C R E A E Consortium to Respond Effectively to the AIDS-TB Epidemic An International Research Partnership Supported by the Bill and Melinda Gates Foundation http://www.tbhiv-create.org
Overview What is the problem? What drives HIV-related TB? The conventional wisdom Alternative approaches CREATE
Highlights of 2005 Global TB Report 8.8 million new cases in 2003 15.4 million prevalent cases 98% in developing countries >10% increase since 1997 Increasing rates in Africa and E. Europe Decreasing elsewhere 1.8 million deaths Leading cause of death in people with HIV DOTS programs detecting 42% of cases
Growth of TB in Africa and Eastern Europe Standardized notification rate 300 250 200 150 100 50 Africa - high HIV Eastern Europe Africa - low HIV v 0 1980 1985 1990 1995 2000
Estimated TB incidence rate, 2003 Rates per 100 000, all forms of TB 0-24 25-49 50-99 100-299 300 or more No estimate The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2004
Estimated number of TB cases, 2003 Number of TB cases < 1000 1000-9 999 10 000-99 999 100 000-999 999 1 000 000 or more No estimate The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2004
Tuberculosis notification rate, 2003 Rate per 100 000, all forms of TB 0-24 25-49 50-99 100 or more No report The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2004
Adults and children estimated to be living with HIV/AIDS as of end 2003 North America 790 000 1.2 million Caribbean 350 000 590 000 Latin America 1.3 1.9 million Western Europe 520 000 680 000 North Africa & Middle East 470 000 730 000 Sub-Saharan Africa 25.0 28.2 million Eastern Europe & Central Asia 1.2 1.8 million East Asia & Pacific 700 000 1.3 million South & South-East Asia 4.6 8.2 million Australia & New Zealand 12 000 18 000 Total: 34 46 million
Estimated TB incidence (per 100,000 population) 1000 800 600 400 200 Dye, 2003 0 TB incidence closely correlated with HIV prevalence in Africa 0 10 20 30 40 HIV prevalence, adults 15-49y
Population Dynamics of TB Latent TB Active TB Primary TB Uninfected/Susceptible
Population Dynamics of TB in a Setting of High HIV Prevalence HIV+ Latent TB HIV+ Active TB Primary TB Uninfected/Susceptible HIV+
Principal Strategies for Controlling HIV-Related TB in 2004 The Conventional Wisdom DOTS TB strategy Reduction in HIV burden through primary prevention Treatment of HIV with HAART coming soon
What is DOTS? Governmental commitment to TB control System for registration and follow up of TB cases Reliable supply of TB drugs Microbiologic confirmation of TB diagnosis Supervision of at least the initial phase of TB therapy
Proportion of TB Patients with Access to DOTS Worldwide, 1995-2000 % With Access to DOTS 50 45 40 35 30 25 20 15 10 5 0 47 42 37 35 32 22 1995 1996 1997 1998 1999 2000 *2002: 28% of cases treated with DOTS
100 Treatment Outcomes by WHO Region: DOTS vs. non-dots 1999 Cohort DOTS Non-DOTS 100 80 80 60 60 40 40 20 20 0 0 AFR AMR EMR EUR SEAR WPR AFR AMR EMR EUR SEAR WPR Treated successfully Not treated successfully Not evaluated World Health Organization
TB in Botswana Pre- and Post- DOTS, Preand Post- HIV 650 TB Incidence per 100,000 550 450 350 250 150 50 DOTS 80 83 86 89 92 95 98 2001 Year Global Tuberculosis Control, WHO Report 2004
Causes of death in HIV-positive patients in Botswana, 1997-1998 104 HIV+ patients who died without diagnosis, unexpectedly or with respiratory disease TB found in 40%, 90% disseminated TB is the leading cause of death in HIV+ patients in a country with a DOTS program that cures >90% of patients registered Ansari, et al., Int J Tuberc Lung Dis 2002; 6:55-63
Reported TB Case Rates in Malawi 1988-2001 250 200 Rate per 100,000 150 100 50 0 88 89 90 91 92 93 94 95 96 97 98 99 '00 '01 Year WHO TB Surveillance Report, 2003
Pulmonary TB cases/100,000 DOTS results in TB incidence decline The case of Peru 220 DOTS 1990 200 180 160 140 120 Pulmonary TB falling at 6%/yr 100 1980 1985 1990 1995 2000
Increased TB Case Finding Preceded the Reduction of TB Incidence in Peru: AFB Smears Performed in Peru, 1987-1997 Thousands 1600 1400 1200 1000 800 600 400 200 0 87 88 89 90 91 92 93 94 95 96 97 Tuberculosis en el Peru, Informe 1997, Ministerio de Salud, Lima, 1998
DOTS and HIV-Related TB DOTS is a critically important strategy for effective management of TB DOTS increases cure rates, reduces mortality and prevents emergence of drug resistance In the setting of HIV prevalence, DOTS alone is not sufficient to control TB incidence
Rising TB Incidence in Setting of Falling HIV Prevalence in Uganda 180 160 140 120 100 80 60 40 20 0 35 30 25 20 15 10 5 0 TB HIV TB notification rate (per 100,000) HIV prevalence (urban) 1990 1992 1994 1996 1998 2000 2002 UNAIDS fact sheet, WHO global TB report
Impact of Highly Active Antiretroviral Therapy on TB Incidence in South Africa TB Cases per 100 PY 18 16 14 12 10 8 6 4 2 0 >350 200-350 <200 HAART No HAART Baseline CD4 Count Badri et al., Lancet 2002;359:2059-64
Tuberculosis in Patients on HAART in Soweto, South Africa 95 patients receiving HAART through expanded access programs (71 adults) Median of 2 years follow up per patient Incidence rates 7.2 cases per 100 PY for adults 3.5 cases per 100 PY for children Median time to TB = 1.8 years, 3 cases in first 3 months Mhlongo, Martinson, Violari, et al., WAC, Bangkok 2004
Impact of HAART on AIDS Mortality in Rio de Janeiro, Brazil Mortality of AIDS per 100,000 Inhabitants by Gender in Rio de Janeiro City - 1984 to 2002 50 45 40 35 Coef./100.000 30 25 20 15 10 5 0 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Year Males Females Total
Results Co-infection - TB diagnosed after AIDS and before AIDS in varying time periods Cases 0 200 400 600 800 1000 0 year 1 year 3 years 5 years 1995 1996 1997 1998 1999 2000 2001 Year
Overall incident TB Results Overall incident AIDS Cases 0 4000 8000 Cases 0 1000 2000 1995 1996 1997 1998 1999 2000 2001 Year 1995 1996 1997 1998 1999 2000 2001 Year Co-infection (within 30 days) Co-infection (within 30 days) Cases 0 100 200 300 Percent 0.00 0.10 0.20 1995 1996 1997 1998 1999 2000 2001 Year 1995 1996 1997 1998 1999 2000 2001 Year
Limitations to Controlling HIV-Related TB with Current Approaches DOTS TB strategy Clearly insufficient May reduce rate of increase, but will not control Reduction in HIV burden through primary prevention TB incidence continues to rise for years Treatment of HIV with HAART May have impact, but ARVs started late TB risk still extremely high
C R E A E Mission To organize, implement and evaluate novel public health strategies to reduce tuberculosis incidence in populations with high rates of HIV and TB co-infection.
C R E A E A brief history Fall 2001 concept sheet submitted June 2002 pilot grant for $3 million September 2002 Annecy planning meeting February 2003 proposals submitted June 2003 London meeting on case finding November 2003 Seattle meeting with BMGF January 2004 final proposal submitted
End of the CREATE Meeting at the Bill and Melinda Gates Foundation, November 2003
Gates Foundation Press Briefing on TB and HIV at the Bangkok AIDS Conference July 15, 2004
CREATE Objectives Design, implement and evaluate a portfolio of community-level trials of new strategies designed to reduce TB incidence in communities with high HIV prevalence. Transform global policies for HIV-related TB through evidence-based advocacy.
Strategies to Reduce TB/HIV in Addition to DOTS Active or intensified case finding to identify cases transmitting infection, and who may die without treatment Treatment of latent TB infection to prevent disease in HIV+ (and HIV-) persons Household HIV/TB interventions linked to cases to promote active case finding, identify candidates for TB preventive therapy (and antiretroviral drugs), and reduce HIV transmission Combined ARV and IPT treatment programs to reduce probability of developing primary or reactivation TB
HIV+ Latent TB IPT ARVs IPT ARVs Primary TB HIV+ Active TB ACF/ICF DOTS HIV+ Uninfected/Susceptible
The CREATE Portfolio: Approved Studies Study Site Intervention(s) Design SA Gold Mines Zambia/South Africa Rio de Janeiro Mass preventive therapy HH interventions, intensified case finding Preventive therapy and ARVs Cluster randomized trial Community randomized trial Phased implementation trial
TB Incidence in South African Miners Case Notification Rates per 100 000 Population 4,000 3,000 Goldminers South Africa 4,156 2,000 1,000 495 0 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000
Community-wide preventive therapy Effect on TB Incidence Per 100,000 population Mass PT 8,000 6,000 4,000 2,000 0 1980 2000 Year 2020
Thibelo TB Preventing TB in Miners Study Setting
Mass Preventive Therapy with INH in South African Gold Miners Design: Cluster randomized trial Setting: 24 mine shafts with 1-3000 workers Intervention: INH for all vs. standard of care (VCT with INH for HIV+, silicotics) Endpoint: TB incidence and prevalence after 5 years
Duration of TB (in years) before diagnosis in Gold Miners HIV-ve 1.79 0.61 HIV+ve p = 0.04 0 1 2 3 Years Reproduced from Churchyard et al (2)
Rates of TB During and After Treatment with INH or Placebo, Randomized by Household G. Comstock, USPHS Bethel, Alaska Trial TB per 1,000 PY 16 14 12 10 8 6 4 2 0 1 2 3 4 5 6 Year After Randomization Placebo INH Adv Tbc Res 1969
Rates of TB in Mines With or Without Mass INH Treatment, 1966 7 6 5 TB Per 1,000 Per Year 4 3 2 1 INH No INH 0 Pair 1 Pair 2 Pair 3 Pair 4 Pair 5 Total Mine Pairs Smit, Proc Mine Med Off Assoc, 1968
ZAMSTAR - the Zambian South African TB and AIDS Reduction trial ZAMBART, UNZA Centre for TB Research, Univ Stellenbosch CBOH, Zambia LDHMT, Zambia City of Cape Town, SA LSHTM, UK
ZAMSTAR
Enhancing case-finding by removing barriers and empowering communities ECF Open Access lab School Intervention Outreach/mobile lab 1. Recruit additional lab technicians 2. Develop IEC 3. Establish ECF register 4. QA 1. Develop school TB/HIV curriculum 2. Twice yearly intervention in all schools in intervention area 3. Establish ECF register 4. QA 1. Manufacture/adapt mobile laboratories 2. Develop IEC/Outreach activities 3. Weekly Outreach activities 4. Establish ECF register 5. QA
Household counseling to improve TB and HIV care and prevention Household HIV/TB Intervention 1. All TB patients recruited 2. Asked for consent and to ask household for consent Visits month 0,1,2,6/8 1. Household members documented and consent 2. TB and HIV group education and counselling 3. All HH members screened for TB 4. HIV+ and children<6 given IPT 5. Adherence support using family network Monitoring (All): TB outcome Additional cases of TB Uptake TC Uptake and adherence IPT Cohort (first 150 each site): Stigma evaluation HIV status (baseline and after 3 years) TB infection (baseline and after 3 years) Cumulative TB incidence
ZAMSTAR Study Design 4-arm Community Randomized Trial Control Improved standard of care Enhanced Tuberculosis Case Finding (ECF) Community level intervention Household level TB and HIV combined activities (HH) Household intervention Both ECF and HH
6 Control 6 ECF Clinic & VCT Clinic & VCT ECF Vs.No ECF Clinic & VCT Clinic & VCT 6 HH 6 ECF+HH
6 Control 6 ECF Clinic & VCT Clinic & VCT HH Vs No HH Clinic & VCT Clinic & VCT 6 HH 6 ECF+HH
Cluster-randomized Trial of INH Preventive Therapy in HIV Clinics in Rio de Janeiro Intervention: Implementation of a comprehensive policy of screening for and treating latent TB in all HIV-infected patients TST and INH PT for all TST+ Incentives/enablers to promote adherence One clinic phased-in each month until ALL clinics are receiving intervention
Methods Study Design Control group: Clinic populations that have not yet been phased-in to begin implementation 29 4 Control Clinic 3 Follow-up 2 1 Intervention 1 2 3 4 5 30 36 42 Month
Reduction in TB cases if 25% of latently infected patients are not eligible for HAART Expected 40% reduction 60% reduction Cases 400 350 300 250 200 150 100 50 0 HAART Non-HAART HAART Non-HAART HAART Non-HAART 15,000 20,000 25,000 HIV clinic population
Controlling TB in HIV-Endemic and Other High Incidence Areas Requires a reassessment of traditional dogma for TB control development of new tools and technologies joint approaches with HIV control programs novel strategies with limited public health precedent C R E A E
Nelson Mandela on TB and HIV Bangkok, 15 July 2004
The world has made defeating AIDS a top priority. This is a blessing. But TB remains ignored. Today we are calling on the world to recognize that we can t fight AIDS unless we do much more to fight TB as well. -Nelson Mandela Bangkok, July 15, 2004
Thank You