Jacob Creswell

Results from early programmatic implementation of Xpert MTB/RIF testing in nine countries

BackgroundThe Xpert MTB/RIF assay has garnered significant interest as a sensitive and rapid diagnostic tool to improve detection of sensitive and drug resistant tuberculosis. However, most existing literature has described the performance of MTB/RIF testing only in study conditions; little information is available on its use in routine case finding. TB REACH is a multi-country initiative focusing on innovative ways to improve case notification.MethodsWe selected a convenience sample of nine TB REACH projects for inclusion to cover a range of implementers, regions and approaches. Standard quarterly reports and machine data from the first 12 months of MTB/RIF implementation in each project were utilized to analyze patient yields, rifampicin resistance, and failed tests. Data was collected from September 2011 to March 2013. A questionnaire was implemented and semi-structured interviews with project staff were conducted to gather information on user experiences and challenges.ResultsAll projects used MTB/RIF testing for people with suspected TB, as opposed to testing for drug resistance among already diagnosed patients. The projects placed 65 machines (196 modules) in a variety of facilities and employed numerous case-finding strategies and testing algorithms. The projects consumed 47,973 MTB/RIF tests. Of valid tests, 7,195 (16.8%) were positive for MTB. A total of 982 rifampicin resistant results were found (13.6% of positive tests). Of all tests conducted, 10.6% failed. The need for continuous power supply was noted by all projects and most used locally procured solutions. There was considerable heterogeneity in how results were reported and recorded, reflecting the lack of standardized guidance in some countries.ConclusionsThe findings of this study begin to fill the gaps among guidelines, research findings, and real-world implementation of MTB/RIF testing. Testing with Xpert MTB/RIF detected a large number of people with TB that routine services failed to detect. The study demonstrates the versatility and impact of the technology, but also outlines various surmountable barriers to implementation. The study is not representative of all early implementer experiences with MTB/RIF testing but rather provides an overview of the shared issues as well as the many different approaches to programmatic MTB/RIF implementation.

Tuberculosis and noncommunicable diseases: neglected links and missed opportunities

Globally, the incidence of tuberculosis (TB) is declining very slowly, and the noncommunicable disease (NCD) burden for many countries is steadily increasing. Several NCDs, such as diabetes mellitus, alcohol use disorders and smoking-related conditions, are responsible for a significant proportion of TB cases globally, and in the European region, represent a larger attributable fraction for TB disease than HIV. Concrete steps are needed to address NCDs and their risk factors. We reviewed published studies involving TB and NCDs, and present a review and discussion of how they are linked, the implications for case detection and management, and how prevention efforts may be strengthened by integration of services. These NCDs put patients at increased risk for developing TB and at risk for poor treatment outcomes. However, they also present an opportunity to provide better care through increased case-detection activities, improved clinical management and better access to care for both TB and NCDs. Hastening the global decline in TB incidence may be assisted by strengthening these types of activities.

Tuberculosis and non-communicable diseases: neglected links, missed opportunities

Globally, the incidence of tuberculosis (TB) is declining very slowly, and the noncommunicable disease (NCD) burden for many countries is steadily increasing. Several NCDs, such as diabetes mellitus, alcohol use disorders and smoking-related conditions, are responsible for a significant proportion of TB cases globally, and in the European region, represent a larger attributable fraction for TB disease than HIV. Concrete steps are needed to address NCDs and their risk factors. We reviewed published studies involving TB and NCDs, and present a review and discussion of how they are linked, the implications for case detection and management, and how prevention efforts may be strengthened by integration of services. These NCDs put patients at increased risk for developing TB and at risk for poor treatment outcomes. However, they also present an opportunity to provide better care through increased case-detection activities, improved clinical management and better access to care for both TB and NCDs. Hastening the global decline in TB incidence may be assisted by strengthening these types of activities.

How is Xpert MTB/RIF being implemented in 22 high tuberculosis burden countries?

Accurate and rapid diagnosis is crucial for tuberculosis control by ensuring a timely start to treatment and reducing transmission. In 2012, almost one third of tuberculosis cases were not diagnosed and/or reported to national tuberculosis programmes (NTPs), and <25% of estimated incident multidrug-resistant (MDR) cases were diagnosed [1]. Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA), a nucleic acid amplification test, was recommended in 2010 by the World Health Organization (WHO) for detection of HIV-associated pulmonary tuberculosis and rifampicin resistance [2]. In 2013, the test was recommended for detection of paediatric tuberculosis and some forms of extrapulmonary tuberculosis (EPTB), as well as an initial test to replace smear microscopy [3]. Xpert MTB/RIF implementation is mainly donor-funded, focused on DST and is not widely used outside South Africa http://ow.ly/CK4NS

Comparative meta-analysis of tuberculosis contact investigation interventions in eleven high burden countries.

Background Screening of household contacts of tuberculosis (TB) patients is a recommended strategy to improve early case detection. While it has been widely implemented in low prevalence countries, the most optimal protocols for contact investigation in high prevalence, low resource settings is yet to be determined. This study evaluated contact investigation interventions in eleven lower and middle income countries and reviewed the association between context or program-related factors and the yield of cases among contacts. Methods We reviewed data from nineteen first wave TB REACH funded projects piloting innovations to improve case detection. These nineteen had fulfilled the eligibility criteria: contact investigation implementation and complete data reporting. We performed a cross-sectional analysis of the percentage yield and case notifications for each project. Implementation strategies were delineated and the association between independent variables and yield was analyzed by fitting a random effects logistic regression. Findings Overall, the nineteen interventions screened 139,052 household contacts, showing great heterogeneity in the percentage yield of microscopy confirmed cases (SS+), ranging from 0.1% to 6.2%). Compared to the most restrictive testing criteria (at least two weeks of cough) the aOR’s for lesser (any TB related symptom) and least (all contacts) restrictive testing criteria were 1.71 (95%CI 0.94−3.13) and 6.90 (95% CI 3.42−13.93) respectively. The aOR for inclusion of SS- and extra-pulmonary TB was 0.31 (95% CI 0.15−0.62) compared to restricting index cases to SS+ TB. Contact investigation contributed between <1% and 14% to all SS+ cases diagnosed in the intervention areas. Conclusions This study confirms that high numbers of active TB cases can be identified through contact investigation in a variety of contexts. However, design and program implementation factors appear to influence the yield of contact investigation and its concomitant contribution to TB case detection.

A pragmatic approach to measuring, monitoring and evaluating interventions for improved tuberculosis case detection

The inability to detect all individuals with active tuberculosis has led to a growing interest in new approaches to improve case detection. Policy makers and program staff face important challenges measuring effectiveness of newly introduced interventions and reviewing feasibility of scaling-up successful approaches. While robust research will continue to be needed to document impact and influence policy, it may not always be feasible for all interventions and programmatic evidence is also critical to understand what can be expected in routine settings. The effects of interventions on early and improved tuberculosis detection can be documented through well-designed program evaluations. We present a pragmatic framework for evaluating and measuring the effect of improved case detection strategies using systematically collected intervention data in combination with routine tuberculosis notification data applying historical and contemporary controls. Standardized process evaluation and systematic documentation of program implementation design, cost and context will contribute to explaining observed levels of success and may help to identify conditions needed for success. Findings can then guide decisions on scale-up and replication in different target populations and settings.

Population-level impact of active tuberculosis case finding in an Asian megacity.

Background The potential population-level impact of private-sector initiatives for tuberculosis (TB) case finding in Southeast Asia remains uncertain. In 2011, the Indus Hospital TB Control Program in Karachi, Pakistan, undertook an aggressive case-finding campaign that doubled notification rates, providing an opportunity to investigate potential population-level effects. Methods We constructed an age-structured compartmental model of TB in the intervention area. We fit the model using field and literature data, assuming that TB incidence equaled the estimated nationwide incidence in Pakistan (primary analysis), or 1.5 times greater (high-incidence scenario). We modeled the intervention as an increase in the rate of formal-sector TB diagnosis and evaluated the potential impact of sustaining this rate for five years. Results In the primary analysis, the five-year intervention averted 24% (95% uncertainty range, UR: 18-30%) of five-year cumulative TB cases and 52% (95% UR: 45-57%) of cumulative TB deaths. Corresponding reductions in the high-incidence scenario were 12% (95% UR: 8-17%) and 27% (95% UR: 21-34%), although the absolute number of lives saved was higher. At the end of five years, TB notification rates in the primary analysis were below their 2010 baseline, incidence had dropped by 45%, and annual mortality had fallen by 72%. About half of the cumulative impact on incidence and mortality could be achieved with a one-year intervention. Conclusions Sustained, multifaceted, and innovative approaches to TB case-finding in Asian megacities can have substantial community-wide epidemiological impact.

Tuberculosis in BRICS: challenges and opportunities for leadership within the post-2015 agenda.

Tuberculosis is a disease of poverty that claims the lives of over a million people annually.1 Globally, tuberculosis is concentrated in low- to middle-income countries. The five countries – Brazil, the Russian Federation, India, China and South Africa – that make up the BRICS group account for 46% of all incident cases of tuberculosis and 40% of all tuberculosis-related mortality. China and India alone account for almost 40% of the estimated global burden of tuberculosis and a similar proportion of all cases notified to the World Health Organization (WHO). South Africa accounts for 30% of the estimated global number of incident cases of tuberculosis–human immunodeficiency virus (HIV) coinfection. In terms of multidrug-resistant tuberculosis (MDR-TB), China, India and the Russian Federation together account for more than half – 56% – of the estimated global burden. Brazil alone accounts for about a third of the western hemisphere’s estimated burdens of tuberculosis and MDR-TB.1 Global efforts to control tuberculosis have had considerable success. These efforts have resulted in substantial progress towards halving tuberculosis prevalence and mortality between 1990 and 2015 (current targets of the Stop TB Partnership) and halting and reversing the incidence of tuberculosis by 2015 (Millennium Development Goal 6c). Despite this progress, about three million people developing tuberculosis are missed by national notification systems each year, only a small fraction of MDR-TB cases are being treated and the poor and vulnerable continue to suffer disproportionally.1 It is time to look at the enormous challenges that will have to be faced in the post-2015 agenda and the expanded leadership role that BRICS can – and should – play in the fight against tuberculosis. The five BRICS countries were grouped together because they were all fast-growing economies but they also have another similarity: they each harbour more tuberculosis cases than any other country or territory in their respective WHO region. In terms of tuberculosis, each also has different weaknesses and challenges to confront. South Africa has a staggering burden of tuberculosis–HIV coinfection. Brazil and the Russian Federation are trying to eradicate intense foci of tuberculosis among some of their most vulnerable subgroups including homeless people, prisoners, people who use drugs and indigenous populations. China is now faced with the challenge of urgently scaling up access to treatment for MDR-TB. India has more missed cases than any other country and it is difficult to assess the quality of tuberculosis care provided in the country’s very active and diverse private sector. Despite these multiple challenges, the five BRICS countries are often considered to be regional and global leaders in the fight against tuberculosis. They provide models of care and are working together to strengthen efforts that may well be instrumental in setting and achieving future global tuberculosis targets. Several examples show how these countries have addressed local challenges on a large scale, delivered important evidence for improving tuberculosis prevention and care and provided critical political support for new tuberculosis-related initiatives and policy advances. In China – after years of poor tuberculosis notification – the government scaled up access to directly observed treatment and now sees a higher proportion of the estimated notifications (89%) than any other high-burden country. The engagement of hospitals in tuberculosis care has also produced major gains. Following problems with the surveillance of severe acute respiratory syndrome in 2003, the surveillance of all communicable diseases was improved and notification of tuberculosis cases became mandatory. Surveillance of tuberculosis is now based on a nationwide network of more than 3000 facilities that are linked in real time. This network has increased the annual number of notifications and improved the quality of the surveillance data.2 India has also recently developed a web-based national notification, banned the use of inaccurate serological tests and made tuberculosis notification mandatory.3 Although Brazil has a thriving private health-care sector, all of the country’s tuberculosis patients receive treatment free of charge, with publicly-provided drugs. This initiative should slow the development of drug resistance because it should reduce the use of substandard drugs and the risk of incomplete treatment. Improving tuberculosis care will require more research and the large-scale assessment of novel interventions. Several of the BRICS countries have been involved in trials of diagnostic tests, vaccines and new drugs. For example, South Africa has played a leading role in the introduction of Xpert MTB/RIF – a rapid molecular test. It was the first country to scale up the use of this test for initial diagnosis. In 2012, this scale-up, which had strong ministerial support, led to more people being diagnosed with MDR-TB than the number of cases that WHO estimated would occur in the country. Brazil and India have also taken leading roles in the large-scale programmatic implementation of new rapid diagnostic tests.4 In addition, China and India are developing “fast-follower” diagnostic technologies to drive down costs and improve access.1 Improving vulnerable populations’ access to quality tuberculosis care is vital in the world’s attempts to reach the three million missing cases of tuberculosis each year. Brazil already has a strong political commitment to reduce social inequalities in health by implementing large-scale social protection schemes. Brazil’s national tuberculosis programme works to enhance community participation, in the Stop TB Partnership.5 By working across the various ministries that handle health and the penal sector – to introduce tuberculosis screening and improve the general conditions, infection control and tuberculosis treatment in prisons – the Russian Federation reduced tuberculosis prevalence in its prisons.6 Over the last decade, the Russian Federation has also achieved major reductions in tuberculosis incidence, prevalence and mortality.1 As the result of India’s recent implementation of a plan to expand drug susceptibility testing, the annual number of people initiating treatment for MDR-TB in 2012 was fourfold higher than for 2011.3 Since the introduction of WHO’s DOTS/Stop TB Strategy, political commitment has formed the bedrock of all successful programmes of tuberculosis control – including those in BRICS. The Ministers of Health of Lesotho, South Africa and Swaziland led the development of the first Heads of State declaration on tuberculosis; the South African Development Community’s statement on tuberculosis in the mining sector. This declaration resulted in major progress in the planning, financing and implementation of multisectoral interventions against mining-associated tuberculosis in southern Africa. All five BRICS countries are providing large levels of domestic funding for tuberculosis care. The Russian Federation, for example, invests the equivalent of more than a billion United States dollars per year in such control. India produces large amounts of anti-tuberculosis medications that are either used domestically or exported. India’s pharmaceutical industry could play a leading role in lowering the cost of treatment of MDR-TB. China, India, the Russian Federation and, particularly, Brazil and South Africa played major roles in shaping WHO’s new post-2015 TB strategy that was initially approved by WHO’s Executive Board in early 2014. It is clear that, in the control of both tuberculosis and HIV, more opportunities exist for enhanced collaboration within BRICS. Senior officials from BRICS gathered in Paris in October 2013 to discuss tuberculosis and HIV. These officials agreed to work towards decreasing the price of drugs and diagnostics and to support research on several key topics: improving service delivery for tuberculosis and HIV, developing and improving electronic information systems and improving the health of individuals who migrate within or between countries. The officials also agreed to support greater collaboration – between BRICS – on economic analyses and modelling, to optimize the allocation of health resources and to maximize efficiency and effectiveness and promote the sustainability of investments. These discussions on tuberculosis and HIV were reported to BRICS’ ministers of health when they met in Cape Town in November 2013. The Ministers agreed that tuberculosis and HIV should be prioritized as areas of work. The senior officials who met in Paris have now been asked to develop an appropriate roadmap of activities to be undertaken and to report progress to the next meeting of BRICS’ ministers of health. BRICS have made progress in tuberculosis control and treatment thanks to high levels of political commitment, the availability of domestic resources, the use of each country’s capacities and strengths and good levels of collaboration between all relevant ministries and other partners. Since these countries bear much of the global burden posed by tuberculosis, it is not surprising that they have taken leading roles in the fight against tuberculosis. To accelerate the progress, each of the BRICS countries needs to continue to innovate, to provide data on the scaling up of new approaches, and to ensure that future global tuberculosis strategies and plans promote bold efforts and set ambitious – but achievable – post-2015 targets.

Implementing rapid testing for tuberculosis in Mozambique

Abstract Problem In Mozambique, pulmonary tuberculosis is primarily diagnosed with sputum smear microscopy. However this method has low sensitivity, especially in people infected with human immunodeficiency virus (HIV). Patients are seldom tested for drug-resistant tuberculosis. Approach The national tuberculosis programme and Health Alliance International introduced rapid testing of smear-negative sputum samples. Samples were tested using a polymerase-chain-reaction-based assay that detects Mycobacterium tuberculosis deoxyribonucleic acid and a mutation indicating rifampicin resistance; Xpert® MTB/RIF (Xpert®). Four machines were deployed in four public hospitals along with a sputum transportation system to transfer samples from selected health centres. Laboratory technicians were trained to operate the machines and clinicians taught to interpret the results. Local setting In 2012, Mozambique had an estimated 140 000 new tuberculosis cases, only 34% of which were diagnosed and treated. Of tuberculosis patients, 58% are HIV-infected. Relevant changes From 2012–2013, 1558 people were newly diagnosed with tuberculosis using sputum smears at intervention sites. Xpert® detected M. tuberculosis in an additional 1081 sputum smear-negative individuals, an increase of 69%. Rifampicin resistance was detected in 58/1081 (5%) of the samples. However, treatment was started in only 82% of patients diagnosed by microscopy and 67% of patients diagnosed with the rapid test. Twelve of 16 Xpert® modules failed calibration within 15 months of implementation. Lessons learnt Using rapid tests to diagnose tuberculosis is promising but logistically challenging. More affordable and durable platforms are needed. All patients diagnosed with tuberculosis need to start and complete treatment, including those who have drug resistant strains.

Screening for HIV among tuberculosis patients: a cross-sectional study in Sindh, Pakistan

Objective To describe feasibility and results of systematic screening of tuberculosis (TB) patients for HIV. Design Cross-sectional study. Setting Six selected sentinel sites (public DOTS clinics) in the province of Sindh, Pakistan. Participants All TB patients aged 16–60 years registered for treatment from April 2008 to March 2012. Measurement Demographic information of registered TB patients, screening for HIV through rapid testing and confirmation by referral lab of Sindh AIDS Control Program, according to national guidelines. Results Of a total of 18 461 registered TB patients, 12 882 fulfilled the inclusion criteria and were given education and counselling. Of those counselled 12 552 (97.4%) were screened for HIV using a rapid test. Men made up 48% of the sample and 76.5% of patients had pulmonary TB. Of the total patients tested, 42 (0.34%) were HIV-positive after confirmatory testing at the Sindh AIDS Control Program Laboratory. Prevalence of HIV among male patients was 0.67% whereas prevalence among female patients was 0.03% (p value <0.001). Prevalence of HIV among pulmonary TB patients was 0.29% and among extrapulmonary TB patients was 0.48% (p value=0.09). Conclusion In public DOTS clinics in Pakistan it is feasible to test TB patients for HIV. Prevalence of HIV is three times higher among TB patients as compared with the general population in Pakistan. Although the results are not representative of Pakistan or Sindh province they cover a large catchment area and closely match WHO estimate for the country. Routinely screening all TB patients for HIV infection, especially targeting men and ensuring antiretroviral therapy, can significantly improve TB/HIV collaborative activities in Pakistan and identify many cases of HIV, improve health outcomes and save lives.