Haileyesus Getahun and colleagues report the development of a simple, standardized tuberculosis (TB) screening rule for resource-constrained settings, to identify people living with HIV who need further investigation for TB disease.

In persons with HIV infection, screening for tuberculosis should include asking questions about a combination of symptoms rather than only about chronic cough. It is likely that antiretroviral therapy and isoniazid preventive therapy can be started safely in people whose screening for all three symptoms is negative, whereas diagnosis in most others will require mycobacterial culture.

Bill and Melinda Gates Foundation.

To accelerate the fight against tuberculosis, major diagnostic challenges need to be addressed urgently. Post-2015 targets are unlikely to be met without the use of novel diagnostics that are more accurate and can be used closer to where patients first seek care in affordable diagnostic algorithms. This article describes the efforts by the stakeholder community that led to the identification of the high-priority diagnostic needs in tuberculosis. Subsequently target product profiles for the high-priority diagnostic needs were developed and reviewed in a World Health Organization (WHO)-led consensus meeting. The high-priority diagnostic needs included (1) a sputum-based replacement test for smear-microscopy; (2) a non-sputum-based biomarker test for all forms of tuberculosis, ideally suitable for use at levels below microscopy centers; (3) a simple, low cost triage test for use by first-contact care providers as a rule-out test, ideally suitable for use by community health workers; and (4) a rapid drug susceptibility test for use at the microscopy center level. The developed target product profiles, along with complimentary work presented in this supplement, will help to facilitate the interaction between the tuberculosis community and the diagnostics industry with the goal to lead the way toward the post-2015 global tuberculosis targets.

SummaryBackgroundPyrazinamide and fluoroquinolones are essential antituberculosis drugs in new rifampicin-sparing regimens. However, little information about the extent of resistance to these drugs at the population level is available.MethodsIn a molecular epidemiology analysis, we used population-based surveys from Azerbaijan, Bangladesh, Belarus, Pakistan, and South Africa to investigate resistance to pyrazinamide and fluoroquinolones among patients with tuberculosis. Resistance to pyrazinamide was assessed by gene sequencing with the detection of resistance-conferring mutations in the pncA gene, and susceptibility testing to fluoroquinolones was conducted using the MGIT system.FindingsPyrazinamide resistance was assessed in 4972 patients. Levels of resistance varied substantially in the surveyed settings (3·0–42·1%). In all settings, pyrazinamide resistance was significantly associated with rifampicin resistance. Among 5015 patients who underwent susceptibility testing to fluoroquinolones, proportions of resistance ranged from 1·0–16·6% for ofloxacin, to 0·5–12·4% for levofloxacin, and 0·9–14·6% for moxifloxacin when tested at 0·5 μg/mL. High levels of ofloxacin resistance were detected in Pakistan. Resistance to moxifloxacin and gatifloxacin when tested at 2 μg/mL was low in all countries.InterpretationAlthough pyrazinamide resistance was significantly associated with rifampicin resistance, this drug may still be effective in 19–63% of patients with rifampicin-resistant tuberculosis. Even though the high level of resistance to ofloxacin found in Pakistan is worrisome because it might be the expression of extensive and unregulated use of fluoroquinolones in some parts of Asia, the negligible levels of resistance to fourth-generation fluoroquinolones documented in all survey sites is an encouraging finding. Rational use of this class of antibiotics should therefore be ensured to preserve its effectiveness.FundingBill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.

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SummaryBackgroundIn many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis.MethodsPopulation-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing.FindingsIsolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and May, 2014. In all tuberculosis cases, the overall pooled sensitivity values for predicting resistance by genetic sequencing were 91% (95% CI 87–94) for rpoB (rifampicin resistance), 86% (74–93) for katG, inhA, and fabG promoter combined (isoniazid resistance), 54% (39–68) for pncA (pyrazinamide resistance), 85% (77–91) for gyrA and gyrB combined (ofloxacin resistance), and 88% (81–92) for gyrA and gyrB combined (moxifloxacin resistance). For nearly all drugs and in most settings, there was a large overlap in the estimated prevalence of drug resistance by genetic sequencing and the estimated prevalence by phenotypic testing.InterpretationGenetic sequencing can be a valuable tool for surveillance of drug resistance, providing new opportunities to monitor drug resistance in tuberculosis in resource-poor countries. Before its widespread adoption for surveillance purposes, there is a need to standardise DNA extraction methods, recording and reporting nomenclature, and data interpretation.FundingBill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.

BackgroundTuberculosis (TB) control is considered primarily a public health concern, and private sector TB treatment has attracted less attention. Thus, the size and characteristics of private sector TB drug sales remain largely unknown.Methodology/Principal FindingsWe used IMS Health data to analyze private TB drug consumption in 10 high burden countries (HBCs), after first mapping how well IMS data coverage overlapped with private markets. We defined private markets as any channels not used or influenced by national TB programs. Private markets in four countries – Pakistan, the Philippines, Indonesia and India – had the largest relative sales volumes; annually, they sold enough first line TB drugs to provide 65–117% of the respective countries' estimated annual incident cases with a standard 6–8 month regimen. First line drug volumes in five countries were predominantly fixed dose combinations (FDCs), but predominantly loose drugs in the other five. Across 10 countries, these drugs were available in 37 (loose drug) plus 74 (FDCs) distinct strengths. There were 54 distinct, significant first line manufacturers (range 2–11 per country), and most companies sold TB drugs in only a single study country. FDC markets were, however, more concentrated, with 4 companies capturing 69% of FDC volume across the ten countries. Among second line drugs, fluoroquinolones were widely available, with significant volumes used for TB in India, Pakistan and Indonesia. However, certain WHO-recommended drugs were not available and in general there were insufficient drug volumes to cover the majority of the expected burden of multidrug-resistant TB (MDR-TB).Conclusions/SignificancePrivate TB drug markets in several HBCs are substantial, stable, and complicated. This calls for appropriate policy and market responses, including expansion of Public-Private Mix (PPM) programs, greater reach, flexibility and appeal of public programs, regulatory and quality enforcement, and expansion of public MDR-TB treatment programs.