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  • During this talk I will provide some background on the country of Tanzania, some history of the Department of Medicine collaboration in Tanzania, a little about the philosophy and core values of the collaboration with Kilimanjaro Christian Medical Centre, and our efforts in training.
    After that I will focus on the research program, reviewing some of our past research accomplishments and the current research portfolio.
    Then I will finish by focusing on some of our ongoing research on febrile illness and where I see the collaboration going in the future.
  • So first to Tanzania.
    As you will know, Tanzania is located in East Africa.
    Tanzania is shown in tan on the map of Africa to your left.
    In the middle map, we see that the Kilimanjaro Region is located in northern Tanzania and skirts the border with Kenya.
    Our collaborative program is based in the town of Moshi circled in red on the map of the Kilimanjaro Region to your right.
    Moshi is the regional capital of Kilimanjaro.
  • Tanzania has a population of 33 million people and a land area of about 886,000 square kilometers; about 10% of the size of the United States.
    Tanzania has a human development index rank of 162nd and a per capita gross domestic product of USD 251, placing it among the least developed of countries.
    The national HIV seroprevalence is approximately 7 percent.
  • This slide shows Kilimanjaro Christian Medical Centre or KCMC, Duke’s main collaborative partner and current base in Tanzania.
    KCMC is one of Tanzania’s four consultant referral hospitals serving a catchment population of approximately 15 million people.
  • This slide gives a history of our collaboration in Tanzania.
    In the mid-1980s in the Coast Region, the Division of Infectious Diseases and International Health began a collaboration with Muhimbili National Hospital in Dar es Salaam.
    One of Duke’s major partners at Muhimbili was Professor John Shao, then Head of the Microbiology Laboratory.
    When Professor Shao moved to northern Tanzania in the mid-1990s to be Executive Director of Kilimanjaro Christian Medical Centre in Moshi the collaboration moved with him.
    During the rest of the 1990s, the collaboration primarily provided opportunities for Duke medical residents to do rotations in Tanzania to experience the practice of medicine there.
    However, through the advocacy of John Hamilton and Professor Shao and following a site visit to Moshi by John Bartlett and Nathan Thielman from the Division of Infectious Diseases in 2002 it was decided to scale up the activities of the collaboration.
    I was recruited as a fulltime faculty member to be based at KCMC and to develop the program along research lines at that time.
    Since that time, collaborations have expanded to other partners around Moshi, including KIWAKKUKI which stands for Kikundi cha Wanawake Kilimanjaro Kupambana na UKIMWI or Women Against AIDS in Kilimanjaro; Kibong’oto National Tuberculosis Hospital; and more recently to Mawenzi Regional Hospital.
    Both Tanzania and Duke partners have advocated for the program’s primary focus to be on HIV prevention, treatment, and care research.
  • The justification for the focus on HIV prevention, treatment, and care is best captured by this graph which is a Kaplan-Meier curve showing the survival of HIV-infected KIWAKKUKI home-based care clients in the Kilimanjaro Region of Tanzania between 2003 and 2005.
    This work, done by Duke Medical student Gayani Tillekertane and her Tanzanian colleague Rehema Kiwera, shows that of 226 clients followed during this period that approximately half were dead after 2 years of follow-up.
    Modifying this curve and reducing new HIV infections is a primary goal of our collaboration.
  • The collaboration is founded on a philosophy and a number of core values.
    Our model is one of ‘research with service,’ which means that the research program should provide training to personnel, should clearly improve patient care or public health, and that we should strive for true collaboration with interdependence of partners and mutual benefit.
    This include Duke making a long-term commitment to our partners, lasting decades, not years, months, or days, and accepting that progress may be slow and being willing to stick to task through both fair weather and foul.
    We also recognize international health as a discipline of medicine having its roots in the specialty of tropical medicine which has a long history of more than 100 years and a primary commitment to the study, control, prevention, and treatment of diseases common in tropical and sub-tropical climates and in developing countries.
    We promote the idea that international health is best practiced from the field in close partnership with our colleagues abroad and we try to minimize short-term ‘public health tourism’ that provides experiences and instead we favor long-term efforts that promote positive change.
    With this in mind, I would like to focus now on our training efforts.
  • This slide summarizes Department of Medicine trainees who have benefited from and contributed to the Tanzania program by rank and type of experience.
    Between 1986 and 1994, 58 persons of all ranks from medical students to faculty worked alongside Tanzanian colleagues in Dar es Salaam.
    After the move to KCMC in 1996 and up to 2001, 30 medicine residents or medical students did short rotations in Tanzania and this program continues through to today thanks to the energy of Ralph Corey and his colleagues at the Hubert-Yeargan Center at Duke.
    Since my arrival in 2002, consistent with our long-term model, we have cut back on short-term experiences in favor of a major commitment to providing opportunities for one to two 3rd medical students per year to spend their research year with us and in the past year have added infectious diseases fellows stays of one or two years.
    Department of Medicine trainees work alongside our Tanzanian colleagues in a ‘twinning’ relationship that fosters mutual respect, exchange of ideas, and that builds the research program as a true collaboration avoiding a unidirectional flow of either research opportunities or of resources.
  • Probably more important than training Duke personnel is on-site capacity-building in Tanzania, and this part of the training mission has flourished over the last 5 year.
    This slide shows the number Tanzanian trainees from 2002 to present who have received short- and long-term training opportunities through the program.
    At last count 73 trainees have received short-term training that has ranged from the Comprehensive Introduction to Clinical Research, to clinical training in specific areas, to research administration.
    And last year two MD-level Study Coordinators from KCMC, Humphrey Shao and Habib Ramadhani, joined the Masters in Health Sciences in Clinical Research programs at Duke.
    All of these efforts contribute to building the capacity at the site to implement a program founded on a ‘research with service’ model.
    Let me now focus on what we mean by research with service, illustrating this with some of the past research accomplishments of the program in Tanzania.
  • This slide lists a selection of research studies that we have completed in the past 5 years on your left and the effect that the research has had on either patient care or public health on your right.
    The first study listed examined the cost-effectiveness of free versus co-pay HIV voluntary counseling and testing. This study allows the Tanzania Ministry of Health to decide whether VCT should be provided free or with a co-payment.
    The second study looked at simple, low cost approaches to identifying HIV-infected patients with CD4 count <200 cells/mm3. The results of this study guide the management of HIV-infected patients in rural and remote areas where laboratory measurement of CD4 count is not available.
    The trimethoprim-sulfamethoxazole study estimates the effect of the World Health Organization recommendation to provide trimethoprim-sulfamethoxazole prophylaxis for all symptomatic, HIV-infected persons in Africa on the emergence of antimicrobial resistance.
    The antiretroviral drug adherence and resistance or ADAR study informs clinicians working in a setting where antiretroviral therapy programs are being rapidly rolled out but viral load testing is not available, how many patients are failing antiretroviral therapy and why.
    And finally, the Tuberculosis and HIV Immune Reconstitution Trial (THIRST) informs national and international guidelines on how to manage antiretroviral therapy in tuberculosis co-infected patients, a common HIV management problem in Africa.
    So having outlined the purpose of these studies, let me review some of the key findings of each.
  • Let’s look first at the cost-effectiveness of free versus co-pay HIV voluntary counseling and testing.
    This study sought to answer the question, ‘Would the provision of free HIV voluntary counseling and testing (VCT) in Tanzania be cost-effective?’
  • To address this question, we studied 813 VCT clients presenting to the KIWAKKUKI VCT Centre in Moshi between May and November 2003, before, during, and after a free VCT campaign.
    We then applied a cost-effectiveness model that included the number of tests done per day, the costs of testing, and the benefits to clients of knowing their HIV serostatus in terms of infections averted and access to treatment.
  • This graph shows the number of persons receiving VCT per day before, during, and after a free VCT testing campaign in Moshi during 2003.
    As you can see, there was a marked significant increase in the number of persons receiving VCT during the free testing period that occurred during July and that an increase was sustained after the free testing period ended.
  • And this table summarizes the cost-effectiveness of VCT in Tanzania under the three scenarios: no free VCT in the left column, a free VCT campaign in the middle, and a sustained free VCT service on the right column.
    VCT has been shown to reduce HIV transmission by reducing high risk behavior among both HIV-infected and HIV-uninfected persons.
    As you can see in the first row of the table, because more people access VCT when it is free, the provision of free VCT results in averting more HIV infections in the community.
    Furthermore in the second row, the cost of averting an HIV infection decreases under the free VCT campaign and sustained free VCT scenarios compared with charging a fee for VCT.
    Increased VCT not only results in more HIV infections averted.
    Because more persons with HIV infection are diagnosed and can then access treatment and care services, disability adjusted life years are gained.
    As you can see in the third and forth row of this table, providing no free VCT means that 1,381 DALYs are gained at a cost of 24.52 United States dollars per DALY, whereas a free VCT campaign leads to a gain of 2,666 DALYs at a cost of 21.34 United States dollar per DALY and sustained free VCT to a gain of 5,597 DALYs at a cost of 20.69 United States dollar per DALY.
  • The second study that I listed looked at simple, low cost approaches to identifying HIV-infected patients with CD4 count <200 cells/mm3, an important immunologic thresh hold for HIV treatment decisions in many African treatment guidelines.
    This study asked the question, ‘How can we identify HIV-infected adults with CD4 count <200/mm3 in settings where laboratory capacity is limited? This is a major challenge in Tanzania where many healthcare facilities manage HIV disease yet lack the capacity to measure CD4 count.
  • This cohort study consisted of 202 subjects recently diagnosed with HIV referred from 3 VCT centees in Moshi between August 2004 and June 2005.
    A World Health Organization HIV Staging history and examination was performed, along with anthropometry (Body Mass Index, skin fold thickness and upper-arm circumference) and simple laboratory tests (erythrocyte sedimentation rate and complete blood count).
    CD4 counts were done by the manual Beckman Coulter method in the KCMC clinical laboratory.
    Bivariable analysis was done to identify clinical findings and simple laboratory measures that were associated with CD4 count less than 200.
    And a partition tree analysis of significant variables was then done to develop a formula to predict low CD4 count.
  • This slide shows the distribution of CD4 count by WHO stage, a common method used to determine the stage of HIV disease in Africa.
    The boxes represent inter-quartile range and the whiskers represent range.
    As you can see, although there is a trend toward declining CD4 count with advancing WHO HIV disease stage, the ability of WHO stage to accurately allocate patients to narrow CD4 count categories is quite limited.
  • This table shows the receiver-operator characteristic area-under the curve with 95% confidence intervals, for the performance of 4 different strategies to predict a CD4 count of less than 200.
    The first strategy uses the original WHO staging guidelines of Stage 3, or 4 or Stage 2 with a total lymphocyte count of <1,200.
    The second used the 2005 revision of the WHO criteria, Stage 3 or 4.
    In the third row is the formula derived from the partition tree of Total Lymphocyte count less than 1,200 or erythrocyte sedimentation rate of greater than 120, or mucocutaneous manifestations.
    And in the final row the same formula or 2005 WHO criteria Stage 3 or 4.
    As you can see, the formula in the third row has the highest receiver-operator characteristic but the final strategy is the most sensitive.
    We believe that sensitivity is more important than specificity in predicting a low CD4 count for provision of antiretroviral therapy, since it is a life-saving intervention.
  • Next, let’s look at the trimethoprim-sulfamethoxazole study which addresses the question ‘What effect is the use of trimethoprim-sulfamethoxazole prophylaxis in persons with symptomatic HIV disease in Africa having on the emergence of antimicrobial resistance?’
  • In this study, we identified 184 clients recently diagnosed with HIV referred from VCT centees in Moshi between August 2004 and December 2005.
    We enrolled these subjects into a prospective observational cohort study.
    Subjects in Arm A were HIV-uninfected.
    Subjects in Arm B were HIV-infected but were asymptomatic so did not received trimethoprim-sulfamethoxazole.
    And subjects in Arm C were HIV-infected but symptomatic so were eligible for trimethoprim-sulfamethoxazole prophylaxis according to WHO recommendations.
    We saw all subjects at baseline and again at weeks 1, 2, 4, and 24.
    At each visit stool was collected and was examined for Escherichia coli non-susceptible to trimethoprim-sulfamethoxazole.
  • This slide summarizes the results of the study.
    Baseline prevalence of non-susceptibility in fecal E. coli was high at 57% in Arm A, 70% in Arm B, and 67% in Arm C.
    The introduction of TMP-SXT rapidly led to non-susceptibility.
    >95% of Arm C patients developed non-susceptible E. coli within 1 week of starting trimethoprim-sulfamethoxazole.
    The proportion developing non-susceptibility over time in Arm C was significantly greater compared with both Arm A and Arm B.
    These findings using fecal E. coli as an indicator organism suggest that widespread trimethoprim-sulfamethoxazole use is likely to be driving the emergence of antimicrobial resistance.
    Since trimethoprim-sulfamethoxazole is widely used in Africa not only for prophylaxis against HIV-associated opportunistic infections, but also for the empiric management of the syndromes of dysentry, fever, and pneumonia, we believe that surveillance for ongoing trimethoprim-sulfamethoxazole efficacy is warranted.
  • Next, let’s look at the antiretroviral drug adherence and resistance or ADAR study. This study looked at ‘how common is virologic failure in patients receiving ART in Tanzania and who fails and why?’
    Answering these questions is an urgent priority as the first phase of the roll out of antiretroviral therapy in Africa occurred with a much greater focus on number of persons placed on treatment than on the quality of treatment programs.
  • To investigate this question we designed a retrospective cohort study of 150 HIV-infected adult patients evaluated between June and August 2005 who had received fixed-dose combination stavudine/lamivudine/nevirapine for 6 months or more.
    We enrolled consecutive patients presenting for routine follow up at the Kilimanjaro Christian Medical Centre adult Infectious Diseases Clinic.
    A standardized questionnaire was developed and administered to all patients that included questions on sociodemographics, economic conditions, HIV and ART knowledge, beliefs, and disclosure, adherence, and access to care.
    Plasma was obtained from patients for a number of virologic evaluations, including for HIV RNA quantitation.
  • This slide summarizes risk factors for virologic failure identified on multivariable analysis.
    On multivariable logistic regression analysis, virologic failure was associated with the proportion of months on ART that were self-funded and disclosure of HIV serostatus to persons other than clinic staff was protective against virologic failure.
  • To understand how self-funded ART is associated with virologic failure, we undertook further analyses.
    We showed that persons who paid for ART were more likely to be maladherent. The correlation coefficient was zero point five four and the p-value was less than zero point zero zero one.
    Therefore, self-funding of ART was associated with maladherence which in turn lead to increased risk for virologic failure.
    This finding underscores central importance of free antiretroviral therapy to the success of HIV treatment programs in resource-poor countries.
  • Finally, I would like to review findings of the Tuberculosis and HIV Immune Reconstitution Syndrome Trial or THIRST.
    This clinical trial sought to answer the question ‘is it better to start antiretroviral therapy immediately or to defer antiretroviral therapy in patients co-infected with tuberculosis?’
  • This randomized, controlled trial, the first antiretroviral clinical trial done in Tanzania, enrolled 70 patients with HIV infection and smear-positive pulmonary tuberculosis.
    All patients were then initiated on tuberculosis treatment and then randomized to half beginning fixed-dose combination zidovudine/lamivudine/abacavir after 2 weeks or half commencing antiretroviral therapy after 8 weeks.
    Patients were then followed for 104 weeks and were monitored clinically for immune reconstitution syndromes, drug toxicity, immunologic response, and virologic suppression.
  • This slide shows the CD4-positive lymphocyte responses among study subjects through study week 48.
    As you can see, substantial rises in CD4 count were observed
  • This slide summarizes other outcomes of THIRST study subjects.
    Three study subjects’ deaths were not thought to be related to study medications.
    Study drug was discontinued in 6 subjects; 2 with dose-limiting anemia, requiring substitution of stavudine for zidovudine and 4 with suspected abacavir hypersensitivity reactions.
    At week 48, 64 or 96% of 67 surviving patients had HIV RNA below 400 copies per mL.
    And of great scientific interest, no case of TB-associated immune reconstitution syndrome have been observed suggesting that the practice of delaying life-saving antiretroviral therapy to prevent immune reconstitution syndrome in tuberculosis-co-infected patients may be unnecessary.
  • So I hope that the five studies that I have just described illustrate the type of work that we are doing and why.
    This slide summarizes the past 5 years of the Duke-KCMC Collaboration in terms of cohorts, sites, and studies.
    At the top, we have developed cohorts of hospitalized patients and capacity to do clinical research at three inpatient facilities; Kibong’oto National Tuberculosis Hospital, Mawenzi Regional Hospital, and Kilimanjaro Christian Medical Centre, shown in the middle in yellow.
    And below, we have also developed two community-based cohorts, one of HIV voluntary counseling and testing attendees and another of HIV home-based care clients, both through our partnership with the community AIDS service organization KIWAKKUKI.
    These cohorts have allowed us to undertake a number of research studies including those that I have just described and many others, shown on your right.
    These patient populations also form the basis of our current and planned research agenda.
  • I would now like to move to a discussion of our current research portfolio.
    This slide shows the KCMC Biotechnology Laboratory, in which over the past 2 years we have developed Microbiology, Immunology, Molecular Virology, and Hematology/Chemistry Sections that operate to the same standards as clinical laboratories in the United States.
    This laboratory underpins and supports our clinical research endeavor.
  • And this slide summarizes grant support for research through the KCMC-Duke Collaboration in northern Tanzania, from 2002 to present.
    The graph shows grant support, by year, in thousands of United States dollars as red bars.
    Individual grants overlay the bars and are listed by grant name with black lines showing duration.
    As you can see, we began the research program in 2002 with no grant support, but have managed to build a portfolio of NIH and other support over the last 5 years such that the collaboration is now operating with more than 2 million dollars in research support per year.
    Let me review briefly how we are using this support to conduct research relevant to clinical and public health problems in Tanzania.
  • Currently we have two industry-sponsored antiretroviral clinical trials underway; the THIRST study that I have already discussed and the lopinavir/ritonavir monotherapy study, shown in the top two rows, we have also recently been funded by the Adult AIDS Clinical Trials Group to be a site for network clinical trials of prevention of mother-to-child transmission of HIV and optimization of adult antiretroviral therapy.
    The studies that we will be participating in during 2007 are listed in the table.
    ***Pause***
  • We are also funded to join the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) to join studies of the optimization of pediatric HIV treatment and additional studies of prevention of mother-to-child transmission of HIV, listed here.
    ***Pause***
  • Moshi is a site for two important HIV vaccine-related research efforts through the Centers for HIV/AIDS Vacccine Immunology or CHAVI program headed by Duke’s Barton Haynes.
    We will be participating in CHAVI protocol 001 to identified women with acute HIV infection to assist in the understanding in early immunologic and virologic events in HIV infection.
    And also CHAVI protocol 003 which looks at correlates of protection in HIV exposed, uninfected women with a particular focus on mucosal immunity.
    ***Pause***
  • This slide shows the two community-based studies that we have planned.
    The first is funded by the International Studies on AIDS-Associated Co-infections or ISAAC program of the US National Institutes of Health and examines the impact of clinical conditions on HIV disease progression.
    The second is funded through the Duke Center for AIDS Research or CFAR. This study examines the effect of mobile HIV voluntary counseling and testing services in rural and remote areas on VCT uptake.
    ***Pause***
  • We also have four hospital-based HIV co-infection studies underway or planned. These examine the etiology of adult febrile illness, the etiology of pediatric febrile illness, the role of improved tuberculosis diagnostics on case management, and a clinical trial of usual versus high-dose fluconazole in cryptococcal meningitis.
    ***Pause***
  • Before finishing, I would like to focus on the adult and pediatric fever studies, highlighted in yellow since the area of febrile illness is of particular personal interest.
  • Febrile illness accounts for 10 to 30 percent of admissions to hospital in northern Tanzania.
    And HIV co-infection is common among inpatients.
    As I mentioned earlier, HIV seroprevalence in the community is around 7%, but is 21% among medical inpatients, and as high as 41% among tuberculosis inpatients.
    However, laboratory capacity to identify etiology of febrile illness is limited.
    Consequently, fever is often managed empirically usually with antimalarials, even when the malaria slide is negative.
    Furthermore, common causes of fever differ from those seen in the west and as a consequence surprisingly little is known about the prevention, diagnosis, and treatment of some leading causes of fever in our setting.
    Let me illustrate some of the challenges that we are addressing through research.
  • This slide summarizes the results of a study of severe febrile illness hospital management in northern Tanzania.
    Our collaborators in ongoing fever studies from the London School of Hygiene and Tropical Medicine studied more than 17,000 hospital admissions in northern Tanzania.
    Of these 4,474 met study criteria for severe febrile illness and had malaria film results confirmed at a reference laboratory.
    Of these patients, 46% were malaria slide positive and 54% were malaria slide negative.
    ***It is notable that 95% of all patients were treated with intravenous quinine for severe malaria, despite more that half having negative malaria films.
    ***Furthermore, of those without malaria only 66% received an antimicrobial for the empiric management of common invasive bacterial infections.
    Not surprisingly then, the case fatality rate was much higher in patients without malaria treated for malaria on your right, than those appropriately treated for malaria on the left; 12% versus 7%.
  • So the next question is what are those people with non-malaria fever dying of and how can we reduce their risk for death?
    This slide summarizes the result of a fever study done in 1995 with colleagues in Dar es Salaam by Drs Archibald and Reller and others from Duke.
    During the study period, all adult patients admitted to the adult medical unit with fever had blood drawn for culture for bacteria, fungi, and for mycobacteria.
    The results of the Dar study are shown on this slide.
  • Notably almost half of the positive blood cultures from HIV-infected patients grew mycobacteria and these mycobacteria were not Mycobacterium avium complex, as we find in the West, but Mycobacterium tuberculosis!
    This was an important finding.
    In addition, non-Typhi serotypes of Salmonella, Streptococcus pneumoniae, and Cryptococcus neoformans were also important causes of bloodstream infection in febrile hospitalized patients.
  • We have recently embarked on a similar study in northern Tanzania designed to take the findings from Dar es Salaam a step further.
    And early results from the northern Tanzania study show a very list of leading causes of fever with M. tuberculosis and non-Typhi Salmonella bloodstream infections predominating among adults, and Salmonella, Streptococcus pneumoniae, and Haemophilus influenzae predominating among children.
    Within this descriptive study, we have nested studies designed to improve patient management for common causes of fever.
  • These nested studies and their goals are listed here.
    A study looking at causes of febrile illness in children admitted to KCMC which is a hospital in a low transmission area for Plasmodium falciparum aims to impact on the effort to modify Integrated Management of Childhood Illness algorithms, the bible of childhood illness management in Africa, to address the empiric treatment of fever where malaria is uncommon.
    A disseminated tuberculosis diagnostics sub-study aims to improve the clinical and laboratory diagnosis of bacteremic disseminated tuberculosis, a poorly understood condition that causes the greatest proportion of fever with bacteremia among hospitalized patients in Africa.
    And finally a non-Typhi Salmonella in HIV case control study will inform prevention guidelines for HIV-associated non-Typhi Salmonella bacteremia in Africa.
    This slide serves as a useful segway to mention the future directions of the program.
  • We plan to continue to work primarily on health problems of importance in Tanzania.
    Our research is moving from descriptive studies characterizing health problems, towards interventional studies designed to improve the prevention, diagnosis, and management of endemic diseases.
    By necessity, the program has been developed with an opportunistic approach to financial support, but over time we would like to develop a more focused research plan that allows us to build on strengths and to follow interests.
    We also hope to expand the training program to provide more opportunities for long-term trainees and to allow promising junior Tanzanian colleagues opportunity to study for advanced degrees.
    This will assist to foster a critical mass of Tanzanian researchers at KCMC who we hope will become independent investigators and life-long collaborators, working on diseases of relevance to Tanzania and East Africa.
  • In conclusion then, I hope that I have given you a sense for the scope of our collaboration in northern Tanzania, an overview of our ethos and research findings to date, and our current plans and direction.
    We believe that through the efforts of many that we have developed a platform for HIV and infectious diseases research with strong collaborative relationships with hospitals, the community, and other researchers.
    We have placed a great emphasis on training and have developed a track record of research with service.
    The growing personnel and infrastructure and high quality laboratory facilities now in place have the potential to underpin an ambitious and growing research agenda in HIV treatment and prevention research, HIV co-infection research, and community studies.
  • I would like to thank the team in Tanzania who make this work possible.
    This is a photograph of the growing team in Moshi, taken last week.
  • And I would like to Acknowledge the huge contributions of every individual listed on this slide without whose commitment the program in Tanzania would neither have begun, nor been sustained.
  • Thank you for your attention.
  • Slide 1

    1. 1. 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
    2. 2. 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
    3. 3. Tanzania • Population 33 million • Area 886,000 km2 • Human development index rank 162nd • Per capita GDP USD 251 • HIV seroprevalence 7.0%
    4. 4. 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
    5. 5. 0 20 40 60 80 100 0 6 12 18 24 Time (months) Survival(%) Survival of KIWAKKUKI home-based care clients, 2003-2005, n=226 Tillekeratne LG, et al. World AIDS Conference 2006, Abstract MoPe0303
    6. 6. 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’
    7. 7. 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
    8. 8. 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
    9. 9. ‘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
    10. 10. • 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
    11. 11. • 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
    12. 12. 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 Numberofclients 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
    13. 13. 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
    14. 14. • 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
    15. 15. • 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
    16. 16. 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 CD4countmm3* WHO stage*Interquartile range, range Morpeth SC, et al. CROI 2005, Boston, Ma., Abstract 638
    17. 17. 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
    18. 18. 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?
    19. 19. • 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
    20. 20. 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
    21. 21. Antiretroviral drug resistance and adherence study (ADAR) • How common is virologic failure in patients receiving ART in Tanzania and who fails and why?
    22. 22. 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
    23. 23. 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
    24. 24. Self-Funded ART and Virologic Failure • Persons paying for ART were more likely to be maladherent r=0.54, p<0.001
    25. 25. 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?
    26. 26. 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
    27. 27. CD4-positive lymphocyte responses Shao HJ, et al. CROI 2006, Abstract 796 n= 70 69 68 67 66 p <0.0001 for temporal trends CD4+count(cells/mm3 ) 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 Row s 11 Excluded Row s 2054 Level Minimum 10% 25% Median 75% 90% Maximum Quantiles Oneway Analysis of CD4_Lymphocyte By Visit_Type
    28. 28. 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
    29. 29. 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
    30. 30. Microbiology Immunology Molecular Virology Hematology and ChemistryCryopreservation KCMC BIOTECHNOLOGY LABORATORY
    31. 31. Grant support for research Duke-KCMC Collaboration, 2002-present 0 500 1,000 1,500 2,000 2,500 2002 2003 2004 2005 2006 2007 Grantsupport(thousandsofUSD) 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)
    32. 32. 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
    33. 33. 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
    34. 34. 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
    35. 35. 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
    36. 36. 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
    37. 37. 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
    38. 38. 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
    39. 39. Reyburn HG, et al. Brit Med J 2004; 329: 1212 95% treated with quinine 66% received antibacterial Severe febrile illness hospital management, northern Tanzania
    40. 40. Muhimbili National Hospital, Dar es Salaam Tanzania, 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
    41. 41. Muhimbili National Hospital, Dar es Salaam Tanzania, 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
    42. 42. 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)
    43. 43. 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
    44. 44. 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
    45. 45. 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
    46. 46. Duke-KCMC Collaboration Team, Moshi, April 2007
    47. 47. 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

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