Fellowship Site: Uganda

The Infectious Diseases Institute (IDI) was established in 2004 as an International Center of excellence for building capacity in Africa for training, clinical care and research on HIV and related infections. IDI was established by a group of infectious disease experts in Uganda and North America (The Academic Alliance). It is located on the Mulago Hospital complex in Kampala, Uganda and is part of Makerere University. The Institute has trained over 2400 people in the care and treatment of HIV, and aspects of pharmacy, lab, and data management. The out-patient clinic has enrolled over 20,000 patients with more than 13,000 in active follow-up and over 6,000 on antiretroviral treatment. A longitudinal clinic cohort database is a rich source of data that has informed many aspects of HIV care and prevention. In addition, the collaborative and rich environment have enabled IDI to attract numerous other studies in malaria, tuberculosis, sexual and reproductive health, Kaposi's sarcoma, and neurocognitive disorders.

Research:

1. Pharmacokinetic Research (on-site PI- Dr. Ceppie Merry)
   Project Description: There are no data on the interaction between Co-artem and any of the antiretroviral agents. Both components of Co-artem are substrates for the 3A4 isoform of cytochrome P450. Despite the lack of data, antiretroviral drugs and/or antituberculous drugs plus Co-artem are co-prescribed often in the African setting. Nevirpaine, efavirenz and rifampicin are known inducers of cytochrome P450 3A4. To evaluate these interactions in HIV infected Ugandan patients using pharmacokinetic studies The aim of these studies is to evaluate the pharmacokinetic interaction between Co-artem and commonly co-prescribed inducers of 3A4 i.e nevirapine, efavirenz and rifampin. Similar studies investigating the interactions between rifampivin and antiretrovirals, co-artem and rifampin, and the impact of pregnancy on nevirapine drug levels are also being studied. The study has the following objectives:
   • Comparison of steady state pharmacokinetics of Co-artem in HIV-infected patients who are receiving nevirapine with HIV-infected patients who do not yet require antiretroviral therapy,
   • Comparison of steady state pharmacokinetics of Co-artem in HIV-infected patients who are receiving efavirenz with HIV-infected patients who do not yet require antiretroviral therapy,
   • Comparison of steady state pharmacokinetics of Co-artem in Ugandan patients who are receiving rifampin with Ugandan patients who are not receiving rifampin therapy.

2. Comparison of the development of thymidine analogue mutations with CD4 monitoring alone versus CD4 monitoring plus viral load monitoring in naїve HIV-1 individuals on first-line antiretroviral therapy in Africa (TAMS) (on-site PIs - Andrew Kambugu and Steve Reynolds)
   Project Description: To determine if monitoring of individuals on ART by clinical evaluation and CD4 counts only (as per WHO recommendations), in the absence of routine virologic monitoring, delays in the detection of virologic failure and leads to a significantly higher rate of accumulation of thymidine analogue mutations (TAMs) when compared to patients whose monitoring includes routine viral load testing. Specific objectives include:
   • To describe the virologic response to ART treatment in patients attending the Infectious Diseases Institute (IDI), Makerere University, Kampala, Uganda at 36 months, in both the general clinic (no routine virologic monitoring) and the ART cohort (have virologic monitoring),
   • To compare the distribution of TAMs in all IDI patients on ART with a detectable viral load at 36 months in the general clinic,
   • To determine the distribution of the number of TAMs among IDI patients on ART with a detectable viral load at 36 months in the ART cohort,
   • To compare the distribution of TAMs in IDI all patients receiving ART (with a detectable viral load at 36 months) with or without routine virologic monitoring.

3. Hepatitis B virologic response in HIV co-infected patients on treatment with open label Truvada versus Combivir containing regimens (on-site PI - Ponsiano Ocama)
   Project Description: Chronic viral infections are now among the leading causes of death all over the world. More than 40 million persons have HIV infection, an estimated 400 million persons have chronic hepatitis B virus infection (HBV) and 170 million have hepatitis C virus (HCV) infection. Because these viruses are transmitted in similar ways, concurrent chronic viral infections are common and the outcome of liver disease is worse in patients co-infected with HIV and the hepatotropic viruses. Lamivudine, Tenofovir and Emtricitabine are effective against both HIV and Hepatitis B virus. Lamivudine failure rates for hepatitis B are higher in co-infected persons than in HBV mono-infection. This study will test the hypothesis that tenofovir combined with emtricitabine (Truvada) produces better HBV viral suppression than lamivudine in HIV/HBV co-infection. Patients will be recruited at the IDI, 66 of these will be historical cohorts on lamivudine containing HAART, and 66 will be recruited and started on Truvada containing HAART. These will be followed up for 1 year and HBV viral loads, HBV genotypic resistance, will be tested at regular intervals in either arm of the study.

4. Immune Reconstitution Inflammatory Syndrome in Ugandan HIV-infected patients after initiation of potent anti-retroviral therapy (on-site PIs - Roy Mugerwa, Andrew Kambugu, David Meya)
   Project Description: Opportunistic infections remain a common and serious complication of HIV infection in both the U.S. and Africa. The introduction of highly active antiretroviral (ARV) therapy has lowered these disease rates, but the use of ARVs has also introduced new complications in the diagnosis, management, and outcomes of patients with AIDS and AIDS-related infections. Advanced HIV infection is seen frequently in resource poor regions because patients often do not present to hospitals or clinics until they have disturbing symptoms indicative of advanced disease and because ARV therapy has not been widely available. Many programs are now providing ARV therapy to underserved regions of the world, such as sub-Saharan Africa, where ARV therapy had not previously been available. ARV therapy usually enhances immune function in HIV-infected patients, even those with advanced disease, and, overall, decreases the risk of opportunistic infections. Patients with profound immunosuppression prior to initiation of ARV therapy, however, are at substantial risk for experiencing an exaggerated inflammatory response that leads to clinical worsening. This pathological response to ARV therapy is known as immune reconstitution inflammatory syndrome (IRIS). The specific aims of this study are to describe IRIS in a cohort of HIV-infected Ugandan patients as they initiate ARVs, and in a subcohort of patients who have cryptococcal meningitis and another cohort with TB at the time of ARV initiation.

5. Prospective observational cohorts in the Infectious Diseases Clinic (on-site PI - Moses Kamya)
   Project Description: With the rollout of PEPFAR and Global Fund to support the rapid initiation of antiretroviral therapy for eligible HIV patients, the Infectious Diseases Clinic rapidly expanded with over 19,000 patients seen, over 13,000 active patients, and over 5,000 on ART. All patients get immunologic monitoring at least every 6 months and have clinical data entered into an electronic database. In addition, a smaller 600 person cohort enrolled between 4/04 and 4/05 has had viral loads obtained every 6 months. Both the clinic and the cohort continue to be a rich source of data for relevant clinical questions with 17 published manuscripts and over 50 abstracts.

6. Preparation for conducting phase III Trials of novel TB vaccines in Ugandan infants and adolescents (on-site PI - Philippa Musoke) Project Description: Using an existing demographic surveillance site of 70,000 people established by the School of Public Health at Makerere University, this grant helps to expand the demographic base to 140,000 people and to create a network of laboratory infrastructure to support Phase IIb and Phase III trials of tuberculosis vaccines. Funding for baseline surveillance of the existing tuberculosis burden as well as operational research to support up-coming TB vaccine trials are included in this funding. Specific aims include: a. To determine the incidence of TB disease in infants and the knowledge, attitudes and practices about TB and willingness to participate in TB vaccination trials and to increase TB awareness in the community b. To determine infant mortality rates and causes of mortality c. To determine rates of cohort retention, and causes of loss to follow up.

Housing Availability:
The IDI maintains a 3 bedroom apartment that is a 15 minute walk from IDI and a 5 minute drive. Very inexpensive ($0.30 one way) mini-bus taxis are available with door-to-door service. Visiting trainees have a unique opportunity to exchange ideas in a relaxed house atmosphere. Laundry, grocery, shopping, cooking, and potable water are all available at the house. Rooms are available for $400-600/month.

Health Issues and Immunizations Needed for this Site:
The usual health precautions for a resource-limited country in a malarious zone apply with need for monitoring foodstuffs, use of bottled water, and recommendations for malaria prophylaxis. Yellow fever vaccine is required for entry into the country as is a valid visa. Tuberculin skin test status should be ascertained prior to entering Uganda as this country is 17th on the high burden TB country list.

See the Centers for Disease Control and Prevention Web site and The Yellow Book: Health Information for International Travel.

The FICRS program mandates that all Scholars see a physician prior to their assignment abroad. The physician will need to complete and sign a brief form.

Safety and Danger Issues:
The U.S. Department of State has not issued any recent travel warnings regarding travel to Uganda, although several of the neighboring countries including Kenya, Democratic Republic of Congo, and Sudan remain on the travel warning list.

See the U.S. State Department Web site for more information.

Language Requirements other than English:
The two official languages in Uganda are Luganda and English. In Kampala, all professionals speak fluent English so language should not be a professional barrier. For patient care, a working knowledge of Luganda would be desirable. On-site language training can easily be arranged.