Research Programs of the Botswana UPenn Partnership Program

Embracing the notion that an eminent 21st-century research institution must engage dynamically with communities around the world to address critical global challenges, UPenn has made an institution-wide commitment to addressing the HIV/AIDS epidemic in Botswana. The people of Botswana have one of the highest rates of HIV in the world, with an overall infection rate of 17% and a 34% infection rate in women between the ages of 15 and 49. The total population of the country is 1.8 million, with an estimated 300,000 infected persons. UPenn’s activities in Botswana began in 2001 at the invitation of the African Comprehensive HIV/AIDS Partnership (ACHAP), a collaboration involving the Government of Botswana, the Bill and Melinda Gates Foundation, and the Merck Foundation. UPenn physicians were invited to help develop and implement a national HIV treatment and prevention program, and to assist in the training of local providers in the management of HIV infected patients. Over the past six years, UPenn’s activities in Botswana have expanded at a rapid pace, and UPenn has established strong partnerships with the Ministry of Health (MOH) and the University of Botswana (UB) to help address the country’s HIV/AIDS crisis. Components of the program are described under Program Description.

 

HIV/AIDS Research Programs
The UPenn CFAR International Core helps promote HIV clinical and translational research studies that focus on medical issues of importance to the country. Through the activities of the CFAR Core, a growing number of UPenn and Botswana researchers are participating in HIV research. The Core activities and research projects are described below.

 

Setup of UPenn’s HIV Clinical Research Program in Botswana
Currently, three research nurses/technicians are supported by UPenn grants. All are housed in research space obtained by the Core to support UPenn’s research initiatives in Botswana. The three individuals share one large office in the Administration Building at the Princess Marina Hospital. Desks, computers, phones, and Internet are available in the office. Study patients are seen either on the inpatient wards at the hospital or in the outpatient HIV clinic. Offices for UPenn faculty are located approximately 5 minutes away from the hospital. The space was recently renovated to include workstations for up to 6 people, each with a computer and high speed Internet. A printer and copier are available in the office.

 

Services Provided by the International Core
i) Providing logistical advice on the feasibility of research protocols in Botswana
A significant role of Core I is to advise CFAR investigators on the types of studies that we are capable of doing in Botswana, which we base on the patient population and the infrastructure available to process samples. Many CFAR investigators are unclear about the feasibility of performing clinical or translational HIV research in Botswana and they need detailed consultations to help formulate cohesive research questions that are relevant to Botswana.

ii) Help with submitting protocols to Botswana IRBs and to complete the NIH checklist
Advise on obtaining IRB consent and other steps needed before a study can open are among the most important functions of the Core. The steps required are numerous and time consuming, and include: a) helping to develop consent forms appropriate for Botswana; b) translating consent forms from English into Setswana and then back into English for submission to the MOH IRB committee; c) helping to prepare protocols for submission to the MOH IRB committee; d) helping to prepare forms for IRB submission to the hospital IRB committee (separate from MOH IRB) for those studies that involve patients at the Princess Marina Hospital; e) helping to complete online training for study personnel to obtain certificates of human subjects research protection; f) helping with documents to obtain Federalwide Assurance (FWA) for foreign performance sites; g) helping to complete checklist for CFAR-funded international studies.

iii) Hiring personnel to carry out research studies
The Core takes primary responsibility for hiring research nurses/technicians in Botswana. The Core writes the contracts for new hires, which requires knowledge of Botswana Human Resource regulations and Botswana tax laws. The Core helps set salaries for new hires based on our experience with the salary structure in Botswana.

iv) Supervising research nurses
UPenn faculty members in Botswana currently employ three nurses/technicians. The Core takes responsibility for supervising the daily activities of all the employees.

v) Sample processing and shipping
The International Core technician processes all samples obtained in studies of CFAR investigators. During the current year the samples included serum, CSF, and tissues from ocular tumors. The Core also stores samples at –80C and arranges for shipment of samples to the USA.

vi) Providing office space, computers, Internet and purchasing supplies for CFAR investigators
The International Core provides the infrastructure for the clinical and translational research programs, including ordering the research supplies, processing payments for the supplies, providing computer and Internet access, purchasing office supplies and providing the desks and office space for the research work.

Space in the HIV clinic at Princess Marina Hospital is in short supply and our research nurses often have difficulty finding a room available to examine patients who are returning for clinical research study visits. We recently submitted an application to ACHAP (Gates and Merck Foundations in collaboration with the Government of Botswana) for additional clinic exam room space to be added to the existing ID clinic. We proposed adding 8 exam rooms to establish three HIV specialty clinics and to expand our access to exam rooms for our study nurses to see clinical research subjects. The three specialty clinics include one devoted to HIV patients with opportunistic infections, another for HIV subjects with metabolic complications, and a third to establish a women’s clinic for cervical cancer screening in HIV patients. The proposal was approved and we expect occupancy of the new clinic to occur by January 2008.

 

Core Users
The number of Core users has steadily increased each year since the initial funding of the Core July 2004. We are particularly pleased that the Developmental Core awarded 3 CFAR pilot project grants for Botswana in 2006 and another was funded in 2007. In addition, grants by Jemmott (NIH), Nathanson/Friedman (UPenn internal funds) were funded in 2007 that focus on enhancing HIV research in Botswana.

 

Educational Activities
UPenn faculty members are very involved in HIV teaching in Botswana. Only those activities geared towards research are discussed below.

Research oriented conferences:
i) Dr. Jeffrey Hafkin organizes a weekly HIV journal club in collaboration with Baylor Pediatrics in Botswana.
ii) Dr. Bisson, Dr. Tebas, Dr. Gluckman and Dr. Kessler each gave a lecture at the International HIV conference in Gaborone in September 2006. Over 800 delegates attended the conference. Topics included predictors of outcomes of HIV infected patients, metabolic complications of HIV, evaluation of CNS infections in HIV patients, and management of HIV/TB co-infected subjects.
iii) Dr. Friedman gave three lectures to providers and investigators in Botswana about HSV-HIV co-infection.
iv) Dr. Gross gave a lecture to providers and investigators in Botswana about adherence to therapy issues in HIV patients.
v) Dr. Francisco Gonzalez gave a lecture on neurologic complications of HIV at the Princess Marina Hospital.
vi) Dr. Harvey Friedman presented a talk describing the UPenn-Botswana Program at UPenn’s annual CFAR retreat on 10/20/06.

 

Core Scientific Accomplishments

i) CFAR pilot project; Dennis Kolson, PI: Clade C as cause of dementia in HIV patients in Botswana
Dr. Kolson proposes to obtain CSF samples, serum and PBMCs from 25 subjects with HIV infection who have CSF samples that are negative for routine pathogens. The Core technician will process the CSF and serum samples of these patients, store them at -80C and -20C respectively, and batch them for shipping to the USA. Once samples are shipped to the States, the Kolson laboratory will compare Clade C isolates from Botswana with Clade B isolates in the USA for infection and cytokine release in neuronal and glial cell cultures. This study is open for enrollment.

ii) CFAR pilot project; Erle Robertson, PI: Causes of ocular surface squamous cell neoplasia (OSSN) in Botswana
This study seeks to define the etiology of a common eye tumor in Botswana that is particularly common in HIV patients, but is rarely seen in the USA. We are working with ophthalmologists at the Princess Marina Hospital to obtain fresh biopsy samples from affected patients. In Philadelphia, the samples will be processed looking for EBV and HPV footprints. This study was opened for enrollment in April 2007 and 20 samples have been evaluated to date.

iii) CFAR pilot project; Ian MacMillan and James Thompson: Use of computer-generated text messaging to improve adherence to HIV therapy
This project is located at the Independent Surgery Clinic in Gaborone. The goal is to use computer technology to remind HIV patients to refill prescriptions for HIV medications and to make follow up appointments. We anticipate this study opening for enrollment in January 2008.

iv) Bagale Chalisa, John and Loretta Jemmott: Community intervention to promote abstinence and related skills among youths in the Republic of Botswana under the President’s Emergency Plan for AIDS Relief
This NIH U26 grant application brings together UPenn CFAR investigators with UB scientists to evaluate HIV prevention strategies in Botswana and to develop clinical research infrastructure at UB. The grant was funded in September 2007.

v) Robert Gross, MD. Genetic polymorphism as a predictor of response to efavirenz therapy
Dr. Gross submitted an NIH grant evaluating the effects of genetic polymorphisms in Botswana as a predictor of response to HIV medications. Dr. Gross collected pilot data in Botswana to support his application.

vi) Gregory Bisson, MD. Development of a clinical prediction rule for an undetectable viral load after initiating antiretroviral therapy
This project aims to use simple predictors such as CD4 count, weight, and baseline viral load to create a clinical prediction rule designed to avoid expensive and unnecessary follow-up viral load monitoring in patients whose probability of being undetectable is very high (e.g., greater than 95%). 375 patients were enrolled to derive a CD4-count based clinical prediction rule for an undetectable viral load. The results showed that if viral load testing were restricted to patients who had a CD4 cell count increase of less then 50 cells, then over 90% of viral loads in patients with undetectable viral loads would be avoided while over 60% of virologic failures would be identified. These results were published in AIDS.

vii) Rob Roy MacGregor, MD and Harvey Friedman, MD. The prevalence of TB and cryptococcal pneumonia in HIV patients admitted to the Princess Marina Hospital medical wards with pulmonary infiltrates
The aims of this study are to determine the proportions of antibiotic-unresponsive pneumonias of unclear etiology that are caused by M. tuberculosis or C. neoformans among adult patients admitted to the medical wards at PMH; to assess the utility of induced sputum, gastric content sampling, blood culture, and urine culture for the diagnosis of TB in patients in whom initial expectorated sputum is not obtainable or is AFB smear negative; to assess the prevalence of pulmonary cryptococcal pneumonia infection; and to collect clinical and basic laboratory data to define characteristic features in patients with pulmonary TB and pulmonary cryptococcal infection.

viii) Gregory Bisson, MD. Evaluation of insurance status and antiretroviral cost as predictors of response to ARV care in the private sector in Botswana
This study evaluated the relationship of antiretroviral regimen cost and insurance coverage and response to therapy among 350 treatment naive adults initiating antiretroviral therapy in a private clinic. Lack of insurance and higher regimen costs were both associated with loss to follow-up after treatment initiation. This project was published in AIDS.

ix) Gregory Bisson, MD. Evaluation of predictors of death early after initiation of ART in Botswana’s National ART Program
This study is a retrospective review of over 500 patients presenting to the HIV clinic at Princess Marina Hospital. The study provided valuable insights into the validity of the clinic data, since medical records and pharmacy data were compared with data extracted from the clinic computer system. This validation effort also involved searching for patients who were noted as “lost” in the database.

x) Gregory Bisson, MD. Evaluation of cryptococcal meningitis at Princess Marina Hospital in Botswana
This prospective study seeks to develop state-of-the-art cryptococcal diagnostics at Princess Marina Hospital; to provide pilot data for future clinical trials of cryptococcal meningitis; and to evaluate microbiologic types of Cryptococcus neoformans seen in this region (e.g., C. neoformans var neoformans vs C. neoformans var gattii). The study involves collaboration with the National Health Laboratory (NHL) in Botswana. Working with the Director of the NHL, we implemented cryptococcal antigen testing and fungal cultures for all patients admitted to the hospital with presumptive meningitis. This project has shown that over half of patients presenting to the hospital with their first episode of cryptococcal meningitis are on antiretroviral therapy, suggesting early immune reconstitution, and that over 25% of all cases of cryptococcal meningitis among patients with AIDS in Botswana are due to C. neoformans var gattii (this is the highest known prevalence of this infection among patients with AIDS).

xi) Neal Nathanson, MD and Harvey Friedman, MD: New health research initiatives in Botswana
Drs. Nathanson and Friedman have applied for funding at UPenn to expand the research ties between UPenn investigators (primarily CFAR investigators) and UB faculty. The grant supports travel to Botswana by UPenn CFAR investigators to identify projects that can be pursued collaboratively and that will hopefully lead to joint grant funding that combines the expertise of investigators at each institution.

 

Publications
Bisson, Gregory P a; Frank, Ian a; Gross, Robert a; Re, Vincent Lo III a; Strom, Jordan B b; Wang, Xingmei a; Mogorosi, Mpho c; Gaolathe, Tendani c; Ndwapi, Ndwapi c; Friedman, Harvey a; Strom, Brian L a; Dickinson, Diana Out-of-pocket costs of HAART limit HIV treatment responses in Botswana's private sector. AIDS. 20(9):1333-1336, June 12, 2006.

Bisson, Gregory P a; Gross, Robert a; Strom, Jordan B b; Rollins, Caitlin a; Bellamy, Scarlett c; Weinstein, Rachel c; Friedman, Harvey d; Dickinson, Diana e; Frank, Ian d; Strom, Brian L c; Gaolathe, Tendani f; Ndwapi, Ndwapi . Diagnostic accuracy of CD4 cell count increase for virologic response after initiating highly active antiretroviral therapy. AIDS. 20(12):1613-1619, August 1, 2006.

Updated by Harvey Friedman, PI of the CFAR International Core 9.30.07