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Control of tuberculosis: analytical methods

Control of tuberculosis: analytical methods. Udo Buchholz, WHO/Stop TB/TME. Subjects of this talk. DOTS TB and HIV DOTS plus - but not: What PPM can contribute How poverty can be addressed The influence of important, modifiable risk factors.

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Control of tuberculosis: analytical methods

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  1. Control of tuberculosis: analytical methods Udo Buchholz, WHO/Stop TB/TME

  2. Subjects of this talk • DOTS • TB and HIV • DOTS plus - but not: • What PPM can contribute • How poverty can be addressed • The influence of important, modifiable risk factors

  3. Evolution of and interaction between evidence, policy and reality Modelling Uncertainty New parameters, New parameter estimates Baseline conditions change Policy Confirmation? Discrepancies? New facts of life (war, HIV, economics, collapse of systems, more/less funding) New options for intervention (new drugs, new diagnostics, new vaccines) Reality

  4. "Tuberculosis can be controlled with existing technologies"1 • Elements of DOTS were shaped through results from: • studies, such as that in Kolin, • analyses of IUATLD-assisted NTPs in Tanzania, Malawi, Nicaragua • theoretical considerations1 • ... and later confirmed by TB models2 1K. Styblo, J.R. Bumgarner. TSRU progress report 1991. 2C. Dye et al. Prospects of worldwide tuberculosis control under the WHO DOTS strategy. The Lancet 1998.

  5. Estimated prevalence, when incidence 100 ss+/100k and prevalence baseline 200 ss+/100k1 • Limitations: • Focus on smear • positive TB only • No inclusion of • HIV and MDR • Analysis of one • generation only 1K. Styblo. Tuberculosis can be controlled with existing technologies. TSRU progress report 1991.

  6. 25% treatment failures remain infectious Fall in incidence rate (% per year) 100% treatment failures remain infectious Cure rate (%) Dynamic modelling: Fall in incidence depends on (1) cure rate, (2) % failures remaining infectious1 1C. Dye et al. Prospects of worldwide tuberculosis control under the WHO DOTS strategy . The Lancet 1998.

  7. How can we measure what DOTS does?

  8. Indicators INPUT Policy environment Human and Financial Resources Infrastructure PROCESS Management Training Drug management Laboratories Communication Advocacy OUTPUT Diagnostic services Treatment services Improved knowledge, attitudes, and practices Reduced stigma OUTCOME Case detection Treatment success IMPACT Prevalence of TB infection Prevalence of TB disease TB morbidity TB mortality Logical and chronological order p7, Compendium of Indicators for Monitoring and Evaluating National Tuberculosis Programs USAID, MEASURE, CDC, WHO, IUATLD, KNCV, MSH. WHO/HTM/TB/2004.344, August 2004

  9. With the ultimate goal... • ... to reduce incidence, prevalence and deaths from TB The MDGs

  10. TB mortality among children 0-4 years old, England and Wales, 1850-1941 DOTS 1990 But there was a decline, e.g. in TB mortality long before DOTS... • ... so how do we know that our achievements are due to DOTS?

  11. Ideally we would like to test DOTS in a RCT DOTS non-DOTS ... but DOTS is a package of (soft) interventions, not a vaccine or drug

  12. Evaluation of DOTS under real-life conditions • Comparison of districts or provinces (DOTS vs. non-DOTS) • Historical control (DOTS vs. before DOTS) • Correlation of concurrent changes in input/process/output indicators with changes in impact indicators (weakest)

  13. Example 1: comparison of DOTS with other districts: China

  14. DOTS since 1996: Impact or just consistent rec/rep? Decline of 4.7% Example 2.1: historical comparison: El Salvador

  15. Example 2.2: historical control (Maldives) – DOTS since 1996 Decline: 9%/yr

  16. Example 3: correlation of concurrent changes in indicators • Average number of slides examined per patient ~ proportion of TB cases that are smear positive ( ~ case detection rate) • Number of persons involved in DOT and defaulter tracing ~ treatment outcome • Number of NGOs involved in NTP programme reporting ~ case detection rate • Etc. ...

  17. Return in notified cases as result of increasing diagnostic efforts (# smears examined), Peru 1Suarez. The dynamics of tuberculosis in response to 10 years of intensive control effort in Peru. JID 2001.

  18. TB/HIV – HIV/AIDS and TB In areas with high HIV-prevalence: • HIV negative persons and HIV negative TB patients • Is HIV increasing MTB transmission? • How can TB in HIV negative persons be controlled? • HIV positive patients • TB treatment • Prevention: • of HIV • of TB by giving HAART • of TB disease by treating latent TB infection (TLTI)

  19. HIV negative TB • Study among South African gold miners1 • Combined data from 4 time periods in cohort studies • DOTS programme in place • Increase of HIV from ~1% in 1991 to 24% in 1999 • Increase of TB from 1000 per 100k (1990) to 4000 per 100k (1999) • Silicosis a strong risk factor for TB •  Changes in MTB transmission should be reflected in incidences among HIV negative gold miners 1E. Corbett. Stable incidence rates of TB among HIV negative South African gold miners during a decade of epidemic HIV-associated TB. JID 2003.

  20. TB notification rates among South African gold miners

  21. Trends in incidence of TB in HIV negative miners P-value for trend = 0.17

  22. Further analysis (1) • Risk factors in univariate analysis: • (1) Age

  23. Further analysis (2) • Risk factors in univariate analysis: • (1) Age • (2) Previous TB • (3) Surface work (protective) • (4) Silicosis grade •  Multivariate analysis to adjust for the different risk factors

  24. referent Multivariate-adjusted incidence rate ratio (IRR) for calendar period as risk factor for TB among HIV neg. gold miners • DOTS seems to be able to control TB among HIV negative persons even in settings with a high burden of HIV-associated TB

  25. Malawi: would there have been a decrease of TB in the absence of HIV?1 1J. Glynn. Trends in tuberculosis and the influence of HIV infection in northern Malawi, 1988-2001. AIDS 2004.

  26. HIV positive TB patients • Model by Currie et al.1 to compare the effectiveness of: • TB chemotherapy - with - • Prevention of HIV • HAART • Prevention of TB disease through TLTI (6-9 months) • Example of Kenya 1CSM Currie. Tuberculosis epidemics driven by HIV: is prevention better than cure? AIDS 2003.

  27. Model output: impact on TB deaths when each intervention is increased by 10% from 2002 Rapid impact of TB cure and detection, but greatest, but late impact of reduction of HIV incidence

  28. TB deaths averted over 10 years with 100% coverage of each intervention Red: HIV prevalence stabilizes at 50% of its current value Blue: ... at 100% of its current value Green: ... at 150% of its current value

  29. Efficacy of treatment of latent TB infection in HIV infected persons • Cochran review (2004) • Efficacy = effect under controlled conditions (RCT) • Effectiveness = effect under real-life conditions, e.g. as measured by case-control studies or retrospective cohort studies • Overall RR = 0.64 (95%CI = 0.51-0.81) Efficacy = 1-RR = 36% • Efficacy among tuberculin skin test positive persons: 0.38 (95%CI = 0.25-0.57) Efficacy = 62%

  30. time without INH 6 months INH time without INH TLTI – works also under routine conditions • South African gold miners • Objective to collect data on effectiveness under routine conditions • Randomized intervention study; each participant had the opportunity to receive the intervention • INH for 6 months, self-administered among HIV positive persons without evidence of active TB • No HAART 1AD Grant. Effect of routine isoniazid preventive therapy on TB incidence among HIV-infected men in South Africa. JAMA 2005.

  31. Results of INH study, S-A gold miners • TB incidence rate before vs. after clinic enrolment dropped from 11.9 to 9 per 100 person-years  IRR = 0.78 • Multivariate analysis and restricting analysis to persons with no h/o TB:IRR = 0.54 (0.35-0.83)  Reduction of TB incidence by 46% • Nevertheless: additional measures are urgently needed

  32. MDR and DOTS plus • National cohort study in Peru • Feasibility of using second-line drugs to treat patients with chronic TB • Encouraging, but not overwhelming results 1PG Suarez. Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. The Lancet 2002.

  33. Preliminary results of the first five DOTS-Plus projects1 • More than 3,000 MDR-TB patients enrolled and 1,047 who have completed treatment • MDR-TB among new cases ranged from 1.5-17.1% • 65% of the MDR-TB cases treated were resistant to both first and second-line drugs • The overall treatment success was 70% • 77% among new patients • 69% among previously treated patients • 3.7% of patients stopped treatment due to adverse events 1Slide thanks to Eva Nathanson, STB/THD

  34. DOTS-Plus - outcomes of 1047 MDR-TB patients

  35. Methodological summary • The evidence for the effect of control interventions in TB includes the following methods: • RCT/intervention study - example: TLTI in HIV-positive S-A gold miners • Surveillance data – ex.: DOTS • Cohort studies – ex.: TB incidence among HIV positive and negative persons • Modelling – the simulation of an experiment – ex.: effect of CT vs. preventive methods on TB cases and mortality

  36. Thank you

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