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Project Descriptions
UCSF has long standing research collaborations in Uganda. UCSF and Ugandan collaborators have established NIH funded research programs in the capital city of Kampala (Makerere University) and in the western Ugandan community of Mbarara (Mbarara University of Science and Technology). Funded projects are evaluating antiretroviral treatment in adults and children and HIV co-infections (KSHV, malaria, TB). Selected active projects including clinical investigators and funding mechanisms are described below.
The Children with HIV and Malaria Project (CHAMP) (NIAID U01 AI062677). Led by Drs. Diane Havlir (UCSF) and Moses Kamya (MU), the specific aims of this ongoing study are to determine if HIV-infected children are at increased risk for symptomatic malaria, to assess the effect of malaria on the progression of HIV disease, to compare the response to therapy for malaria in HIV-infected and uninfected children and to asses the effect of TMP/SMX prophylaxis on the selection of drug-resistant malaria parasites. The CHAMP cohort also offers an outstanding opportunity to follow a cohort of Ugandan children with HIV infection and varied levels of immunodeficiency while they receive standard HIV treatment. Contact: Dr. Diane Havlir
Study of Malaria Treatment and Drug Resistance (NIAID UO1 AI52142). The study led by Drs. Philip Rosenthal (UCSF), Grant Dorsey (UCSF) and Moses Kamya (MU) is comparing three leading combination antimalarial regimens, amodiaquine/sulfadoxine/pyrimethamine, artemether/lumefantrine, and amodiaquine/artesunate in a representative sample of 601 children living in Kampala, and enrolled in 2004-05. Specific aims of the study are 1) to compare the efficacies of combination antimalarial therapies using a longitudinal design, 2) to follow plasmodial genetic polymorphisms as longitudinal markers of antimalarial drug resistance, and 3) to evaluate the roles of host genetic polymorphisms in antimalarial drug resistance and the incidence of clinical malaria. This study serves as an HIV- control for the CHAMP study described above, allowing comparisons of HIV+ and HIV – children in responses to antimalarial therapy and a host of other parameters, including incidence of other infections, drug toxicities, and drug pharmacokinetics. Contact: Dr. Philip Rosenthal or or Dr. Grant Dorsey
Kaposi’s Sarcoma and HIV infection: In sub-Saharan Africa, the intersection between the HIV epidemic and the endemic nature of Kaposi's sarcoma-associated herpesvirus (KSHV) infection has caused Kaposi's sarcoma (KS) to become the most common malignancy in the region. In HIV-infected patients with KS in the U.S., use of highly active antiretroviral therapy (HAART) often causes regression of KS even in the absence of chemotherapy. However, little is known about which antiretroviral drugs are critical to convey HAART's effect on KS. In particular, recent data suggest that protease inhibitors (PIs) also have direct anti-KS effects. To address the hypothesis that PI-containing HAART is superior to PI-sparing HAART in promoting KS regression, Dr. Jeff Martin and colleagues from UCSF along with Dr. Edward Mbidde in Kampala are performing a randomized trial. The study also has several fruitful observational components including to: a) evaluate which parameters are predictive of KS regression on HAART; b) examine the effect of HAART on KSHV-related virologic activity and host immune response to KSHV, including whether HAART reduces levels of KSHV shedding and infectiousness; and c) investigate KS-associated immune reconstitution inflammatory syndrome. The work therefore encompasses the investigation of three entities -- HIV, KSHV infection, and KS - any of which the Doris Duke can focus his/her research. In addition to the research, the trial has the responsibility for treating over 200 persons HIV infection and thus the Duke scholar has the opportunity to observe how antiretroviral drugs can have a powerful impact on individual patients. A Duke scholar is sought to have a high level of responsibility in study implementation, working side-by-side with Ugandan physicians and managing the day-to-day fieldwork. Contact: Dr. Jeffrey Martin
HIV and TB: The Punctuated Antiretroviral Treatment (PART) trial is a randomized study of immediate versus delayed antiretroviral therapy in HIV infected TB patients. This is a joint MU/CWRU/ UCSF collaboration led by Drs. Roy Mugerwa (Makerere), Chris Whalen (CWRU) and Diane Havlir (UCSF). The primary aim of this study is to test the hypothesis that a short course of antiretroviral therapy in HIV + persons with a high CD4 cell count and TB will delay accelerated HIV disease progression. The secondary aims are to evaluate rates of TB clearance, immune reconstitution syndrome and tolerance of TB medications. This study provides an excellent opportunity to address questions of HIV disease in persons with high CD4 cell counts. Contact: Dr. Diane Havlir
HIV Testing in TB clinic: Family based home vs. clinic testing This is a recently funded R01 study led by UCSF epidemiologist Dr. Edwin Charlebois and Dr. Mugerwa from MU. The study is aimed at identifying optimal strategies for HIV testing. Specific aims of the study are 1) to determine the uptake of and barriers to voluntary counseling and testing (VCT) among a cross-sectional sample of 2,000 patients offered same-day results HIV VCT at the TB clinic, 2) to conduct a randomized trial among 600 households, comparing VCT uptake between home- and clinic-based VCT for family and household members of TB evaluation patients, and 3) to investigate the effectiveness of home-and clinic-based VCT in linking HIV infected persons among the 600 randomized households to HIV medical care and social support. This study provides opportunities to study HIV discordant couples and families as well as co-infections such as TB, KSHV, and malaria. Contact: Dr. Edwin Charlebois
Response to Antiretroviral therapy in rural Uganda: UARTO The UARTO cohort is an R01 funded study led by Drs. David Bangsberg (UCSF) and Andia (Mbarara University of Science and Technology) which was initiated July, 2005 in Mbarara, Uganda. This is a 500 person prospective cohort study of therapy adherence, pharmacogenomics, T cell activation, and HIV clade in individuals initiating antiretroviral therapy in Mbarara. The primary objective of the UARTO study is to determine predictors of virologic failure and antiretroviral resistance. Contact: Dr. David Bangsberg
DDCF support for studies in Uganda. A Distinguished Clinical Scientist award to Philip Rosenthal, entitled "Translational studies of antimalarial drug resistance" has funded studies in Kampala since late 2004. Specific aims of the project are 1) assessment of associations between the complexity and diversity of malaria infections and treatment outcomes, 2) characterization of the selection of drug resistant malaria parasites, and 3) determination of molecular mechanisms of antimalarial drug resistance. A Clinical Scientist Development Award, entitled "Interactions between HIV and Malaria in African Children," was recently awarded to Grant Dorsey. Specific aims are 1) to compare the incidence of malaria in HIV infected and uninfected children, 2) to compare the safety, tolerability, and efficacy of ACT for uncomplicated malaria in HIV infected and uninfected children, and 3) to assess the effect of ARV use on malaria incidence among HIV infected children. Contact: Dr. David Bangsberg or Dr. Phil Rosenthal
Mulago Inpatient Noninvasive Diagnosis of Opportunistic Pneumonia Study (MIND) and International HIV-associated Opportunistic Pneumonias (IHOP) Study. Led by Laurence Huang, MD (UCSF Principal Investigator) and William Worodria, MBChB, MMed (Makerere University Principal Investigator), these longitudinal studies of hospitalized HIV-infected patients with pneumonia provide a platform for clinical, scientific, and operations training and research on the diagnosis and prognosis of acute respiratory illness in a resource-limited setting with a high burden of HIV and tuberculosis. With funding from the National Heart, Lung, and Blood Institute at the NIH, we are building a rolling cohort of 600 patients to compare the performance of traditional diagnostic methods to that of novel immunologic and nucleic-acid-based technologies for diagnosis of pulmonary tuberculosis (TB), Pneumocystis pneumonia (PCP), and other HIV-associated respiratory conditions. We are also investigating how establishing a diagnosis and prognosis for opportunistic conditions in HIV-infected patients affects patient outcomes, such as the likelihood of immune reconstitution disorders or of pathogen resistance to antimicrobial drugs, and how it affects systems outcomes, such as costs and health policies. Opportunities exist for medical students to conduct defined 1-year research studies that would be incorporated within the framework of the ongoing studies. Contact: Dr. Laurence Huang
HIV Research Activities in Kenya The Kenya Medical Research Institute (KEMRI)-UCSF Program focuses on HIV and STI prevention research and the evaluation and provision of HIV/AIDS care, including antiretroviral treatment in adults and children. The UCSF PI is Craig Cohen, MD, MPH, and the KEMRI PI is Elizabeth Bukusi, PhD, M.Med, MbChB. If you are interested in participating in any of the following programs, please contact Dr. Craig Cohen or Rachel True, Program Manager.
The VivaGel Study Research on topical microbicides has emerged as an alternative treatment modality to address the growing need of women to control their risk of exposure to STIs. Drs. Craig Cohen (UCSF) and Elizabeth Bukusi (KEMRI) are leading a phase 1 microbicide trial in Kisumu, Kenya and San Francisco, CA. The study is a multi-site, randomized, double blind, placebo-controlled trial of the safety and tolerability of vaginal use of VivaGelä. The primary study objective is to determine the safety and tolerability of VivaGelä applied vaginally twice daily for 14 days in HIV negative and STI-free young women. The secondary objective is to report the effect of VivaGelä applied vaginally twice daily for 14 days on the immune microenvironment in the lower genital tract of young women. Based on the results of this initial study, Dr. Cohen plans to conduct phase II and phase III studies in 18-24 year old population, and eventually in the population most at most risk of STIs and HIV, 14-18 year olds.
Family AIDS Care and Education Services (FACES)
is an innovative program in Nairobi and western Kenya (Nyanza Province) which operates a family-oriented model of HIV care and treatment funded through the US President’s Emergency Plan for AIDS Relief (PEPfAR). The FACES family model of care focuses on identifying and enrolling all HIV infected family members and retaining and supporting them in care. The model includes: encouraging HIV testing of partners and children; assisting with disclosure to both adults and children; providing joint family clinic appointments; support groups for pregnant women with HIV, and their husbands; and a "kids club".
FACES plans to significantly expand within the next program year. The expansion will include increasing clinic sites in Suba District, implementing the program in Migori and Kuria Districts, and expanding services to include PMTCT (prevention of mother-to-child transmission) and TB services.
A growing part of the FACES model is the Student Training Program (STEP). The Training Program has two components: the medical student track and the resident track. Medical students from UCSF, University of Nairobi, and University of British Columbia are selected four times a year for the clinical or research elective. Each spends a minimum of one month at a FACES site; projects can be up to a year and students are closely mentored by clinic staff. The medical students in the research elective work on tailored studies; third and fourth year students work directly with patients to gain clinical experience.
In addition, FACES serves as a platform for conducting clinical and operational research related to HIV care and treatment. Future studies include an evaluation of HIV care and treatment into PMTCT programs, and integration of family planning services into HIV care and treatment. Patient data are being electronically stored and are available for analysis.
Anti-Retroviral Therapy Impact Study (ARTIS)
The effect of antiretroviral therapy (ART) scale-up in Africa on sexual risk behaviors and the prevention of new HIV infections is unknown. Models demonstrating that ART can reduce HIV incidence also show that small increases in risky sexual behaviors can mask and reverse gains achieved by therapy. Studies from the developed world suggest that prevalence of unprotected sex and incidence of sexually transmitted infections have increased since the introduction of ART. It is possible that misperceptions about ART or reduced concern about HIV because of ART availability lead to more permissive sexual behavior in both HIV-infected persons and the general population.
The purpose of this study is to examine the association of ART expansion and ART-related beliefs with risky sexual behaviors and prevalence of sexually transmitted infections (STI) and HIV in the general population of Kisumu, the Municipality with the highest HIV seroprevalence in Kenya. Similarly, the association of ART expansion and ART-related beliefs with risky sexual behaviors in HIV-infected persons receiving ART will also be explored. We will conduct cross-sectional surveys to evaluate knowledge and beliefs about ART and the impact of these changes on sexual risk behaviors. Surveys of the general population will be conducted by sampling 40 sentinel clusters within the Municipality of Kisumu. Surveys of HIV positive patients on ART will be conducted at our PEPFAR-funded ART rollout program in Kenya, entitled Family AIDS Care and Education Services (FACES). Understanding public perceptions of ART and their effects on sexual risk behaviors that lead to an increased risk of STI and HIV is essential for designing prevention interventions that address the changing landscape of HIV with the availability of ART. ARTIS completed data analysis in October 2006. Data are currently available for analysis.
Couples Intervention Study (CIS) UCSF leads the Kisumu, Kenya site for the multisite trial conducted by the University of Washington to assess the impact of suppression of genital herpes on HIV transmission. This randomized, double-blind, placebo-controlled trial will enroll HIV-discordant couples among whom the HIV-positive partner is also herpes simplex virus type 2 (HSV-2) seropositive and has a CD4 >250. The HIV-positive partners will then be randomized to receive daily acyclovir (400 mg bid) to suppress HSV-2 or placebo. Our hypothesis is that suppression of HSV-2 in the HIV-positive partner through standard daily doses of acyclovir will reduce HIV transmission in these couples by 50%. To date, our site has screened and enrolled over 1000 and 400 HIV-serodiscordant couples, respectively. In addition, our team helped to establish couples HIV counseling and testing (CHCT) facilities in Kisumu, and has trained and monitors over 200 voluntary counseling and testing (VCT) counselors to perform CHCT.
The largest UCSF international HIV research program is in Zimbabwe. This program is predominantly focused on HIV prevention. The UZ-UCSF Collaborative Research Program was founded in 1995 by Drs. Nancy Padian from UCSF and Mike Mbivzo and Mike Chirenje in collaboration with faculty from the School of Medicine at the University of Zimbabwe. Through this partnership, the UZ-UCSF Program has evolved into the largest HIV research unit in Zimbabwe and one of the largest and most productive in the world. Since 1995, the collaboration has grown from one protocol to more than 12 completed studies and 17 current or planned and approved trials, with over $10 million in annual funding. The UZ-UCSF Program has a state-of-the-art research infrastructure, including 12 research sites (nine clinic-based, and three community/rural-based), one DAIDS certified central laboratory and seven site laboratories, a registered central pharmacy and four site pharmacies, and over 450 highly-trained research staff. More than 17,000 participants have been enrolled in completed protocols and 7,000 are currently enrolled in ongoing studies. Staff are trained and certified in Good Clinical Practices (GCP) and Good Laboratory Practices (GLP), Quality Assurance/Quality Control (QA/QC), study operations, data management, and research administration. The program has developed exemplary community linkages, with internationally recognized community advisory boards providing input and guidance on research development, implementation, and dissemination. The UZ-UCSF program has a well-established management and administrative infrastructure, providing strong centralized fiscal management, human resources, procurement, QA/QC, ethics, data management, laboratory, pharmacy, training, and counseling services to all studies conducted through the program through a series of centralized departments. The UZ-UCSF Executive Committee, comprised of scientific leaders representing UZ, UCSF, and other Zimbabwean and international partner institutions, provides leadership and direction for the overall program, and facilitates linkages with local, national, and international policymakers. Contact Dr. Nancy Padian