive. Human immunodeficiency virus and tuberculosis are coendemic in many high prevalence locations, making parallel diagnosis of these conditions an important consideration. Despite its clear advantages, POC testing has important limitations, and laboratory-based testing will continue to be an important component of future diagnostic networks. Ideally, a strategic deployment plan should be used to define where and how POC technologies can be most efficiently and cost effectively integrated into diagnostic algorithms and existing test networks prior to widespread scale-up. In this fashion, the global community can best harness the tremendous capacity of novel diagnostics in fighting these 2 scourges.

Missed opportunities for tuberculosis prevention in New York City, 2003.

BACKGROUND: Proper management and prevention can radically decrease the incidence of tuberculosis (TB). To further decrease TB cases in New York City, every opportunity for prevention must be utilized. This study sought to identify patients whose disease could have been prevented and describe missed opportunities for TB prevention. METHODS: Patients diagnosed with TB from April to July, 2003 were identified using the New York City TB registry. Surveillance data, medical records, and patient interviews were used to determine whether patients missed a prevention opportunity or potential for screening. Preventable TB was defined as inappropriate screening of contacts and immigrants, inappropriate treatment of persons with prior TB diagnoses, or those who tested positive for latent TB infection (LTBI) as contacts, immigration, or in community settings. Potentially preventable TB was defined as occurring when those eligible for LTBI screening in community settings were not screened more than 1 year before TB diagnosis. Patients classified as having preventable or potentially preventable TB were grouped as patients with missed opportunities. We calculated the odds of missing a prevention opportunity using logistic regression. RESULTS: Among the 218 study patients, 22% had preventable TB and 35% had potentially preventable TB. The most common missed opportunity among patients with preventable TB was the failure to initiate LTBI treatment. Birth outside of the United States was not associated with missing a prevention opportunity (odds ratio [OR] = 1.31, confidence interval [CI] = 0.71-2.39); however, extended travel outside of the United States increased the odds (OR = 2.51, CI = 1.19-5.69), particularly among non-US-born patients (OR = 3.01, CI = 1.21-8.59). Missed screening opportunities related to pregnancy, employment, or school attendance were encountered by over half of the study patients. CONCLUSIONS: The majority of New York City TB patients in our cohort experienced at least 1 missed opportunity for prevention. Further study is warranted to determine whether LTBI treatment eligibility should be extended to those who travel for extended periods, particularly among the non-US-born patients.

Universal genotyping in tuberculosis control program, New York City, 2001-2003.

In 2001, New York City implemented genotyping to its tuberculosis (TB) control activities by using IS6110 restriction fragment length polymorphism (RFLP) and spoligotyping to type isolates from culture-positive TB patients. Results are used to identify previously unknown links among genotypically clustered patients, unidentified sites of transmission, and potential false-positive cultures. From 2001 to 2003, spoligotype and IS6110-based RFLP results were obtained for 90.7% of eligible and 93.7% of submitted isolates. Fifty-nine (2.4%) of 2,437 patient isolates had false-positive culture results, and 205 genotype clusters were identified, with 2-81 cases per cluster. Cluster investigations yielded 57 additional links and 17 additional sites of transmission. Four additional TB cases were identified as a result of case finding initiated through cluster investigations. Length of unnecessary treatment decreased among patients with false-positive cultures.