Modelling Innovative Tools for Tuberculosis Ivor Langley Basra Doulla, MoH, Tanzania Hsien-Ho Lin, NTU, Taiwan Kerry Millington Bertie Squire HaCRIC11 - SEPTEMBER 2011
Modelling Innovative Tools for Tuberculosis WHERE?.the archetypal disease of poverty World Health Organisation (2010), Stop, 2010/11 Tuberculosis Global facts 2
Agenda BACKGROUND THE PROBLEM & OPPORTUNITY? THE APPROACH RESULTS CONCLUSIONS NEXT STAGES 3
Modelling Innovative Tools for Tuberculosis WHY? More than two billion people, equal to one third of the world s population, are infected with bacilli. One in every 10 of those people will become sick with active. A total of 1.7 million people died from in 2009, equal to about 4700 deaths a day. is a disease of poverty with the majority of deaths in the developing world, affecting mostly young adults. This despite their being good and effective drug treatment (6months) World Health Organisation (2010), Stop, 2010/11 Tuberculosis Global facts 4
What are the Problems? ACCESS TO DIAGNOSIS Case detection is only around 45% in the highest burden countries Costly for patients to access diagnosis in developing countries Kemp JR, Mann G, Simwaka BN, Salaniponi FM, Squire SB (2007), Can Malawi's poor afford free tuberculosis services? 5 Patient and household costs associated with a tuberculosis diagnosis in Lilongwe. Bull World Health Organ. 2007; 580-5.
What are the Problems? SPEED OF DIAGNOSIS Minimum of 4 visits to a diagnostic centre to receive diagnosis Leading to high default rate during diagnosis ~15% Multi-Drug Resistant (MDR-) diagnosis takes up to 3-4 months is contagious and spreads through the air. If not treated, each person infects 10-15 people/yr Receive Treatment Medicine At end of intermediate phases if smear Positive Test For Drug Resistance and put on MDR - Treatment if found Smear Positive ing Every 2 wks for Medicines Diagnosed At end of intermediate phases if smear negative Smear Negative Receive Diagnosis Treatment Monitoring No Found Cure Provide Sputum Sample 2 Becomes Sick with cough Health Clinic Suspect Provide Sputum Sample 1 Squire SB, Belaye AK, Kashoti A, Salaniponi FM, Mundy CJ, Theobald S, et al. (2005), 'Lost' smear-positive pulmonary The tuberculosis Liverpool School cases: of Tropical where Medicine are they and why did we lose them? Int J Tuberc Lung Dis. 2005; 9(1): 25-31. 6
What are the Problems? ACCURACY OF DIAGNOSIS Sputum Smear Microscopy only detects around 30 70% of cases Accuracy is much worse for HIV+ patients (typically 40% of cases) Secondary techniques such as chest x-ray and short course antibiotics treatment are likely to have high false positive rate 25-50% is a leading killer among people living with HIV Hargreaves NJ, Kadzakumanja O, Whitty CJ, Salaniponi FM, Harries AD, Squire SB (2001). 'Smear-negative' pulmonary tuberculosis The Liverpool in School a DOTS of Tropical programme: Medicine poor outcomes in an area of high HIV seroprevalence. IJTLD. 2001; 5:847-54 7
What is the opportunity? New Technologies The introduction and scale-up of new tools for the diagnosis of Tuberculosis () in developing countries has the potential to make a huge difference to the lives of millions of people living in poverty e.g. Solid Culture DST by Proportion Method LED Fluorescence Microscopy Liquid Culture MGIT Line Probe Assay HAIN Xpert M/RIF Small The Liverpool PM, Pai School M. (2010), of Tropical Tuberculosis Medicine diagnosis - time for a game change. N Engl J Med. 2010; 363(11): 1070-1. 8
Modelling Innovative Tools for Tuberculosis OBJECTIVE?. to facilitate effective uptake of the most appropriate diagnostic technology and algorithms in developing countries.. to do this we must address the key questions of policy makers and funders. 9
Policy Makers and Funders Questions? Impact Assessment Framework* Patients Health System Community EFFICACY - How well does it work? How many more patients with will be diagnosed? How many more patients will be cured? EQUITY - Who benefits and why? Which patients will benefit? - The poor, HIV+? HEALTH SYSTEM - Operational effects? What will be the effect on staffing, Infrastructure, procurement, bottlenecks and capacity? SCALE-UP - Impacts of national rollout? How will it effect access to care and patient costs? How much will it cost to Implement, maintain, & run? Is it sustainable? How will it effect transmission? & MDR- incidence? prevalence? POLICY - How does it compare to other technologies? How cost effective is it compared to other approaches? Now and in the future? * Mann G, Squire SB, Bissell K, Eliseev P, Du Toit E, Hesseling A, et al. (2010), Beyond accuracy: creating a The Liverpool comprehensive School of Tropical evidence Medicine base for diagnostic tools. Int J Tuberc Lung Dis. 2010; 14(12): 1518-24. 10
Our Approach to these Questions? Some questions could be and are being addressed as part of Laboratory Tests Demonstration Trials Randomised controlled trials Modelling is required to complement these trials to particular address questions of Effects on Patient Outcomes and Health System Infrastructure Impacts of national scale-up Cost Effectiveness Context related operational issues Transmission impacts We decided to use Discrete Event Simulation linked to Transmission Modelling WHY? 11
Key Features of Discrete Event Simulation? FEATURE Core Data Driven REQUIREMENT With a limited set of core data available for diagnostic centres in the developing world the models need to be able to run on this limited data with key assumptions discussed with experts and tested through sensitivity analysis. Flexible So that models can be used to understand a variety of diagnostic approaches and across a wide range of different settings in the developing world they must be easily and quickly reconfigurable. Visual In order to provide policy makers with confidence in the model accuracy, its outputs, and to assist in validation the model must be visual and present a simple but realistic schematic image of the health system being modelled. Powerful In order to link to longer term transmission modelling and to speed model runs there must be sufficient processing power to simulate up to 10 years within 1 hour of modelling time. Stochastic To model variables such as patient arrivals, power outages, and default probabilities the modelling tool must have the ability to model uncertainty based on user defined and statistical probability distributions. Interactive What-If scenarios must be quickly and interactively testable. Portable In order to demonstrate and validate the model on location in remote rural diagnostic centres the model must be portable. Transferable In order to give personnel within National Programmes (NTP) the opportunity to experiment and evaluate appropriate tools and impacts for themselves in individual diagnostic centres it must be possible to transfer executable versions of the model for ongoing evaluation within the NTP 12
Why this approach rather than the more usual Decision Analysis? A. MODEL OPERATIONAL BOTTLENECKS The approach takes account of the complex interactions in the health system between patients, staff and processes. The resultant bottlenecks affect the outputs e.g. patient default. B. VISUAL- The approach gives a visual representation that enables policy makers to engage with the modelling and assist in validation - its not a black box. C. MATCHES THE W.H.O. OUTPUT REQUIREMENTS OF TRIALS The models produce all the detailed outputs to an Excel spreadsheet specifically required by the WHO for monitoring implementation of Xpert M/RIF D. COMPREHENSIVE - The approach includes patient, health system, and transmission impacts. These are linked e.g. improvements in operational performance affect time to diagnosis which affects incidence, which in turn affects the operation, patient access, and health system costs. E. MULTI-PURPOSE The models can be used to model individual diagnostic centres or country scale-up. The models can therefore inform country level policy decisions or assist in implementation in specific districts 13
Modelling Approach? - Design A detailed model was developed using the WITNESS Simulation Software. Patients are modelled through each process from Health Clinics into a and through to Treatment where appropriate. 14
Modelling Approach? - Design Sputum samples are modelled through the lab process. The lab model shows a schematic of the process and includes microscopy and Xpert M/RIF with flows defined for each sample by rules defined in an input data files Lab technicians and assistants as well as clinical staff as modelled as resources 15
Modelling Approach? - Design Samples from patients where there is a risk of drug resistance are transported to the Central Reference Lab for Drug Sensitivity Testing. 16
LAB TESTS COMPLETED TOTAL NEW SUSPECTS RETREAT TREATMENT MONITORING TOTAL Micrsoscopy GeneXpert Micrsoscopy GeneXpert Micrsoscopy NEW SUSPECTS RETREAT TREATMENT MONITORING TOTAL Year Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Micro GX Total Micro GX Total Micro Micro GX Total RIF Sensitive RIF Resistant RIF Sensitive RIF Resistant RIF Sensitive RIF Resistant RIF Sensitive RIF Resistant RIF+% RIF+% RIF+% QTR1 0 0 0 10386 0 49503 255 0 0 697 0 0 0 216 1440 0 0.0% 60144 17.3% 0.4% 60144 17.3% 0 0.0% 697 100.0% 0.0% 697 100.0% 1656 13.0% 1656 13.0% 60841 18.2% 0.4% 64153 17.9% QTR2 0 0 0 24552 5 106444 495 0 0 2107 0 0 0 834 15114 0 0.0% 131496 18.7% 0.4% 131496 18.7% 0 0.0% 2107 100.0% 0.0% 2107 100.0% 15948 5.2% 15948 5.2% 133603 20.0% 0.4% 165499 17.1% QTR3 0 LAB 0 TESTS COMPLETED 0 37385 14 158436 606 0 0 3168 0 0 0 1270 47234 0 0.0% 196441 19.0% 0.3% 196441 19.0% 0 0.0% 3168 100.0% 0.0% 3168 100.0% 48504 2.6% 48504 2.6% 199609 20.3% 0.3% 296617 14.5% QTR4 0 TOTAL 0 0 49067 14 213168 630 0 0 4393 0 0 0 1601 86032 0 0.0% 262879 18.7% 0.2% 262879 18.7% 0 0.0% 4393 100.0% 0.0% 4393 100.0% 87633 1.8% 87633 1.8% 267272 20.0% 0.2% 442538 12.8% QTR1 1 0 0 62480 24 NEW 269317 SUSPECTS 635 0 0 5134 0 0 RETREAT 0 2205 121671 TREATMENT 0 MONITORING 0.0% 332456 18.8% 0.2% 332456 18.8% 0 0.0% 5134 100.0% 0.0% 5134 100.0% TOTAL 123876 1.8% 123876 1.8% 337590 20.0% 0.2% 585342 12.3% QTR2 1 0 0 74887 Micrsoscopy 34 324382 760 GeneXpert 0 0 6354 Micrsoscopy 0 0 GeneXpert 0 2615 157839 0 Micrsoscopy 0.0% 400063 18.7% 0.2% 400063 NEW SUSPECTS 18.7% 0 0.0% 6354 100.0% 0.0% 6354 RETREAT 100.0% 160454 1.6% TREATMENT 160454 MONITORING 1.6% 406417 20.0% 0.2% 727325 TOTAL 11.9% QTR3 1 0 Year 0 Positive 87870 Negative 34 377930 Positive 770 Negative 0 0 Positive 7774 Negative 23 0 Positive 0 3321 Negative 194110 Positive 0 0.0% Negative 466604 Micro 18.8% 0.2% 466604 GX 18.8% 0 Total 0.0% 7797 Micro 100.0% 0.3% 7797 GX 100.0% 197431 Total 1.7% 197431 Micro 1.7% 474401 Micro 20.2% 0.2% 869263 GX 11.8% Total QTR4 1 0 0 102091 34 RIF Sensitive 433179 RIF Resistant 785 RIF Sensitive 0 RIF Resistant 0 8483 23 RIF Sensitive 0 RIF Resistant 0 RIF Sensitive 4222 RIF Resistant 230341 0 0.0% 536089 19.1% 0.2% 536089 19.1% RIF+% 0 0.0% 8506 100.0% 0.3% 8506 100.0% RIF+% 234563 +ve 1.8% rate 234563 1.8% 544595 20.3% 0.2% 1013721 11.7% RIF+% QTR1 2 0QTR1 00 0115591 0 48 10386 484988 0 920 495030 255 0 09733 0 23 697 0 0 0 04618 0268971 2160 0.0% 1440 6015470 19.2% 0.0% 0.2% 60144601547 17.3% 19.2% 0.4% 0 60144 0.0% 17.3% 9756 0 100.0% 0.0% 0.2% 697 9756 100.0% 100.0% 0.0% 273589 697 100.0% 1.7% 273589 1656 1.7% 13.0% 611303 1656 20.5% 13.0% 0.2% 608411158481 18.2% 11.6% 0.4% 64153 17.9% QTR2 2 0QTR2 00 0127988 0 48 24552 538919 51075 1064440 495 0 010494 0 23 2107 0 0 0 05072 0308890 8340 0.0% 15114 6680300 19.2% 0.0% 0.2% 131496668030 18.7% 19.2% 0.4% 0 1314960.0% 18.7% 10517 0 100.0% 0.0% 0.2% 2107 10517 100.0% 100.0% 0.0% 313962 2107 100.0% 1.6% 313962 15948 1.6% 5.2% 678547 15948 20.4% 5.2% 0.2% 133603 1306471 20.0% 11.4% 0.4% 165499 17.1% QTR3 2 0QTR3 0 LAB 0 0 TESTS COMPLETED 140463 0 53 37385 594255 141225 1584360 606 0 011719 0 23 3168 0 0 0 05622 0346138 1270 0 0.0% 47234 7359960 19.1% 0.0% 0.2% 196441735996 19.0% 19.1% 0.3% 0 1964410.0% 19.0% 11742 0 100.0% 0.0% 0.2% 3168 11742 100.0% 100.0% 0.0% 351760 3168 100.0% 1.6% 351760 48504 1.6% 2.6% 747738 48504 20.4% 2.6% 0.2% 199609 1451258 20.3% 11.3% 0.3% 296617 14.5% QTR4 2 0QTR4 0 TOTAL 0 0153045 0 154 49067 648647 141245 2131680 630 0 012807 0 28 4393 0 0 0 06464 0382143 1601 0 0.0% 86032 8030910 19.1% 0.0% 0.2% 262879803091 18.7% 19.1% 0.2% 0 2628790.0% 18.7% 12835 0 100.0% 0.0% 0.2% 4393 12835 100.0% 100.0% 0.0% 388607 4393 100.0% 1.7% 388607 87633 1.7% 1.8% 815926 87633 20.3% 1.8% 0.2% 267272 1593140 20.0% 11.2% 0.2% 442538 12.8% QTR1 3 0QTR1 10 0164943 0 154 62480 705334 24 NEW 1351 269317 SUSPECTS 0 635 0 014257 0 28 5134 0 0 0 0 RETREAT 7456 0419160 2205 0 0.0% 121671 TREATMENT 8717820 MONITORING 18.9% 0.0% 0.2% 332456871782 18.8% 18.9% 0.2% 0 3324560.0% 18.8% 14285 0 100.0% 0.0% 0.2% 5134 14285 100.0% 100.0% 0.0% 426616 5134 100.0% TOTAL 1.7% 426616 123876 1.7% 1.8% 886067 12387620.2% 1.8% 0.2% 337590 1739299 20.0% 11.2% 0.2% 585342 12.3% QTR2 3 0QTR2 10 0178772 0 154 74887 Micrsoscopy 760360 341764 3243820 760 GeneXpert 0 015463 0 28 6354 Micrsoscopy 0 0 0 0 GeneXpert 7679 0456421 2615 0 0.0% 157839 9410500 Micrsoscopy 19.0% 0.0% 0.2% 400063941050 18.7% 19.0% 0.2% 0 400063 NEW SUSPECTS 0.0% 18.7% 15491 0 100.0% 0.0% 0.2% 6354 15491 100.0% 100.0% 0.0% 464100 6354 RETREAT 100.0% 1.7% 464100 160454 1.7% 1.6% TREATMENT 956541 160454 MONITORING 20.3% 1.6% 0.2% 406417 1884741 20.0% 11.1% 0.2% 727325 TOTAL 11.9% QTR3 3 0QTR3 10 0 Year 191521 0 Positive 154 87870 Negative 814517 341885 377930 Positive 0 770 Negative 0 016257 0 Positive 28 7774 Negative 0 23 0 0 Positive 8203 0493090 3321 Negative 0 0.0% 194110 Positive 10080770 19.0% 0.0% Negative 0.2% 466604 Micro 1008077 18.8% 19.0% 0.2% 0 466604 GX 0.0% 18.8% 16285 0 Total 100.0% 0.0% 0.2% 7797 Micro 16285 100.0% 100.0% 0.3% 501293 7797 GX 100.0% 1.6% 501293 197431 Total 1.6% 1.7% 1024362 197431 Micro 20.3% 1.7% 0.2% 474401 Micro 2026948 20.2% 11.1% 0.2% 869263 GX 11.8% Total QTR4 3 0QTR4 10 0204459 0 159 102091 871736 34 RIF Sensitive 1995 433179 RIF Resistant 0 785 RIF Sensitive 0 0 RIF Resistant 17192 0 28 8483 0 23 RIF Sensitive 0 0 RIF Resistant 8790 0 RIF Sensitive 532752 4222 RIF Resistant 0 0.0% 230341 10783490 19.0% 0.0% 0.2% 536089 1078349 19.1% 19.0% 0.2% 0 536089 0.0% 19.1% RIF+% 17220 0 100.0% 0.0% 0.2% 8506 17220 100.0% 100.0% 0.3% 541542 8506 100.0% RIF+% 1.6% 541542 234563 +ve 1.6% 1.8% rate 1095569 234563 20.2% 1.8% 0.2% 544595 2178653 20.3% 11.0% 0.2% 1013721 11.7% RIF+% QTR1 4 0QTR1 20 0QTR1 0 217244 0 0 164 115591 0 924028 48 10386 2207 484988 0 0 920 49503 0 0 255 18054 0 0 67 9733 0 0 23 697 0 0 0 9523 0 0 571113 4618 0 0 0.0% 268971 216 11436430 19.0% 0.0% 1440 0.2% 6015470 1143643 19.2% 0.0% 19.0% 0.2% 60144 0 601547 17.3% 0.0% 19.2% 0.4% 18121 0 60144 100.0% 0.0% 17.3% 0.4% 9756 0 18121 100.0% 0.0% 100.0% 0.2% 697 580636 9756 100.0% 100.0% 0.0% 1.6% 580636 273589 697 100.0% 1.6% 1.7% 1161764 273589 1656 20.3% 1.7% 13.0% 0.2% 611303 1656 2323036 20.5% 13.0% 11.0% 0.2% 608411158481 18.2% 11.6% 0.4% 64153 17.9% QTR2 4 0QTR2 20 0QTR2 0 228348 0 0 265 127988 0 976900 48 24552 2371 538919 5 0 1075 106444 0 0 495 18925 0 0 67 10494 0 0 23 2107 0 0 0 10005 0 0 607374 5072 0 0 0.0% 308890 834 12078840 18.9% 0.0% 15114 0.2% 6680300 1207884 19.2% 0.0% 18.9% 0.2% 131496 0 668030 18.7% 0.0% 19.2% 0.4% 18992 0 131496 100.0% 0.0% 18.7% 0.4% 10517 0 18992 100.0% 0.0% 100.0% 0.2% 2107 617379 10517 100.0% 100.0% 0.0% 1.6% 617379 313962 2107 100.0% 1.6% 1.6% 1226876 313962 15948 20.2% 1.6% 5.2% 0.2% 678547 15948 2461634 20.4% 5.2% 10.9% 0.2% 133603 1306471 20.0% 11.4% 0.4% 165499 17.1% QTR3 4 0QTR3 20 0QTR3 0 LAB 242159 0 0 TESTS COMPLETED 270 140463 0 1034796 53 37385 2620 594255 14 0 1225 158436 0 0 606 20136 0 0 67 11719 0 0 23 3168 0 0 0 10872 0 0 643168 5622 0 0 0.0% 346138 1270 12798450 18.9% 0.0% 47234 0.2% 7359960 1279845 19.1% 0.0% 18.9% 0.2% 196441 0 735996 19.0% 0.0% 19.1% 0.3% 20203 0 196441 100.0% 0.0% 19.0% 0.3% 11742 0 20203 100.0% 0.0% 100.0% 0.2% 3168 654040 11742 100.0% 100.0% 0.0% 1.7% 654040 351760 3168 100.0% 1.7% 1.6% 1300048 351760 48504 20.2% 1.6% 2.6% 0.2% 747738 48504 2608128 20.4% 2.6% 10.9% 0.2% 199609 1451258 20.3% 11.3% 0.3% 296617 14.5% QTR4 4 0QTR4 20 0QTR4 0 TOTAL 254456 0 0 270 153045 0 1091989 154 49067 2890 648647 14 0 1245 213168 0 0 630 21615 0 0 67 12807 0 0 28 4393 0 0 0 11381 0 0 678982 6464 0 0 0.0% 382143 1601 13496050 18.9% 0.0% 86032 0.2% 8030910 1349605 19.1% 0.0% 18.9% 0.2% 262879 0 803091 18.7% 0.0% 19.1% 0.2% 21682 0 262879 100.0% 0.0% 18.7% 0.3% 12835 0 21682 100.0% 0.0% 100.0% 0.2% 4393 690363 12835 100.0% 100.0% 0.0% 1.6% 690363 388607 4393 100.0% 1.6% 1.7% 1371287 388607 87633 20.2% 1.7% 1.8% 0.2% 815926 87633 2752013 20.3% 1.8% 10.9% 0.2% 267272 1593140 20.0% 11.2% 0.2% 442538 12.8% QTR1 5 0QTR1 30 0QTR1 1 267876 0 0 314 164943 0 1146738 154 62480 3024 705334 24 NEW 0 1351 269317 SUSPECTS 0 0 635 22882 0 0 67 14257 0 0 28 5134 0 0 0 12315 0 0 RETREAT 716280 7456 0 0 0.0% 419160 2205 14179520 18.9% 0.0% 121671 TREATMENT 0.2% 8717820 MONITORING 1417952 18.9% 0.0% 18.9% 0.2% 332456 0 871782 18.8% 0.0% 18.9% 0.2% 22949 0 332456 100.0% 0.0% 18.8% 0.3% 14285 0 22949 100.0% 0.0% 100.0% 0.2% 5134 728595 14285 100.0% 100.0% 0.0% 1.7% 728595 426616 5134 100.0% TOTAL 1.7% 1.7% 1440901 426616 123876 20.2% 1.7% 1.8% 0.2% 886067 123876 2898091 20.2% 1.8% 10.9% 0.2% 337590 1739299 20.0% 11.2% 0.2% 585342 12.3% QTR2 5 0QTR2 30 0QTR2 1 281302 0 0 381 178772 0 1199144 154 74887 Micrsoscopy 3139 760360 34 0 1764 324382 0 0 760 GeneXpert 24070 0 0 67 15463 0 0 28 6354 Micrsoscopy 0 0 0 13186 0 0 GeneXpert 754661 7679 0 0 0.0% 456421 2615 14839660 19.0% 0.0% 157839 0.2% 9410500 Micrsoscopy 1483966 19.0% 0.0% 19.0% 0.2% 400063 0 941050 18.7% 0.0% 19.0% 0.2% 24137 0 400063 NEW SUSPECTS 100.0% 0.0% 18.7% 0.3% 15491 0 24137 100.0% 0.0% 100.0% 0.2% 6354 767847 15491 100.0% 100.0% 0.0% 1.7% 767847 464100 6354 RETREAT 100.0% 1.7% 1.7% 1508103 464100 160454 20.3% 1.7% 1.6% TREATMENT 0.2% 956541 160454 MONITORING 3043797 20.3% 1.6% 10.9% 0.2% 406417 1884741 20.0% 11.1% 0.2% 727325 TOTAL 11.9% QTR3 5 0QTR3 30 0QTR3 1 293099 0 0 Year 588 191521 0 Positive 1252241 154 87870 Negative 3163 814517 34 0 1885 377930 Positive 0 0 770 Negative 25438 0 0 72 16257 0 Positive 0 28 7774 Negative 0 0 23 13573 0 0 Positive 795412 8203 0 0 0.0% 493090 3321 Negative 15490910 19.0% 0.0% 194110 Positive 0.2% 10080770 1549091 19.0% 0.0% Negative 19.0% 0.2% 466604 Micro 01008077 18.8% 0.0% 19.0% 0.2% 25510 0 466604 GX 100.0% 0.0% 18.8% 0.3% 16285 0 Total 25510 100.0% 0.0% 100.0% 0.2% 7797 Micro 808985 16285 100.0% 100.0% 0.3% 1.7% 808985 501293 7797 GX 100.0% 1.7% 1.6% 1574601 501293 197431 Total 20.3% 1.6% 1.7% 0.2% 1024362 197431 Micro 3192571 20.3% 1.7% 10.8% 0.2% 474401 Micro 2026948 20.2% 11.1% 0.2% 869263 GX 11.8% Total QTR4 5 0QTR4 30 0QTR4 1 305602 0 0 588 204459 0 1307122 159 102091 3299 871736 34 RIF Sensitive 0 1995 433179 RIF Resistant 0 0 785 RIF Sensitive 26692 0 0 RIF Resistant 72 17192 0 0 28 8483 0 0 23 RIF Sensitive 13992 0 0 RIF Resistant 831971 8790 0 RIF Sensitive 0 0.0% 532752 4222 RIF Resistant 16166110 18.9% 0.0% 230341 0.2% 10783490 1616611 19.0% 0.0% 18.9% 0.2% 536089 01078349 19.1% 0.0% 19.0% 0.2% 26764 0 536089 100.0% 0.0% 19.1% RIF+% 0.3% 17220 0 26764 100.0% 0.0% 100.0% 0.2% 8506 845963 17220 100.0% 100.0% 0.3% 1.7% 845963 541542 8506 100.0% RIF+% 1.7% 1.6% 1643375 541542 234563 +ve 20.3% 1.6% 1.8% rate 0.2% 1095569 234563 3335301 20.2% 1.8% 10.8% 0.2% 544595 2178653 20.3% 11.0% 0.2% 1013721 11.7% RIF+% QTR1 6 0QTR1 40 0QTR1 2 317096 0 0QTR1 0 588 217244 0 0 1361429 164 115591 0 3342 924028 48 10386 0 2207 484988 0 0 0 920 49503 28007 0 0 255 72 18054 0 0 0 67 9733 0 0 0 23 697 14734 0 0 0 868367 9523 0 0 0 0.0% 571113 4618 0 16824550 18.9% 0.0% 268971 216 0.2% 11436430 1682455 19.0% 0.0% 1440 18.9% 0.2% 6015470 01143643 19.2% 0.0% 0.0% 19.0% 0.2% 60144 28079 0 601547 17.3% 100.0% 0.0% 19.2% 0.4% 0.3% 18121 0 60144 28079 100.0% 0.0% 17.3% 100.0% 0.4% 9756 0 883101 18121 100.0% 0.0% 100.0% 0.2% 697 1.7% 883101 580636 9756 100.0% 100.0% 0.0% 1.7% 1.6% 1710534 580636 273589 697 100.0% 20.2% 1.6% 1.7% 0.2% 1161764 273589 1656 3476736 20.3% 1.7% 13.0% 10.8% 0.2% 611303 1656 2323036 20.5% 13.0% 11.0% 0.2% 608411158481 18.2% 11.6% 0.4% 64153 17.9% QTR2 6 0QTR2 40 0QTR2 2 329929 0 0QTR2 0 602 228348 0 0 1414999 265 127988 0 3453 976900 48 24552 0 2371 538919 5 0 0 1075 106444 29308 0 0 495 72 18925 0 0 0 67 10494 0 0 0 23 2107 15278 0 0 0 905074 10005 0 0 0 0.0% 607374 5072 0 17489830 18.9% 0.0% 308890 834 0.2% 12078840 1748983 18.9% 0.0% 15114 18.9% 0.2% 6680300 01207884 19.2% 0.0% 0.0% 18.9% 0.2% 131496 29380 0668030 18.7% 100.0% 0.0% 19.2% 0.4% 0.2% 18992 0 131496 29380 100.0% 0.0% 18.7% 100.0% 0.4% 10517 0 920352 18992 100.0% 0.0% 100.0% 0.2% 2107 1.7% 920352 617379 10517 100.0% 100.0% 0.0% 1.7% 1.6% 1778363 617379 313962 2107 100.0% 20.2% 1.6% 1.6% 0.2% 1226876 313962 15948 3619067 20.2% 1.6% 5.2% 10.8% 0.2% 678547 15948 2461634 20.4% 5.2% 10.9% 0.2% 133603 1306471 20.0% 11.4% 0.4% 165499 17.1% QTR3 6 0QTR3 40 0QTR3 2 343320 0 0QTR3 0 607 242159 0 0 1473276 270 140463 0 3462 1034796 53 37385 0 2620 594255 14 0 0 1225 158436 30327 0 0 606 77 20136 0 0 0 67 11719 0 0 0 23 3168 15879 0 0 0 941842 10872 0 0 0 0.0% 643168 5622 0 18206650 18.9% 0.0% 346138 1270 0.2% 12798450 1820665 18.9% 0.0% 47234 18.9% 0.2% 7359960 01279845 19.1% 0.0% 0.0% 18.9% 0.2% 196441 30404 0 735996 19.0% 100.0% 0.0% 19.1% 0.3% 0.3% 20203 0 196441 30404 100.0% 0.0% 19.0% 100.0% 0.3% 11742 0 957721 20203 100.0% 0.0% 100.0% 0.2% 3168 1.7% 957721 654040 11742 100.0% 100.0% 0.0% 1.7% 1.7% 1851069 654040 351760 3168 100.0% 20.2% 1.7% 1.6% 0.2% 1300048 351760 48504 3766511 20.2% 1.6% 2.6% 10.8% 0.2% 747738 48504 2608128 20.4% 2.6% 10.9% 0.2% 199609 1451258 20.3% 11.3% 0.3% 296617 14.5% QTR4 6 0QTR4 40 0QTR4 2 357437 0 0QTR4 0 708 254456 0 0 1524412 270 153045 0 3572 1091989 154 49067 0 2890 648647 14 0 0 1245 213168 31088 0 0 630 77 21615 0 0 0 67 12807 0 0 0 28 4393 16581 0 0 0 980609 11381 0 0 0 0.0% 678982 6464 0 18861290 19.0% 0.0% 382143 1601 0.2% 13496050 1886129 18.9% 0.0% 86032 19.0% 0.2% 8030910 01349605 19.1% 0.0% 0.0% 18.9% 0.2% 262879 31165 0 803091 18.7% 100.0% 0.0% 19.1% 0.2% 0.2% 21682 0 262879 31165 100.0% 0.0% 18.7% 100.0% 0.3% 12835 0 997190 21682 100.0% 0.0% 100.0% 0.2% 4393 1.7% 997190 690363 12835 100.0% 100.0% 0.0% 1.7% 1.6% 1917294 690363 388607 4393 100.0% 20.3% 1.6% 1.7% 0.2% 1371287 388607 87633 3911674 20.2% 1.7% 1.8% 10.8% 0.2% 815926 87633 2752013 20.3% 1.8% 10.9% 0.2% 267272 1593140 20.0% 11.2% 0.2% 442538 12.8% QTR1 7 QTR1 5 0QTR1 30 0QTR1 1 267876 0 0 314 164943 0 1146738 154 62480 3024 705334 24 0 1351 269317 0 0 635 22882 0 0 67 14257 0 0 28 5134 0 0 0 12315 0 0 716280 7456 0 0 0.0% 419160 2205 14179520 18.9% 0.0% 121671 0.2% 8717820 1417952 18.9% 0.0% 18.9% 0.2% 332456 0 871782 18.8% 0.0% 18.9% 0.2% 22949 0 332456 100.0% 0.0% 18.8% 0.3% 14285 0 22949 100.0% 0.0% 100.0% 0.2% 5134 728595 14285 100.0% 100.0% 0.0% 1.7% 728595 426616 5134 100.0% 1.7% 1.7% 1440901 426616 123876 20.2% 1.7% 1.8% 0.2% 886067 123876 2898091 20.2% 1.8% 10.9% 0.2% 337590 1739299 20.0% 11.2% 0.2% 585342 12.3% QTR2 7 QTR2 5 0QTR2 30 0QTR2 1 281302 0 0 381 178772 0 1199144 154 74887 3139 760360 34 0 1764 324382 0 0 760 24070 0 0 67 15463 0 0 28 6354 0 0 0 13186 0 0 754661 7679 0 0 0.0% 456421 2615 14839660 19.0% 0.0% 157839 0.2% 9410500 1483966 19.0% 0.0% 19.0% 0.2% 400063 0 941050 18.7% 0.0% 19.0% 0.2% 24137 0 400063 100.0% 0.0% 18.7% 0.3% 15491 0 24137 100.0% 0.0% 100.0% 0.2% 6354 767847 15491 100.0% 100.0% 0.0% 1.7% 767847 464100 6354 100.0% 1.7% 1.7% 1508103 464100 160454 20.3% 1.7% 1.6% 0.2% 956541 160454 3043797 20.3% 1.6% 10.9% 0.2% 406417 1884741 20.0% 11.1% 0.2% 727325 11.9% QTR3 7 QTR3 5 0QTR3 30 0QTR3 1 293099 0 0 588 191521 0 1252241 154 87870 3163 814517 34 0 1885 377930 0 0 770 25438 0 0 72 16257 0 0 28 7774 0 0 23 13573 0 0 795412 8203 0 0 0.0% 493090 3321 15490910 19.0% 0.0% 194110 0.2% 10080770 1549091 19.0% 0.0% 19.0% 0.2% 466604 01008077 18.8% 0.0% 19.0% 0.2% 25510 0 466604 100.0% 0.0% 18.8% 0.3% 16285 0 25510 100.0% 0.0% 100.0% 0.2% 7797 808985 16285 100.0% 100.0% 0.3% 1.7% 808985 501293 7797 100.0% 1.7% 1.6% 1574601 501293 197431 20.3% 1.6% 1.7% 0.2% 1024362 197431 3192571 20.3% 1.7% 10.8% 0.2% 474401 2026948 20.2% 11.1% 0.2% 869263 11.8% QTR4 7 QTR4 5 0QTR4 30 0QTR4 1 305602 0 0 588 204459 0 1307122 159 102091 3299 871736 34 0 1995 433179 0 0 785 26692 0 0 72 17192 0 0 28 8483 0 0 23 13992 0 0 831971 8790 0 0 0.0% 532752 4222 16166110 18.9% 0.0% 230341 0.2% 10783490 1616611 19.0% 0.0% 18.9% 0.2% 536089 01078349 19.1% 0.0% 19.0% 0.2% 26764 0 536089 100.0% 0.0% 19.1% 0.3% 17220 0 26764 100.0% 0.0% 100.0% 0.2% 8506 845963 17220 100.0% 100.0% 0.3% 1.7% 845963 541542 8506 100.0% 1.7% 1.6% 1643375 541542 234563 20.3% 1.6% 1.8% 0.2% 1095569 234563 3335301 20.2% 1.8% 10.8% 0.2% 544595 2178653 20.3% 11.0% 0.2% 1013721 11.7% QTR1 8 QTR1 6 0QTR1 40 0QTR1 2 317096 0 0 588 217244 0 1361429 164 115591 3342 924028 48 0 2207 484988 0 0 920 28007 0 0 72 18054 0 0 67 9733 0 0 23 14734 0 0 868367 9523 0 0 0.0% 571113 4618 16824550 18.9% 0.0% 268971 0.2% 11436430 1682455 19.0% 0.0% 18.9% 0.2% 601547 01143643 19.2% 0.0% 19.0% 0.2% 28079 0 601547 100.0% 0.0% 19.2% 0.3% 18121 0 28079 100.0% 0.0% 100.0% 0.4% 9756 883101 18121 100.0% 100.0% 0.2% 1.7% 883101 580636 9756 100.0% 1.7% 1.6% 1710534 580636 273589 20.2% 1.6% 1.7% 0.2% 1161764 273589 3476736 20.3% 1.7% 10.8% 0.2% 611303 2323036 20.5% 11.0% 0.2% 1158481 11.6% QTR2 8 QTR2 6 0QTR2 40 0QTR2 2 329929 0 0 602 228348 0 1414999 265 127988 3453 976900 48 0 2371 538919 0 0 1075 29308 0 0 72 18925 0 0 67 10494 0 0 23 15278 0 0 905074 10005 0 0 0.0% 607374 5072 17489830 18.9% 0.0% 308890 0.2% 12078840 1748983 18.9% 0.0% 18.9% 0.2% 668030 01207884 19.2% 0.0% 18.9% 0.2% 29380 0 668030 100.0% 0.0% 19.2% 0.2% 18992 0 29380 100.0% 0.0% 100.0% 0.4% 10517 920352 18992 100.0% 100.0% 0.2% 1.7% 920352 617379 10517 100.0% 1.7% 1.6% 1778363 617379 313962 20.2% 1.6% 1.6% 0.2% 1226876 313962 3619067 20.2% 1.6% 10.8% 0.2% 678547 2461634 20.4% 10.9% 0.2% 1306471 11.4% QTR3 8 QTR3 6 0QTR3 40 0QTR3 2 343320 0 0 607 242159 0 1473276 270 140463 3462 1034796 53 0 2620 594255 0 0 1225 30327 0 0 77 20136 0 0 67 11719 0 0 23 15879 0 0 941842 10872 0 0 0.0% 643168 5622 18206650 18.9% 0.0% 346138 0.2% 12798450 1820665 18.9% 0.0% 18.9% 0.2% 735996 01279845 19.1% 0.0% 18.9% 0.2% 30404 0 735996 100.0% 0.0% 19.1% 0.3% 20203 0 30404 100.0% 0.0% 100.0% 0.3% 11742 957721 20203 100.0% 100.0% 0.2% 1.7% 957721 654040 11742 100.0% 1.7% 1.7% 1851069 654040 351760 20.2% 1.7% 1.6% 0.2% 1300048 351760 3766511 20.2% 1.6% 10.8% 0.2% 747738 2608128 20.4% 10.9% 0.2% 1451258 11.3% QTR4 8 QTR4 6 0QTR4 40 0QTR4 2 357437 0 0 708 254456 0 1524412 270 153045 3572 1091989 154 0 2890 648647 0 0 1245 31088 0 0 77 21615 0 0 67 12807 0 0 28 16581 0 0 980609 11381 0 0 0.0% 678982 6464 18861290 19.0% 0.0% 382143 0.2% 13496050 1886129 18.9% 0.0% 19.0% 0.2% 803091 01349605 19.1% 0.0% 18.9% 0.2% 31165 0 803091 100.0% 0.0% 19.1% 0.2% 21682 0 31165 100.0% 0.0% 100.0% 0.3% 12835 997190 21682 100.0% 100.0% 0.2% 1.7% 997190 690363 12835 100.0% 1.7% 1.6% 1917294 690363 388607 20.3% 1.6% 1.7% 0.2% 1371287 388607 3911674 20.2% 1.7% 10.8% 0.2% 815926 2752013 20.3% 10.9% 0.2% 1593140 11.2% QTR1 9 QTR1 7 QTR1 5 0QTR1 30 0267876 0 314 164943 1146738 1543024 7053340 13510 022882 0 67 142570 28 0 012315 0716280 7456 0 0.0% 419160 14179520 18.9% 0.0% 0.2% 871782 1417952 18.9% 18.9% 0.2% 0 8717820.0% 18.9% 22949 0 100.0% 0.0% 0.3% 1428522949 100.0% 100.0% 0.2% 728595 14285 100.0% 1.7% 728595 426616 1.7% 1.7% 1440901 42661620.2% 1.7% 0.2% 886067 2898091 20.2% 10.9% 0.2% 1739299 11.2% QTR2 9 QTR2 7 QTR2 5 0QTR2 30 0281302 0 381 178772 1199144 1543139 7603600 17640 024070 0 67 154630 28 0 013186 0754661 7679 0 0.0% 456421 14839660 19.0% 0.0% 0.2% 941050 1483966 19.0% 19.0% 0.2% 0 9410500.0% 19.0% 24137 0 100.0% 0.0% 0.3% 1549124137 100.0% 100.0% 0.2% 767847 15491 100.0% 1.7% 767847 464100 1.7% 1.7% 1508103 46410020.3% 1.7% 0.2% 956541 3043797 20.3% 10.9% 0.2% 1884741 11.1% QTR3 9 QTR3 7 QTR3 5 0QTR3 30 0293099 0 588 191521 1252241 1543163 8145170 18850 025438 0 72 162570 28 0 013573 0795412 8203 0 0.0% 493090 15490910 19.0% 0.0% 0.2% 1008077 1549091 19.0% 19.0% 0.2% 010080770.0% 19.0% 25510 0 100.0% 0.0% 0.3% 1628525510 100.0% 100.0% 0.2% 808985 16285 100.0% 1.7% 808985 501293 1.7% 1.6% 1574601 50129320.3% 1.6% 0.2% 1024362 3192571 20.3% 10.8% 0.2% 2026948 11.1% QTR4 9 QTR4 7 QTR4 5 0QTR4 30 0305602 0 588 204459 1307122 1593299 8717360 19950 026692 0 72 171920 28 0 013992 0831971 8790 0 0.0% 532752 16166110 18.9% 0.0% 0.2% 1078349 1616611 19.0% 18.9% 0.2% 010783490.0% 19.0% 26764 0 100.0% 0.0% 0.3% 1722026764 100.0% 100.0% 0.2% 845963 17220 100.0% 1.7% 845963 541542 1.7% 1.6% 1643375 54154220.3% 1.6% 0.2% 1095569 3335301 20.2% 10.8% 0.2% 2178653 11.0% QTR1 10 QTR1 8 QTR1 6 0QTR1 40 0317096 0 588 217244 1361429 1643342 9240280 22070 028007 0 72 180540 67 0 014734 0868367 9523 0 0.0% 571113 16824550 18.9% 0.0% 0.2% 1143643 1682455 19.0% 18.9% 0.2% 011436430.0% 19.0% 28079 0 100.0% 0.0% 0.3% 1812128079 100.0% 100.0% 0.4% 883101 18121 100.0% 1.7% 883101 580636 1.7% 1.6% 1710534 58063620.2% 1.6% 0.2% 1161764 3476736 20.3% 10.8% 0.2% 2323036 11.0% QTR2 10 QTR2 8 QTR2 6 0QTR2 40 0329929 0 602 228348 1414999 2653453 9769000 23710 029308 0 72 189250 67 0 015278 0905074 100050 0.0% 607374 17489830 18.9% 0.0% 0.2% 1207884 1748983 18.9% 18.9% 0.2% 012078840.0% 18.9% 29380 0 100.0% 0.0% 0.2% 1899229380 100.0% 100.0% 0.4% 920352 18992 100.0% 1.7% 920352 617379 1.7% 1.6% 1778363 61737920.2% 1.6% 0.2% 1226876 3619067 20.2% 10.8% 0.2% 2461634 10.9% QTR3 10 QTR3 8 QTR3 6 0QTR3 40 0343320 0 607 242159 1473276 2703462 1034796 0 26200 030327 0 77 201360 67 0 015879 0941842 10872 0 0.0% 643168 18206650 18.9% 0.0% 0.2% 1279845 1820665 18.9% 18.9% 0.2% 012798450.0% 18.9% 30404 0 100.0% 0.0% 0.3% 2020330404 100.0% 100.0% 0.3% 957721 20203 100.0% 1.7% 957721 654040 1.7% 1.7% 1851069 65404020.2% 1.7% 0.2% 1300048 3766511 20.2% 10.8% 0.2% 2608128 10.9% QTR4 10 QTR4 8 QTR4 6 0QTR4 40 0357437 0 708 254456 1524412 2703572 1091989 0 28900 031088 0 77 216150 67 0 016581 0980609 11381 0 0.0% 678982 18861290 19.0% 0.0% 0.2% 1349605 1886129 18.9% 19.0% 0.2% 013496050.0% 18.9% 31165 0 100.0% 0.0% 0.2% 21682 31165 100.0% 100.0% 0.3% 997190 21682 100.0% 1.7% 997190 690363 1.7% 1.6% 1917294 69036320.3% 1.6% 0.2% 1371287 3911674 20.2% 10.8% 0.2% 2752013 10.9% QTR1 9 QTR1 7 QTR1 5 0 0 267876 314 1146738 3024 0 0 22882 67 0 0 12315 716280 0 0.0% 1417952 18.9% 0.2% 1417952 18.9% 0 0.0% 22949 100.0% 0.3% 22949 100.0% 728595 1.7% 728595 1.7% 1440901 20.2% 0.2% 2898091 10.9% QTR2 9 QTR2 7 QTR2 5 0 0 281302 381 1199144 3139 0 0 24070 67 0 0 13186 754661 0 0.0% 1483966 19.0% 0.2% 1483966 19.0% 0 0.0% 24137 100.0% 0.3% 24137 100.0% 767847 1.7% 767847 1.7% 1508103 20.3% 0.2% 3043797 10.9% QTR3 9 QTR3 7 QTR3 5 0 0 293099 588 1252241 3163 0 0 25438 72 0 0 13573 795412 0 0.0% 1549091 19.0% 0.2% 1549091 19.0% 0 0.0% 25510 100.0% 0.3% 25510 100.0% 808985 1.7% 808985 1.7% 1574601 20.3% 0.2% 3192571 10.8% QTR4 9 QTR4 7 QTR4 5 0 0 305602 588 1307122 3299 0 0 26692 72 0 0 13992 831971 0 0.0% 1616611 18.9% 0.2% 1616611 18.9% 0 0.0% 26764 100.0% 0.3% 26764 100.0% 845963 1.7% 845963 1.7% 1643375 20.3% 0.2% 3335301 10.8% QTR1 10 QTR1 8 QTR1 6 0 0 317096 588 1361429 3342 0 0 28007 72 0 0 14734 868367 0 0.0% 1682455 18.9% 0.2% 1682455 18.9% 0 0.0% 28079 100.0% 0.3% 28079 100.0% 883101 1.7% 883101 1.7% 1710534 20.2% 0.2% 3476736 10.8% QTR2 10 QTR2 8 QTR2 6 0 0 329929 602 1414999 3453 0 0 29308 72 0 0 15278 905074 0 0.0% 1748983 18.9% 0.2% 1748983 18.9% 0 0.0% 29380 100.0% 0.2% 29380 100.0% 920352 1.7% 920352 1.7% 1778363 20.2% 0.2% 3619067 10.8% QTR3 10 QTR3 8 QTR3 6 0 0 343320 607 1473276 3462 0 0 30327 77 0 0 15879 941842 0 0.0% 1820665 18.9% 0.2% 1820665 18.9% 0 0.0% 30404 100.0% 0.3% 30404 100.0% 957721 1.7% 957721 1.7% 1851069 20.2% 0.2% 3766511 10.8% QTR4 10 QTR4 8 QTR4 6 0 0 357437 708 1524412 3572 0 0 31088 77 0 0 16581 980609 0 0.0% 1886129 19.0% 0.2% 1886129 19.0% 0 0.0% 31165 100.0% 0.2% 31165 100.0% 997190 1.7% 997190 1.7% 1917294 20.3% 0.2% 3911674 10.8% QTR1 9 QTR1 7 QTR2 9 QTR2 7 QTR3 9 QTR3 7 QTR4 9 QTR4 7 QTR1 10 QTR1 8 QTR2 10 QTR2 8 QTR3 10 QTR3 8 QTR4 10 QTR4 8 QTR1 9 QTR2 9 QTR3 9 QTR4 9 QTR1 10 QTR2 10 QTR3 10 QTR4 10 Modelling Approach? - Design EXCEL WORKBOOK Data is output to an Excel Workbook every Quarter in line with the World Health Organisation requirements for trials of diagnostics 17
Modelling Design - Linking to Transmission Modelling for Scale-Up Patient & Health System Impacts Time to diagnosis Default Rates Cure Rates Incidence Transmission Impacts Lin HH, Langley I, Mwenda R, et al. (2011), A modelling framework to support the selection and implementation of new tuberculosis diagnostic tools. Int J Tuberc Lung Dis 15(8):996 1004, doi:10.5588/ijtld.11.0062 18
Modelling Approach? Data Collation & Model Calibration Directed by sponsor to test approach in Tanzania. One of the 22 Highest burden countries Measure Count Population 44million New cases per year 80k p.a. cases Treated 64k p.a. HIV+% in Incidence 47% Treatment Cure Rate 87% Health Facility Count Central Reference Lab 1 Zonal Laboratories 2 Regions 27 Districts 168 Laboratories >900 Sources Basra Doulla, Ministry of Health, Dar es Salaam, Tanzania 19
Modelling Approach? Data Collation & Model Calibration Minimum Data Requirements for each diagnostic district Parameter Example Data from Tanzania Current Tools ZN Microscopy & X-ray Laboratory Staff 2 lab technicians cases per year New Smear +ve 560 New Smear -ve 450 Retreatment 93 HIV+ rate in Cases 42.0% Smear +ve Rate - New Suspects 11.4% Assumptions were validated with experts, published literature, and could be subject to sensitivity analysis e.g. Accuracy (Sensitivity and Specificity) of the alternative tests suspect and treatment default rates processes and treatment times Costing information 20
OPTION 1 - BASE CASE ZN Microscopy At end of intermediate phases if smear Positive Test For Drug Resistance and put on MDR - Treatment if found Treatment Monitoring 30mins Becomes Sick with cough Receive Treatment Medicine Smear Positive 11.4% ing Every 2 wks for Medicines At end of intermediate phases if smear negative 10.0% Diagnosed Smear Negative Receive Diagnosis No Found Cure 78.6% 30mins 30mins Provide Sputum Sample 2 Health Clinic Suspect Provide Sputum Sample 1 21
OPTION 2 LED Fluorescence Microscopy At end of intermediate phases if smear Positive Test For Drug Resistance and put on MDR - Treatment if found Treatment Monitoring 20mins Becomes Sick with cough $1,100 per micro Receive Treatment Medicine Smear Positive 13.4% ing Every 2 wks for Medicines At end of intermediate phases if smear negative 7.9% Diagnosed Smear Negative Receive Diagnosis No Found Cure 78.7% 20mins 20mins Provide Sputum Sample 2 Health Clinic Suspect Provide Sputum Sample 1 $1.50 per sample 22
OPTION 3 Xpert M/RIF Microscopy Receive Treatment Medicine At end of intermediate phases if smear Positive Test For Drug Resistance and put on MDR - Treatment if found Smear Positive 20.2% ing Every 2 wks for Medicines At end of intermediate phases if smear negative 1.6% Diagnosed Smear Negative Receive Diagnosis Treatment Monitoring No Found 20mins Cure 78.2% Becomes Sick with cough Health Clinic 131mins Suspect Provide Sputum Sample 1 $17,000 per machine $10.70 per sample FIND (2010), FIND negotiated prices for Xpert M/RIF and Country list, (Accessed June 2011, http://www.finddiagnostics.org/ about/whatwedo/ successes/find-negotiated-prices/xpert_mtb_rif.html 23
OPTION 4 Xpert for HIV+ / LED for HIV- At end of intermediate phases if smear Positive Test For Drug Resistance and put on MDR - Treatment if found Treatment Monitoring Becomes Sick with cough HIV- Receive Treatment Medicine Smear Positive ing Every 2 wks for Medicines Diagnosed At end of intermediate phases if smear negative Cure No Found Health Clinic Suspect Provide Sputum Sample 1 $1,100 per micro $1.50 per sample Smear Negative Receive Diagnosis Provide Sputum Sample 2 At end of intermediate phases if smear Positive Test For Drug Resistance and put on MDR - Treatment if found Treatment Monitoring Becomes Sick with cough HIV+ Receive Treatment Medicine Smear Positive ing Every 2 wks for Medicines Diagnosed At end of intermediate phases if smear negative Smear Negative Cure No Found Health Clinic Suspect Provide Sputum Sample 1 $17,000 per machine $10.70 per sample Receive Diagnosis 24
OUTPUTS Example Patient Outcomes - for 1 diagnostic district in Tanzania Time to Diagnosis (DAYS) ZN LED Xpert Xpert/LED -39% -29% -9% 0.00 5.00 10.00 15.00 20.00 25.00 30.00 Default rates ZN LED Xpert Xpert/LED Default, 15.6% Default, 13.9% Default, 10.7% Default, 10.7% Complete, 84.4% Complete, 86.1% Complete, 89.3% Complete, 89.3% 25
OUTPUTS Patient Outcomes of Patients Cured each Year ZN LED +5%% Xpert +16% Xpert/LED +11% 0 200 400 600 800 1,000 1,200 26
OUTPUTS Example Health System Outcomes of Sputum Samples Analysed p.a. Running Costs ($k p.a.) ZN ZN LED LED +0.2% Xpert Xpert +49% Xpert/LED Xpert/LED +27% 0 5000 10000 15000 20000 0 20 40 60 80 100 120 140 160 27
PATIENT OUTCOMES ZN XPERT/LED MICROSCOPY M/RIF AROUND 69.5% 77.2% 73.6% 66.6% OF PATIENTS/SUSPECTS SEEKING DIAGNOSIS ARE CORRECTLY DIAGNOSED AND TREATED FOR 28
OUTPUTS Cost Effectiveness Analysis Incremental Cost Effectiveness can be used to compare interventions Difference to Base Case A LED Micro. B Xpert Full C Xpert Part Incremental DALY averted/ yr 399 1,220 843 (95% Confidence Intervals) (259-539) (1011-1429) (655-1032) Incremental costs/ Additional Cure $0.8 (95% Confidence Intervals) (0.4-1.1) Incremental costs/ DALY averted (95% Confidence Intervals) Sensitivity of Incremental costs/ DALY averted to Xpert cost per test $16.9 (max) rather than $10.7 (min) $0.08 (0.05-0.11) $0.08 (0.05-0.11) $353 (299-406) $38.3 $38.3 (31.8-44.9) $67.8 (56.3-79.4) +77% $282 (233-331) $30.3 (23.5-37.1) $48.4 (37.5-59.2) +60% Disability Adjusted Life Year (DALY) averted is used to measure the success of the intervention in reducing the number of years of life lost and the number of years lived with disability. The incremental cost divided by the DALY averted gives an incremental cost ratio 29
Conclusions Discrete Event Simulation of options for diagnostics in the developing world:- is a practical and effective approach provides comprehensive information can be linked to transmission models engages policy makers in validation and questioning enables complex interactions to be taken into account can take longer to develop than some other approaches, but once developed can easily be adapted to other contexts 30
What Next? Model impacts of Scale-up across Tanzania Implement the model in the Ministry of Health in Tanzania for modelling individual diagnostic centres Apply the modelling approach to other contexts Malawi Brazil High MDR- settings Lin HH, Langley I, Mwenda R, et al. (2011), A modelling framework to support the selection and implementation of new tuberculosis diagnostic tools. Int J Tuberc Lung Dis 15(8):996 1004, doi:10.5588/ijtld.11.0062 31
Acknowledgment USAID YaDiul Mukadi Tanzania NTLP Dr Saidi Egwaga Basra Doulla Malawi MOH Reuben Mwenda Lanner Group Geoff Hook Liverpool School of Tropical Medicine Bertie Squire Gillian Mann Kerry Millington Harvard School of Public Health Ted Cohen Megan Murray 32