A Collaborative Health Research and
Service Program in northern Tanzania
John A. Crump, MB, ChB, DTM&H
Assistant Professor of Medicine
Division of Infectious Diseases and International
Health
Senior Lecturer, Kilimanjaro Christian Medical
College
Overview
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•
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•
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Tanzania
Medicine collaboration in Tanzania
Philosophy and core values
Training
Research
– Past research accomplishments
– Current research portfolio
• Focus on febrile illness studies
• Future directions
Tanzania
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•
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Population 33 million
Area 886,000 km2
Human development index rank 162nd
Per capita GDP USD 251
HIV seroprevalence 7.0%
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
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–
–
–
Place faculty, develop research program
KIWAKUKKI, Moshi
Kibong’oto National Tuberculosis Hospital, Sanya Juu
Mawenzi Regional Hospital, Moshi
• HIV prevention, treatment and care
Survival of KIWAKKUKI home-based care
clients, 2003-2005, n=226
100
Survival (%)
80
60
40
20
0
0
6
12
18
24
Time (months)
Tillekeratne LG, et al. World AIDS Conference 2006, Abstract MoPe0303
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’
Department of Medicine Trainees
Rank
Type
KCMC
(2002-present)
TOTAL
Faculty
Infectious diseases
3
0
2
5
Fellows
Infectious diseases
7
0
1
8
Residents
Medicine
38
20
14
72
Medical
students
Research year
0
0
6
6
Medical
students
Short rotations
~10
10
0
20
58
30
23
111
TOTAL
MNH
KCMC
(1986-1994) (1996-2001)
Tanzanian trainees 2002-present
Number
trainees
Description
Short-term
73
Comprehensive Introduction to Clinical Research
Administration
Pharmacy
Laboratory (Flow cytometry, PBMC)
Clinical (HIV, gynecology)
Good Clinical Practice/Good Clinical Laboratory Practice
Research/Clinical trials
Research Ethics
Data management and analysis
Long-term
2
Masters of Health Sciences
‘Research with Service’
Study
Effect on patient care/public health
Cost-effectiveness of free HIV
voluntary counseling and testing
Allows the Ministry of Health to decide
whether VCT should be free or with copay
Simple, low cost approaches to
identifying HIV-infected patients
Guides management of HIV-infected
patients in rural and remote areas
with CD4 count <200 cells/mm3
Trimethoprim-sulfamethoxazole
study
Estimates the effect of widespread TMPSXT prophylaxis on emergence of
antimicrobial resistance
Antiretroviral drug adherence and
resistance study (ADAR)
Informs clinicians how many patients
are failing ART and why
Tuberculosis and HIV immune
reconstitution syndrome trial
(THIRST)
Informs national and international
guidelines on how to manage ART in TB
co-infected patients
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?
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
Persons receiving VCT per day
KIWAKKUKI VCT, 2003
n=813
Mean daily volume prior to free testing
22
Mean 15.0 p<0.0001
20
Mean daily volume during free testing
18
Mean daily volume after free testing
Number of clients
16
Mean 7.1 p<0.0001
14
12
10
Mean 4.1
8
6
4
2
0
2
9
16 23
June
30
5
14 21
July
28
4
9
18 25
August
1
8
15
22 29
September
6
13
20 27
October
3
10
November
2003
Thielman NM, et al. Am J Public Health 2006; 96: 114-9
Cost-Effectiveness of VCT
No free VCT
Free VCT
campaign
Sustained
free VCT
Infections averted
67.9
131.0
275.0
Cost per infection
averted (USD)
169.69
105.12
91.89
DALYs gained
1,381.4
2,666.0
5,597.2
24.52
21.34
20.69
Cost per DALY (USD)
Thielman NM, et al. Am J Public Health 2006; 96: 114-9
Simple, low cost approaches to
identifying patients with
CD4 count <200 cells/mm3
• How can we identify HIV-infected adults with
CD4 count <200/mm3 in settings where
laboratory capacity is limited?
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 <200/mm3
• Partition tree analysis of significant variables
Distribution of CD4 count by WHO stage,
Moshi, Tanzania, 2004-5
CD4 count mm3*
1,400
1,200
1,000
800
600
400
200
0
Stage 1
*Interquartile range, range
Stage 2
Stage 3
Stage 4
WHO stage
Morpeth SC, et al. CROI 2005, Boston, Ma., Abstract 638
Number of recently diagnosed HIV-infected
persons who would be triaged to treatment using
4 different strategies, by CD4-count stratum
ROC AUC* (95% CI)
Sensitivity (95% CI)
Specificity (95% CI)
Original WHO stage 3 or 4 or stage
2 with TLC<1,200
0.5976
(0.54-0.66)
0.81
(0.76-0.87)
0.38
(0.31-0.45)
2005 WHO stage 3 or 4
0.5543
(0.49-0.62)
0.75
(0.69-0.81)
0.36
(0.29-0.43)
TLC <1,200 or ESR ≥120 or
mucocutaneous manifestations
0.7411
(0.68-0.80)
0.85
(0.80-0.90)
0.63
(0.56-0.70)
2005 WHO stage 3 or 4 or TLC
<1,200 or ESR ≥120 or
mucocutaneous manifestations
0.5920
(0.54-0.64)
0.93
(0.89-0.96)
0.26
(0.20-0.32)
*Receiver-operator characteristics area-under-the-curve
Morpeth SC, et al. CROI 2005, abstract 638a
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?
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
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 nonsusceptibility
– >95% of Arm C patients had non-susceptible E.
coli within 1 week of TMP-SXT
– Arm C vs. Arm A p=0.007
– Arm C vs. Arm B p=0.020
Antiretroviral drug resistance and
adherence study (ADAR)
• How common is virologic failure in patients
receiving ART in Tanzania and who fails and
why?
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
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–
–
–
–
Sociodemographics
Economic conditions
HIV and ART knowledge, beliefs, disclosure
Adherence
Access to care
• Plasma
– HIV RNA quantitation
Risk Factors for Virologic Failure
Multivariable Analysis*
OR
95% CI
p-value
Proportion on months on ART self-funded > median
4.2
1.7 10.5
0.002
Anyone beside clinic staff know HIV serostatus
0.11
0.02 0.74
0.023
*Model controlled for age and gender and included variables with p<0.1 from biavriable analysis
Ramadhani HO, et al. World AIDS Conference 2006, abstract ThLb0213
Self-Funded ART and Virologic Failure
• Persons paying for ART were more likely to
be maladherent
r=0.54, p<0.001
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?
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
CD4-positive lymphocyte responses
Oneway Analysis of CD4_Lymphocyte By Visit_Type
500
CD4+ count (cells/mm3)
400
300
200
100
p <0.0001 for temporal trends
0
Entry
Week 12
Entry
Missing Row s
Week 12
11
n=2054 70
69
Excluded Row s
Minimum
10%
25%
Median
75%
Week 36
Week
24
Visit_Type
Week 36
68
Quantiles
Level
Week 24
90%
Maximum
67
Week 48
Week 48
66
Shao HJ, et al. CROI 2006, Abstract 796
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 <400
copies/mL
• To date, no cases of TB-associated immune
reconstitution syndrome have been observed
HIV seroprevalence
Kibong’oto Tuberculosis
Hospitalized patients
Mawenzi Regional
KCMC
THIRST
ADAR
HIV inpatient characteristics
Sociodemographics (VCT)
Tuberculosis symptoms
HIV VCT clients
HIV staging
TMP-SXT
Community-based subjects
Cost-effectiveness
HIV HBC clients
HIV-seroincidence
Sociodemographics (HBC)
Morbidity and survival
KCMC
BIOTECHNOLOGY
LABORATORY
Microbiology
Immunology
Molecular Virology
Cryopreservation
Hematology and Chemistry
Grant support for research
Duke-KCMC Collaboration, 2002-present
Grant support (thousands of USD)
Clinical Research Site
2,500
Abbott (LPV/RTV)
CHAVI
2,000
CFAR (Clin Core)
ISAAC
1,500
AITRP
1,000
GSK (THIRST)
CIPRA R03
500
CFAR (ADAR)
Roche Laboratories (VCT)
CFAR (Cervical Ca)
0
2002
2003
2004
2005
Year
2006
2007
Adult HIV treatment studies
Grant name
Research area
Protocol
Funding source
NA
Treatment of
HIV/TB coinfection
THIRST: Tuberculosis and HIV
immune reconstitution syndrome
trial
GSK
NA
Simplification of
antiretroviral
therapy
Lopinavir/Ritonavir monotherapy
study
Abbott
AACTG
Prevention of
mother-to-child
transmission of
HIV
5207: Prevention of maternal
nevirapine resistance
US NIH
AACTG
Optimization of
adult HIV
treatment
5230: Lopinavir/Ritonavir for
patients who failing NNRTIregimen
US NIH
AACTG
Optimization of
adult HIV
treatment
5237: Atazanavir/Ritonavir alone
vs. Atazanavir/Ritonavir With Two
NRTIs
US NIH
Pediatric HIV treatment studies
Grant name
Research area
Protocol
Funding source
IMPAACT
Optimization of
pediatric HIV
treatment
1060: NNRTI-based versus PIbased antiretroviral therapy in HIVinfected infants
US NIH
IMPAACT
Prevention of
mother-to-child
transmission of
HIV
1067: Three-drug regimen for
prevention of mother-to-child
transmission
US NIH
HIV vaccine-related research
Grant name
Research area
Protocol
Funding source
CHAVI
HIV vaccine basic
science
001: Acute HIV infection
US NIH
CHAVI
HIV vaccine basic
science
003: Correlates of protection in
HIV exposed, uninfected
US NIH
Community studies
Grant name
Research area
Protocol
Funding source
ISAAC
HIV co-infections
001: HIV disease progression in a
community cohort
US NIH
CFAR
Voluntary
counseling and
testing
Effect of mobile VCT services on
HIV testing uptake
US NIH
HIV co-infection studies
Grant name
Research area
Protocol
Funding source
ISAAC
HIV co-infections
002: Adult febrile illness
US NIH
ISAAC
HIV co-infections
003: Pediatric febrile illness
US NIH
ISAAC
HIV co-infections
004: Tuberculosis diagnostics
US NIH
ISAAC
HIV co-infections
005: Cryptococcoal meningitis
treatment
US NIH
HIV co-infection studies
Grant name
Research area
Protocol
Funding source
ISAAC
HIV co-infections
002: Adult febrile illness
US NIH
ISAAC
HIV co-infections
003: Pediatric febrile illness
US NIH
ISAAC
HIV co-infections
004: Tuberculosis diagnostics
US NIH
ISAAC
HIV co-infections
005: Cryptococcoal meningitis
treatment
US NIH
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
Severe febrile illness hospital management,
northern Tanzania
95% treated with quinine
66% received antibacterial
Reyburn HG, et al. Brit Med J 2004; 329: 1212
Muhimbili National Hospital, Dar es Salaam
Tanzania, 1995
Organism
HIV serostatus
HIV-infected
(n=282)
n
(%)
HIV-uninfected
(n=235)
n
(%)
Non-Typhi Salmonella
23
(19)
6
(22)
Strept pneumoniae
6
(5)
5
(19)
Escherichia coli
7
(6)
5
(19)
Crypto neoformans
10
(8)
0
(0)
Mycobacteria
57
(48)
4
(15)
Other
15
(13)
7
(26)
Total
118
(100)
27
(100)
Archibald LK, et al. Clin Infect Dis 1998; 26: 290
Muhimbili National Hospital, Dar es Salaam
Tanzania, 1995
Organism
HIV serostatus
HIV-infected
(n=282)
n
(%)
HIV-uninfected
(n=235)
n
(%)
Non-Typhi Salmonella
23
(19)
6
(22)
Strept pneumoniae
6
(5)
5
(19)
Escherichia coli
7
(6)
5
(19)
Crypto neoformans
10
(8)
0
(0)
Mycobacteria
57
(48)
4
(15)
Other
15
(13)
7
(26)
Total
118
(100)
27
(100)
Archibald LK, et al. Clin Infect Dis 1998; 26: 290
KCMC, Moshi, Tanzania, 2007
Pathogen
Adult blood cultures
(n=127)
Pediatric blood cultures
(n=181)
n
(%)
n
(%)
M. tuberculosis
8
(6)
NA
NA
M. avium complex
1
(1)
NA
NA
Non-Typhi Salmonella
3
(2)
1
(1)
Salmonella Typhi
2
(2)
7
(4)
S. pneumoniae
0
(0)
2
(1)
H. influenzae
0
(0)
3
(2)
E. coli
0
(0)
3
(2)
S. aureus
2
(2)
0
(0)
C. neoformans
1
(1)
0
(0)
Other
0
(0)
1
(1)
Total
17
(13)
17
(9)
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 HIVassociated non-Typhi Salmonella bacteremia in
Africa
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
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
Duke-KCMC Collaboration Team,
Moshi, April 2007
Acknowledgements
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Duke University Medical Center
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•
John D. Hamilton, MD
John A. Bartlett, MD
Nathan M. Thielman, MD, MPH
Charles Muiruri
L. Barth Reller, MD, DTM&H
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
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Rehema A. Kiwera, AdvDipClinMed
Dafrosa K. Itemba, BA
•
Kilimanjaro Christian Medical
Centre
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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