Impact assessment of new tuberculosis diagnostic tools and algorithms to support policy makers in low and middle income countries : an innovative modelling approach.

In many low and middle income countries the infectious disease tuberculosis is a leading and persistent cause of death, sickness and hardship. This is despite an effective and readily available treatment regimen. Better diagnostics and more rapid initiation of patients onto treatment is essential if the high burden of tuberculosis in these settings is to be substantially reduced, as there is currently no effective vaccine. There is an encouraging pipeline of improved diagnostic tools and algorithms being developed, some of which have been endorsed by the World Health Organization (e.g. Xpert MTB/RIF). These new diagnostic tools have the potential to overcome many of the weaknesses of the present processes, however they might substantially increase the demands on scarce resources and funds. In addition, whether these new diagnostics should replace existing methods or be used in combination with them is unclear. Before national tuberculosis programmes can scale-up new diagnostics, policy makers need to understand the effects on patients, the health system, and the wider population. Failure to do so could lead to poor performance outcomes, unsustainable implementation, and wasted resources. An innovative linked modelling approach is proposed that brings together detailed operational models of patient pathways with transmission models to provide the comprehensive projections required. The studies that make up this research first explore the concept of linked modelling, then in the second study develop a detailed operational model incorporating cost-effectiveness analysis. The third study uses the linked modelling approach to explore eight alternative diagnostic algorithms in Tanzania. It provides comprehensive projections of patient, health system and community impacts including cost-effectiveness analysis, from which the national tuberculosis programme can develop a strategy for scale-up of new diagnostics across the country. Having shown how the approach of linked operational and transmission modelling can assist policy makers, the fourth and fifth studies review the process of impact assessment and recommend how it can be improved, and how the lessons from this research in tuberculosis diagnostics might apply to other health decisions in low and middle income countries. The linked modelling approach is feasible and relevant in supporting rational decision making for tuberculosis diagnostics in low and middle income countries. The results from using the approach in Tanzania show that full scale-up of Xpert MTB/RIF is a cost-effective option with an incremental cost-effectiveness ratio of US$169 per DALY averted (95% credible interval, 104–265), and has the potential to significantly reduce the national tuberculosis burden. Substantial levels of funding would need to be mobilised to translate this into clinical practice. In the context of Tanzania, targeting Xpert MTB/RIF to HIV-positive patients only, was not cost-effective compared to rollout of LED fluorescence microscopy with two samples collected on the same day. Review of the Impact Assessment Framework and operational modelling used in these studies found the approaches had many other potential applications, for example for decisions around human parasitic disease diagnostics and tuberculosis treatment. In Tanzania full scale-up of Xpert MTB/RIF should be progressed in districts where resources and funding are available. LED fluorescence microscopy using two samples collected on the same day should be considered in other districts. Tuberculosis programmes should use the operational modelling approach to prioritise the implementation of new diagnostics by district. The operational and linked operational and transmission modelling approaches have many other potential applications in other contexts and disease areas and these should be further researched

Operational modelling: the mechanisms influencing TB diagnostic yield in an Xpert MTB/RIF-based algorithm

SETTING: Cape Town, South Africa. OBJECTIVE: To compare the diagnostic yield for smear/culture and Xpert® MTB/RIF algorithms and to investigate the mechanisms influencing tuberculosis (TB) yield. METHOD: We developed and validated an operational model of the TB diagnostic process, first with the smear/culture algorithm and then with the Xpert algorithm. We modelled scenarios by varying TB prevalence, adherence to diagnostic algorithms and human immunodeficiency virus (HIV) status. This enabled direct comparisons of diagnostic yield in the two algorithms to be made. RESULTS: Routine data showed that diagnostic yield had decreased over the period of the Xpert algorithm roll-out compared to the yield when the smear/culture algorithm was in place. However, modelling yield under identical conditions indicated a 13.3% increase in diagnostic yield from the Xpert algorithm compared to smear/culture. The model demonstrated that the extensive use of culture in the smear/culture algorithm and the decline in TB prevalence are the main factors contributing to not finding an increase in diagnostic yield in the routine data. CONCLUSION: We demonstrate the benefits of an operational model to determine the effect of scale-up of a new diagnostic algorithm, and recommend that policy makers use operational modelling to make appropriate decisions before new diagnostic algorithms are scaled up

Health workers perception of the shorter regimen in MDR-TB treatment. Qualitative evidence from Ethiopia

BACKGROUND: Ethiopia has recently adopted the 9-month MDR-TB treatment regimen within its national TB control programme. The aim of this study is to identify and understand country specific gaps between policy and practice. We also identify concerns relating to the shorter regimen (compared to the standard regimen), from a health worker, patient, and health system perspective. Understanding these issues will be useful for programmes implementing shorter TB regimens. METHODS: Health workers managing patients enrolled into the randomised clinical trial were selected from St. Peters and AHRI hospitals, Addis Ababa, Ethiopia. A snowball sampling technique was used to recruit key informants from each staff category (clinicians and nurses) along the clinical treatment pathway. In-depth interviews were conducted with 14 health workers using a semi-structured interview guide. Thematic data analysis was performed using Atlas.ti software. RESULTS: Health workers perceived the benefits of the shorter treatment for patients to include returning to work sooner, fewer side effects, reduced pill-burden and fewer health facility visits. The low pill-burden, mild side effects and the shorter duration of the regimen were perceived to reduce patients’ psychological distress and increase their adherence to treatment. There were benefits for staff from workload reduction and reduced patient exposure while the health system benefited from resource savings. CONCLUSION: Most respondents considered the advantages of the shorter regimen to outweigh the disadvantages. Health workers’ satisfaction was high due to the decrease in workload, resulting from the shorter nature of the regimen, fewer side effects and better patient compliance. Building strong collaboration between the local government and partners was identified as key to ensuring affordability and sustainability of the new regimen. Ongoing training to strengthen the staff capacity in managing the regimen will be required

Economic evaluation of short treatment for multidrugresistant tuberculosis, Ethiopia and South Africa : the STREAM trial

OBJECTIVE STREAM was a phase-III non-inferiority randomised controlled trial (RCT) to evaluate a shortened regimen for multi-drug resistant tuberculosis (MDR-TB), and included the first-ever within-trial economic evaluation of such regimens, reported here. METHODS We compared the costs of ‘Long’ (20-22 months) and ‘Short’ (9-11 months) regimens in Ethiopia and South Africa. Cost data were collected from trial participants, and health system costs estimated using ‘bottom-up’ and ‘top-down’ costing approaches. A cost-effectiveness analysis was conducted with the trial primary outcome as the measure of effectiveness, including a probabilistic sensitivity analysis (PSA) to illustrate decision uncertainty. FINDINGS The Short-regimen reduced healthcare costs per case by 21% in South Africa (US$8,341 Long vs US$6,619 Short) and 25% in Ethiopia (US$6,097 Long vs US$4,552 Short). The largest component of this saving was medication in South Africa (67%) and social support in Ethiopia (35%). In Ethiopia, participants on the Short-regimen reported reductions in dietary supplementation expenditure (US$225 per case (95$13 (95%CI 11-14), South Africa US$64 (95$19,000 (Ethiopia) or <US$14,500 (South Africa). CONCLUSION The Short-regimen provided substantial health system cost savings and reduced financial burden on participants. Shorter regimens are likely to be cost-effective in most settings, and an effective strategy to support the WHO goal of eliminating catastrophic costs in T

Assessment of the patient, health system, and population eff ects of Xpert MTB/RIF and alternative diagnostics for tuberculosis in Tanzania: an integrated modelling approach

Background Several promising new diagnostic methods and algorithms for tuberculosis have been endorsed by WHO. National tuberculosis programmes now face the decision on which methods to implement and where to place them in the diagnostic algorithm. Methods We used an integrated model to assess the eff ects of diff erent algorithms of Xpert MTB/RIF and lightemitting diode (LED) fl uorescence microscopy in Tanzania. To understand the eff ects of new diagnostics from the patient, health system, and population perspective, the model incorporated and linked a detailed operational component and a transmission component. The model was designed to represent the operational and epidemiological context of Tanzania and was used to compare the eff ects and cost-eff ectiveness of diff erent diagnostic options. Findings Among the diagnostic options considered, we identifi ed three strategies as cost eff ective in Tanzania. Full scale-up of Xpert would have the greatest population-level eff ect with the highest incremental cost: 346 000 disability-adjusted life-years (DALYs) averted with an additional cost of US$36·9 million over 10 years. The incremental cost-eff ectiveness ratio (ICER) of Xpert scale-up ($169 per DALY averted, 95% credible interval [CrI] 104–265) is below the willingness-to-pay threshold ($599) for Tanzania. Same-day LED fl uorescence microscopy is the next most eff ective strategy with an ICER of$45 (95% CrI 25–74), followed by LED fl uorescence microscopy with an ICER of $29 (6–59). Compared with same-day LED fl uorescence microscopy and Xpert full rollout, targeted use of Xpert in presumptive tuberculosis cases with HIV infection, either as an initial diagnostic test or as a followon test to microscopy, would produce DALY gains at a higher incremental cost and therefore is dominated in the context of Tanzania. Interpretation For Tanzania, this integrated modelling approach predicts that full rollout of Xpert is a cost-eff ective option for tuberculosis diagnosis and has the potential to substantially reduce the national tuberculosis burden. It also estimates the substantial level of funding that will need to be mobilised to translate this into clinical practice. This approach could be adapted and replicated in other developing countries to inform rational health policy formulation

Integrating HIV, syphilis, malaria and anaemia point-of-care testing (POCT) for antenatal care at dispensaries in western Kenya: discrete-event simulation modelling of operational impact

Background Despite WHO advocating for an integrated approach to antenatal care (ANC), testing coverage for conditions other than HIV remains low and women are referred to distant laboratories for testing. Using point-of-care tests (POCTs) at peripheral dispensaries could improve access to testing and timely treatment. However, the effect of providing additional services on nurse workload and client wait times are unknown. We use discrete-event simulation (DES) modelling to understand the effect of providing four point-of-care tests for ANC on nurse utilization and wait times for women seeking maternal and child health (MCH) services. Methods We collected detailed time-motion data over 20 days from one high volume dispensary in western Kenya during the 8-month implementation period (2014–2015) of the intervention. We constructed a simulation model using empirical arrival distributions, activity durations and client pathways of women seeking MCH services. We removed the intervention from the model to obtain wait times, length-of-stay and nurse utilization rates for the baseline scenario where only HIV testing was offered for ANC. Additionally, we modelled a scenario where nurse consultations were set to have minimum durations for sufficient delivery of all WHO-recommended services. Results A total of 183 women visited the dispensary for MCH services and 14 of these women received point-of-care testing (POCT). The mean difference in total waiting time was 2 min (95%CI: < 1–4 min, p = 0.026) for MCH women when integrated POCT was given, and 9 min (95%CI: 4–14 min, p < 0.001) when integrated POCT with adequate ANC consult times was given compared to the baseline scenario. Mean length-of-stay increased by 2 min (95%CI: < 1–4 min, p = 0.015) with integrated POCT and by 16 min (95%CI: 10–21 min, p < 0.001) with integrated POCT and adequate consult times compared to the baseline scenario. The two nurses’ overall daily utilization in the scenario with sufficient minimum consult durations were 72 and 75%. Conclusion The intervention had a modest overall impact on wait times and length-of-stay for women seeking MCH services while ensuring pregnant women received essential diagnostic testing. Nurse utilization rates fluctuated among days: nurses experienced spikes in workload on some days but were under-utilized on the majority of days. Overall, our model suggests there was sufficient time to deliver all WHO’s required ANC activities and offer integrated testing for ANC first and re-visits with the current number of healthcare staff. Further investigations on improving healthcare worker, availability, performance and quality of care are needed. Delivering four point-of-care tests together for ANC at dispensary level would be a low burden strategy to improve ANC

Patient-cost survey for tuberculosis in the context of patient-pathway modelling.

ETTING: Eight tuberculosis treatment sites in Cavite Province, the Philippines, including two sites specialising in management of multidrug-resistant tuberculosis (MDR-TB).OBJECTIVE: To evaluate costs incurred by TB patients and to determine the proportion of households that faced catastrophic costs, then to consider cost survey responses alongside results of detailed patient-pathway modelling.DESIGN: Clustered cross-sectional survey using a field testing version of the WHO TB patient-costing tool and protocol; face-to-face interviews with 194 patients conducted in May-August 2016. Costs included direct-medical, direct non-medical and indirect costs using the human capital approach. Patients were deemed to incur catastrophic expenditure if TB-related costs exceeded 20% of annual household income. Patient pathways were modelled following multiple health staff interviews.RESULTS: Estimated mean cost incurred by patients with drug-susceptible TB was US$321 vs.$2356 for MDR-TB patients. Catastrophic costs were suffered by 28% of drug-susceptible and 80% of MDR-TB patients, with lost income being the largest contributor. Patient-pathway modelling suggested most patients had under-reported health visits.CONCLUSION: Survey results indicate that patient costs are large for all patients in Cavite, particularly for MDR-TB patients. Patient-pathway modelling suggests these costs are an underestimate due to poor recollection of health visits, suggesting that the WHO instrument and protocol could be improved to better capture the diagnostic journey

Routine surveillance for the identification of drug resistant Tuberculosis in Tanzania: A cross-sectional study of stakeholders' perceptions

<p>Background: Routine surveillance is required to monitor the performance of tuberculosis diagnostic programme and is essential for the rapid detection of drug resistance. The main objective of this study was to explore the effectiveness and stakeholder perception of the current routine surveillance system for previously treated tuberculosis cases in Tanzania with a view to identify interventions to improve and accelerate positive patient outcomes.<b></b></p> <p>Methods:<b> </b>A study using quantitative and qualitative methods of data collection including in-depth interviews and focus group discussions with health care service providers was conducted in four regions. Quantitative data were extracted from the routine databases to assess performance.</p> <p>Results: Quantitative findings from 2011 to 2013 showed 2,750 specimens from previously treated TB cases were received at the reference laboratory. The number increased year on year, but even in the most recent year was only 61% of that expected. The median and interquartile range of turnaround time in days from specimen reception to results reported for smear microscopy, culture and drug susceptibility testing were 1(1, 1), 61(43, 71) and 129(72, 170) respectively. Contaminated specimens were reported in 3.6% of cases. The qualitative analysis showed the system of sending specimens using postal services was seen to be efficient by participants. However, there were many challenges and significant delays in specimens reaching the reference laboratory associated with lack of funds to transfer specimens, weak form completion, inadequate training and poor supervision. These all adversely affected the implementation of the routine surveillance system.</p> Conclusions: Many issues limit the effectiveness of the routine surveillance system in Tanzania. Priority areas for strengthening are; specimen transportation, supervision and availability of commodities. A pilot study of a revised routine surveillance system that takes into account the observations from this study alongside improved access to drug susceptibility testing using Xpert MTB/RIF should be considere

Reducing delays to multidrug-resistant tuberculosis case detection through a revised routine surveillance system

Background: Implementation of an effective Tuberculosis Routine Surveillance System in low-income countries like Tanzania is problematic, despite being an essential tool for the detection and effective monitoring of drug resistant tuberculosis. Long delays in specimen transportation from the facilities to reference laboratory and results dissemination back to the health facilities, result in poor patient management, particularly where multidrug-resistant tuberculosis disease is present. Methods: Following a detailed qualitative study, a pilot intervention of a revised Tuberculosis Routine Surveillance System was implemented in Mwanza region, Tanzania. This included the use of rapid molecular methods for the detection of both tuberculosis and drug resistance using Xpert MTB/RIF in some Mwanza sites, the use of Xpert MTB/RIF and Line Probe Assay at the Central Tuberculosis Reference Laboratory, a revised communication strategy and interventions to address the issue of poor form completion. A before and after comparison of the intervention on the number of drug resistant tuberculosis cases identified and the time taken for results feedback to the requesting site was reported. Results: The revised system for previously treated cases tested at the Central Reference Laboratory was able to obtain the following findings; the number of cases tested increased from 75 in 2016 to 185 in 2017. The times for specimen transportation from health facilities to the reference laboratory were reduced by 22% (from 9 to 7 days). The median time for the district to receive results was reduced by 36% (from 11 to 7 days). Overall the number of drug resistant tuberculosis cases starting treatment increased by 67% (from 12 to 20). Conclusion: Detection of drug resistance could significantly be enhanced, and delays reduced by introduction of new technologies and improved routine surveillance system, including better communication using mobile applications such as ‘WhatsApp’ and close follow-ups. A larger scale study is now merited to ascertain if these benefits are robust across different context