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