Dr. Stephen D. Lawn

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Research Priorities in HIV/TB
Dr. Stephen D. Lawn
Desmond Tutu HIV Centre Institute of Infectious
Disease Molecular Medicine University of Cape
Town
Department of Infectious Tropical Diseases,
London School of Hygiene Tropical Medicine,
London, UK
2

• 1. Impact of HIV / TB epidemic on global burden
  of TB
• 2. Data from Western Cape, South Africa to
  highlight key research questions
• 3. Why HIV / TB research should be high priority

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Present Status of Global Tuberculosis Control
In 2005 2 billion latent infection 8.8 million
new cases of TB 1.6 million deaths

WHO Report 2007 Global Tuberculosis Control
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(No Transcript)
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Trends in notification rates in 4 regions
Industrialised countries
Middle East North Africa
Former Soviet Union
Africa - High HIV prevalence countries
Global Tuberculosis Control. WHO Report 2003.
WHO/HTM/TB/2004.331
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Estimated Global TB Incidence
WHO Report 2007 Global Tuberculosis Control
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• Goals to halve 1990 prevalence and death rates
  by 2015

WHO Report 2007 Global Tuberculosis Control
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(No Transcript)
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Botswana DOTS has not controlled HIV-Associated
TB
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WHO, 2005 Maputo a regional emergency
requiring urgent and extraordinary actions
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Cape Town, South Africa

• The challenges of HIV / TB
• in the TB clinic
• in the community
• in the ART clinic

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• Impact of HIV on the Epidemiology of
  Tuberculosis in a Peri-Urban Community in South
  Africa the Need for Age-Specific Interventions
• Lawn et al. Clin Infect Dis 2006 42 1040-47

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The Challenge of HIV in the TB Clinic
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Change in TB Case Load
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• HIV testing gt60 TB patients HIV (11 not
  tested)
• Retreatment rates increased from 3 to 24 (87
  HIV)
• High mortality risk 16-35 mortality risk
  during TB treatment
• (rev. by Mukadi et al 2001)

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The Challenge of HIV/TB in the Community
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(No Transcript)
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Change in Age-Specific TB Notifications
1996-2004
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Changes in Age-Specific Notification Rates
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TB and HIV rates among 20-40 year-olds
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Undiagnosed Tuberculosis in a Community with High
HIV-prevalence Implications for TB
Control. Wood R, Middelkoop K, Myer L, Grant AD,
Whitelaw A, Lawn SD, Kaplan G, Huebner R,
McIntyre J, Bekker LG. Am J Respir Crit Care
Med. January 2007
Active TB Case Finding and HIV-testing in random
population sample
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Cross-Sectional Community Survey for TB and HIV
10 Sample of Adult Population
23HIV
9 HIV-infected patients had PTB
(5 undiagnosed) Case finding proportions for
HIV- TB 0.67 and for HIV TB 0.37
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Conclusions

• Staggering increase in TB case-load
• There is a huge burden of undiagnosed TB among
  HIV (symptoms poorly predictive)
• DOTS alone is insufficient

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Many issues

• TB diagnosis
• How to improve DOTS?
• Adjunctive strategies to DOTS?
• Active case-finding
• Isoniazid prophylaxis
• Sources / sites of TB
  transmission?

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The Challenge of TB in the ART Clinic
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Lawn et al. Burden of tuberculosis in an
antiretroviral treatment programme in sub-Saharan
Africa impact on treatment outcomes and
implications for tuberculosis control. AIDS 2006
20 1605-12
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Screening for TB at Entry to ART Programme
ART
Referrals
1 month
Programme entry
ART initiation
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• 52 had a 1 episode of completed TB treatment
• 26 had prevalent TB
• 10 developed incident TB during 1st year ART

Lawn et al. AIDS 2006 20 1605-12
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Burden of TB During ART
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How may ART impact TB Control?
HIV on ART 3 years
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Many Questions re TB and ART

• Screening for TB at ART programme entry
• Delivery concurrent TB Rx and ART
• Diagnosis / management / prevention of TB immune
  reconstitution disease
• Infection control in the ART clinic
• Effect of ART on TB control

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RESEARCH AGENDA
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Some Key Research Areas

• Diagnostics
• Active case finding
• Preventive therapy
• Infection control
• Integration of TB and HIV services

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Sensitivity of smear in HIV-infection as low as
20
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Current TB Diagnostics
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Technology
District Laboratory
Portion of population served
faster than culture
Current diagnostic service Solid culture 30d
Peripheral Lab
more sensitive than smear
Current diagnostic service Microscopy 20-60
sensitive
Clinic (true POC)
Reaching new patients
HIV diagnosis 15 mins TB diagnosis 3 weeks!!!
simpler than microscopy
Current diagnostic service None
30
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Active Case Finding

• All HIV patients
• VCT efficiency
• Other groups
• Need for screening tool
• New diagnostics

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Isoniazid Preventive Therapy (IPT)
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IPT in HIV Patients

• It works
• How to implement it?
• Excluding active TB?
• Risk drug resistance?
• Duration?
• Uptake / compliance
• Co-toxicity with d4T

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• Excluding active TB data are confusing
• Data from CDC BOTUSA Project, Botswana
• Mosimaneotsile et al. Lancet 2003
• Symptoms / signs adequate screen
• CXR not needed
• Samandari et al. CROI 2007
• n 2768
• 12 asymptomatic HIV patients had abnormal CXR
• 9 had active TB

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• High rates of sub-clinical TB
• Wood et al. AJRCCM 2007. South Africa
• Mtei et al. Clin Infect Dis 2005. Tanzania
• Corbett et al. PLoS Med 2007. Zimbabwe
• INAH resistance
• Meta-analysis trend towards increased risk of
  inah resistance (Balcells et al. EID 2006)
• Risk in v. high TB burden settings under
  non-research conditions?

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• Country policies on IPT
• Botswana has programme for HIV
• Kenya has dismissed IPT as intervention after
  national consultation
• Burundi has funding for IPT programme but wants
  reprogramme this into operational research to
  answer the many unanswered questions

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Infection Control
TB concentrated in ART clinics / medical wards In
Gugulethu, 1 in 3 patients has TB at programme
entry or in first year ART
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• How to screen for potentially infectious patients
• Caring for Health Care Workers
• Interventions
• Air flow
• UV light
• How to study intervention effects

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Integration of TB and HIV Services
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Need good models of how integration can be
achieved at national, regional, district and
clinic levels Need to demonstrate benefits Need
to overcome concerns eg. nosocomial TB
transmission
TB and ART clinics 1 mile apart and are run by
separate city and provincial administrations
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PRIORITISATION OF HIV / TB RESEARCH
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Research priority-setting criteria
traditional approach
Adapted from Rudan et al. Lancet Infect Dis 2007
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Research priority-setting criteria
approach needed
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WHO, 2005 Maputo a regional emergency
requiring urgent and extraordinary
actions that must be informed and made
possible through urgent and extraordinary
research!!
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Acknowledgements
Desmond Tutu HIV Centre Robin Wood Linda-Gail
Bekker Keren Middelkoop Landon Myer Motasim Badri
DTHC staff WHO / STOP TB Haileyesus Getahun