A Collaborative Health Research and Service Program in northern Tanzania

1
A Collaborative Health Research and Service
Program in northern Tanzania

• John A. Crump, MB, ChB, DTMH
• Assistant Professor of Medicine
• Division of Infectious Diseases and International
  Health
  
• Senior Lecturer, Kilimanjaro Christian Medical
  College
  

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Overview

• Tanzania
• Medicine collaboration in Tanzania
• Philosophy and core values
• Training
• Research
• Past research accomplishments
• Current research portfolio
• Focus on febrile illness studies
• Future directions

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Tanzania

• Population 33 million
• Area 886,000 km2
• Human development index rank 162nd
• Per capita GDP USD 251
• HIV seroprevalence 7.0

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History of collaboration in Tanzania

• 1986-1994 Coast
• Muhimbili National Hospital, Dar es Salaam
• Mid-1990s northern Tanzania
• Kilimanjaro Christian Medical Centre, Moshi
• Medical resident rotations
• 2002 scale-up of activities
• Place faculty, develop research program
• KIWAKUKKI, Moshi
• Kibongoto National Tuberculosis Hospital, Sanya
  Juu
  
• Mawenzi Regional Hospital, Moshi
• HIV prevention, treatment and care

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Survival of KIWAKKUKI home-based care clients,
2003-2005, n226
Tillekeratne LG, et al. World AIDS Conference
2006, Abstract MoPe0303
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Philosophy and core values

• Research with service
• Training
• Patient care and public health
• True collaboration
• Long-term commitment
• Decades not years, months or days
• Progress may be slow
• Fair weather and foul
• International health as a discipline
• 100 year history
• International health best practiced from the
  field
  
• Minimize public health tourism

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Department of Medicine Trainees
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Tanzanian trainees 2002-present
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Research with Service
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Cost-effectiveness of free versus co-pay HIV
voluntary counseling and testing

• Would provision of free HIV voluntary counseling
  and testing (VCT) in Tanzania be cost-effective?
  

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Methods

• 813 VCT clients
• KIWAKKUKI
• May Nov 2003
• Before, during, after free VCT campaign
• Cost-effectiveness model
• Number of tests per day
• Costs of testing
• Benefits of knowing HIV serostatus infections
  averted, access to treatment
  

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Persons receiving VCT per day KIWAKKUKI VCT,
2003 n813
Mean daily volume prior to free testing
Mean 15.0 pMean daily volume during free testing
Mean daily volume after free testing
Mean 7.1 pNumber of clients
Mean 4.1
June
August
July
September
October
November
2003
Thielman NM, et al. Am J Public Health 2006 96
114-9
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Cost-Effectiveness of VCT
Thielman NM, et al. Am J Public Health 2006 96
114-9
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Simple, low cost approaches to identifying
patients with CD4 count

How can we identify HIV-infected adults with CD4
count capacity is limited?

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Methods

• 202 subjects recently diagnosed with HIV
  referred
  
• VCT centers
• Aug 2004 Jun 2005
• WHO staging history and examination,
  anthropometry and simple lab tests
  
• ESR
• CBC
• CD4 count by manual Beckman Coulter method
• Bivariable analysis to predict CD4
• Partition tree analysis of significant variables

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Distribution of CD4 count by WHO stage, Moshi,
Tanzania, 2004-5
CD4 count mm3
WHO stage
Interquartile range, range
Morpeth SC, et al. CROI 2005, Boston, Ma.,
Abstract 638
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Number of recently diagnosed HIV-infected persons
who would be triaged to treatment using 4
different strategies, by CD4-count stratum
Receiver-operator characteristics
area-under-the-curve
Morpeth SC, et al. CROI 2005, abstract 638a
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Trimethoprim-sulfamethoxazole study

• What effect is use of TMP-SXT prophylaxis in
  persons with symptomatic HIV disease in Africa
  having on emergence of antimicrobial resistance?

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Methods

• 184 subjects recently diagnosed with HIV
  referred
  
• VCT centers
• Aug 2004 Dec 2005
• Prospective observational cohort study
• Arm A HIV-uninfected
• Arm B HIV-infected, asymptomatic (no TMP-SXT)
• Arm C HIV-infected, symptomatic (TMP-SXT)
• Follow-up
• Baseline
• Weeks 1, 2, 4, 24
• Stool
• Screened for Escherichia coli not susceptible to
  TMP-SXT

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Results

• Baseline non-susceptibility was high
• Arm A 26 (57) of 46
• Arm B 28 (70) of 40
• Arm C 41 (67) of 61
• Introduction on TMP-SXT rapidly led to
  non-susceptibility
  
• 95 of Arm C patients had non-susceptible E.
  coli within 1 week of TMP-SXT
  
• Arm C vs. Arm A p0.007
• Arm C vs. Arm B p0.020

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Antiretroviral drug resistance and adherence
study (ADAR)

• How common is virologic failure in patients
  receiving ART in Tanzania and who fails and why?

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Methods

• Retrospective cohort study
• 150 HIV-infected adult patients, June-August
  2005
  
• FDC D4T/3TC/NVP 6 months
• Consecutive patients presenting for follow up
• Standardized questionnaire
• Sociodemographics
• Economic conditions
• HIV and ART knowledge, beliefs, disclosure
• Adherence
• Access to care
• Plasma
• HIV RNA quantitation

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Risk Factors for Virologic FailureMultivariable
Analysis
Model controlled for age and gender and included
variables with pRamadhani HO, et al. World AIDS Conference 2006,
abstract ThLb0213
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Self-Funded ART and Virologic Failure

• Persons paying for ART were more likely to be
  maladherent
  
• r0.54, p

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Tuberculosis and HIV Immune Reconstitution
Syndrome Trial (THIRST)

• Is it better to start ART immediately or to defer
  ART in patients co-infected with tuberculosis?

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Methods

• Randomized, controlled trial
• 70 patients with HIV infection and smear-positive
  pulmonary tuberculosis
  
• Initiate TB treatment then FDC ZDV/LMV/ABC
  after
  
• 2 weeks
• 8 weeks
• Follow-up
• 104 weeks

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CD4-positive lymphocyte responses
CD4 count (cells/mm3)
p Entry
Week 12
Week 36
Week 48
Week 24
n 70 69
68 67
66
Shao HJ, et al. CROI 2006, Abstract 796
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Outcomes

• 3 study subjects deaths were not thought to be
  related to study medications
  
• ZDV/LMV/ABC was discontinued in 6 subjects
• - 2 with dose-limiting anemia, requiring
  substitution of stavudine for ZDV
  
• - 4 with suspected ABC hypersensitivity
  reactions
  
• At week 48, 64 (96) of 67 had HIV RNA copies/mL
  
• To date, no cases of TB-associated immune
  reconstitution syndrome have been observed
  

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HIV seroprevalence
Kibongoto Tuberculosis
THIRST
Hospitalized patients
Mawenzi Regional
ADAR
KCMC
HIV inpatient characteristics
Sociodemographics (VCT)
Tuberculosis symptoms
HIV VCT clients
HIV staging
TMP-SXT
Community-based subjects
Cost-effectiveness
HIV-seroincidence
HIV HBC clients
Sociodemographics (HBC)
Morbidity and survival
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KCMC BIOTECHNOLOGY LABORATORY
Microbiology
Molecular Virology
Hematology and Chemistry
Cryopreservation
Immunology
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Grant support for researchDuke-KCMC
Collaboration, 2002-present
Clinical Research Site
Abbott (LPV/RTV)
CHAVI
CFAR (Clin Core)
ISAAC
Grant support (thousands of USD)
AITRP
GSK (THIRST)
CIPRA R03
CFAR (ADAR)
Roche Laboratories (VCT)
CFAR (Cervical Ca)
Year
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Adult HIV treatment studies
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Pediatric HIV treatment studies
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HIV vaccine-related research
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Community studies
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HIV co-infection studies
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HIV co-infection studies
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Febrile illness in northern Tanzania

• Febrile illness accounts for 10-30 of admissions
  to hospital in northern Tanzania
  
• HIV co-infection is common among inpatients
• Community 7 (2004)
• Medical inpatients 21 (2000)
• Tuberculosis inpatients 41 (2000)
• Laboratory capacity is limited
• Fever is often managed empirically with
  antimalarials, even when slide negative
  
• Causes of fever differ from those in the west
• Little work has been done on prevention,
  diagnosis, and treatment of leading causes of
  fever

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Severe febrile illness hospital management,
northern Tanzania
Reyburn HG, et al. Brit Med J 2004 329 1212
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Muhimbili National Hospital, Dar es
SalaamTanzania, 1995
Archibald LK, et al. Clin Infect Dis 1998 26
290
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Muhimbili National Hospital, Dar es
SalaamTanzania, 1995
Archibald LK, et al. Clin Infect Dis 1998 26
290
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KCMC, Moshi, Tanzania, 2007
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Nested studies and goals

• Causes of febrile illness in children admitted to
  hospital in a low transmission area of
  P.falciparum
  
• To impact on Integrated Management of Childhood
  Illness (IMCI) algorithms
  
• Disseminated tuberculosis diagnostics study
• To improve the clinical and laboratory diagnosis
  of disseminated tuberculosis
  
• Non-Typhi Salmonella in HIV case-control study
• To inform prevention guidelines for
  HIV-associated non-Typhi Salmonella bacteremia in
  Africa

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Future directions

• Continue to work on health problems of importance
  in Tanzania
  
• Descriptive ? interventional studies
• Opportunistic ? focused research plan
• Expand the training program
• Long-term training
• Advanced degrees
• Assist to foster a critical mass of researchers
  at KCMC
  
• Independent investigators
• Life-long collaborators

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Conclusions

• Platform for HIV and infectious diseases
  research
  
• Strong collaborative relationships with hospital,
  community, and other researchers
  
• Emphasis on training
• Track record of research with service
• Growing personnel and infrastructure
• High quality laboratory facilities
• Potential to underpin ambitious and growing
  research agenda
  
• HIV treatment and prevention research
• HIV co-infection research
• Community studies

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Duke-KCMC Collaboration Team, Moshi, April 2007
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Acknowledgements

• Duke University Medical Center
• John D. Hamilton, MD
• John A. Bartlett, MD
• Nathan M. Thielman, MD, MPH
• Charles Muiruri
• L. Barth Reller, MD, DTMH
• G. Ralph Corey, MD
• Barton F. Haynes, MD
• Michael Merson, MD
• Anne B. Morrissey, MS
• Jean Gratz, MS
• Julia Giner, RN
• Jan Ostermann, PhD
• Gary M. Cox, MD
• Carol Dukes Hamilton, MD
• Coleen K. Cunningham, MD
• KIWAKKUKI
• Rehema A. Kiwera, AdvDipClinMed

• Kilimanjaro Christian Medical Centre
• John F. Shao, MD, PhD
• Mark E. Swai, MD
• Humphrey J. Shao, MD
• Habib O. Ramadhani, MD
• Florida P. Muro, MD
• Bahati P. Msaki, MD
• Emmanual Balandya, MD
• Venance P. Maro, MD
• Grace D. Kinabo, MD
• Levina Msuya, MD
• Werner Schimana, MD
• Moses W. Sichangi, MSc
• Francis P. Karia, MBA
• Ahaz T. Kulanga, MBA

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