a collaborative health research and service program in northern tanzania john a. crump, mb, chb,...
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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
• 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
• 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– Place faculty, develop research program– KIWAKUKKI, Moshi– Kibong’oto National Tuberculosis Hospital, Sanya Juu– Mawenzi Regional Hospital, Moshi
• HIV prevention, treatment and care
0
20
40
60
80
100
0 6 12 18 24
Time (months)
Su
rviv
al
(%)
Survival of KIWAKKUKI home-based care clients, 2003-2005, n=226
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 MNH
(1986-1994)
KCMC
(1996-2001)
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
TOTAL 58 30 23 111
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 co-pay
Simple, low cost approaches to identifying HIV-infected patients
with CD4 count <200 cells/mm3
Guides management of HIV-infected patients in rural and remote areas
Trimethoprim-sulfamethoxazole study
Estimates the effect of widespread TMP-SXT 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
• Would provision of free HIV voluntary counseling and testing (VCT) in Tanzania be cost-effective?
Cost-effectiveness of free versus co-pay HIV voluntary counseling and testing
• 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
Methods
0
2
4
6
8
10
12
14
16
18
20
22
2 9 16 23 30 5 14 21 28 4 9 18 25 1 8 15 22 29 6 13 20 27 3 10
June AugustJuly September October November
2003
Nu
mb
er
of
cli
en
ts
Mean 15.0 p<0.0001
Mean 7.1 p<0.0001
Mean 4.1
Mean daily volume prior to free testing
Mean daily volume during free testing
Mean daily volume after free testing
Persons receiving VCT per day KIWAKKUKI VCT, 2003
n=813
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
Cost per DALY (USD) 24.52 21.34 20.69
Thielman NM, et al. Am J Public Health 2006; 96: 114-9
• How can we identify HIV-infected adults with CD4 count <200/mm3 in settings where laboratory capacity is limited?
Simple, low cost approaches to identifying patients with
CD4 count <200 cells/mm3
• 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
Methods
Distribution of CD4 count by WHO stage, Moshi, Tanzania, 2004-5
0
200
400
600
800
1,000
1,200
1,400
Stage 1 Stage 2 Stage 3 Stage 4
CD
4 co
un
t m
m3*
WHO stage*Interquartile range, range
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?
• 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
Methods
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 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– Sociodemographics– Economic conditions– HIV and ART knowledge, beliefs, disclosure– Adherence– Access to care
• Plasma– HIV RNA quantitation
Risk Factors for Virologic FailureMultivariable 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
Shao HJ, et al. CROI 2006, Abstract 796
n= 70 69 68 67 66
p <0.0001 for temporal trends
CD
4+
co
un
t (
ce
lls
/mm
3 )
Entry Week 12 Week 36Week 24 Week 48
0
100
200
300
400
500
Entry Week 12 Week 24 Week 36 Week 48
Visit_Type
Missing Rows 11
Excluded Rows 2054
Entry
Week 12
Week 24
Week 36
Week 48
Level
9
29
76
101
132
Minimum
32
59
100.8
142
177.2
10%
57.25
97.5
127.5
181
201
25%
103
140
186
213
249
Median
155.5
192.5
245
287
311
75%
213.8
271
300.8
337
392.8
90%
384
440
447
483
510
Maximum
Quantiles
Oneway Analysis of CD4_Lymphocyte By Visit_Type
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
Hospitalized patients
Community-based subjects
HIV VCT clients
HIV HBC clients
Sociodemographics (VCT)
Cost-effectiveness
HIV-seroincidence
Tuberculosis symptoms
Sociodemographics (HBC)
Morbidity and survival
KCMC
Kibong’oto Tuberculosis
Mawenzi Regional
HIV seroprevalence
HIV inpatient characteristics
TMP-SXT
HIV staging
THIRST
ADAR
Microbiology
Immunology
Molecular Virology
Hematology and ChemistryCryopreservation
KCMC BIOTECHNOLOGY
LABORATORY
Grant support for researchDuke-KCMC Collaboration, 2002-present
0
500
1,000
1,500
2,000
2,500
2002 2003 2004 2005 2006 2007
Gra
nt
sup
po
rt (
tho
usa
nd
s o
f U
SD
)
Year
Roche Laboratories (VCT)
Clinical Research Site
CIPRA R03
GSK (THIRST)
ISAAC
AITRP
CFAR (Clin Core)
CHAVI
CFAR (ADAR)
CFAR (Cervical Ca)
Abbott (LPV/RTV)
Adult HIV treatment studies
Grant name Research area Protocol Funding source
NA Treatment of HIV/TB co-infection
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 NNRTI-regimen
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 PI-based antiretroviral therapy in HIV-infected 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
Reyburn HG, et al. Brit Med J 2004; 329: 1212
95% treated with quinine
66% received antibacterial
Severe febrile illness hospital management, northern Tanzania
Muhimbili National Hospital, Dar es SalaamTanzania, 1995
Organism HIV serostatus
HIV-infected
(n=282)
HIV-uninfected
(n=235)n (%) 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 SalaamTanzania, 1995
Organism HIV serostatus
HIV-infected
(n=282)
HIV-uninfected
(n=235)n (%) 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
PathogenAdult 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 HIV-
associated 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
• Duke University Medical Center– 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– Rehema A. Kiwera, AdvDipClinMed– Dafrosa K. Itemba, BA
• 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