Hepatocellular carcinoma (HCC) is very common in Sub-Saharan Africa due to highly prevalent chronic viral infections, including hepatitis C (HCV). Currently, patients in sub-Saharan Africa typically present in late stage disease, having a life expectancy of just three months. Earlier diagnosis could reduce HCC mortality in two ways: 1) patients with viral hepatitis would be staged earlier and tumors, if present, would be smaller and therefore easier to treat with alcohol ablation, the current standard of care in the region; and 2) patients identified earlier with chronic HCV could be treated with direct acting antiviral agents (DAAs) leading to reduced morbidity including less HCC. The goal of this proposal is to develop low cost point-of-care diagnostic tests to detect and monitor the treatment of active HCV infections. The first test to be developed will be an HCV core antigen qualitative test to identify patients with an active HCV infection. This assay will be ported on the LYNX immunoassay platform developed in collaboration with the Northwestern Global Health Foundation (NGHF). The test conditions developed for the LYNX p24 Antigen Rapid Lateral Flow Assay for Rapid Diagnosis of HIV Infection in Infants will be adapted to address a highly analogous problem: the detection of the HCV core antigen viral marker from plasma. The second test will be a multiplexed HCV viral load assay to determine when to initiate therapy and to monitor the viral response to DAA treatment. This assay will be ported onto the Savanna integrated nucleic acid extraction, amplification & detection system that is currently being developed in collaboration with the Quidel Corporation and Northwestern Global Health Foundation (NGHF). The test conditions developed for the Savanna RealTime HIV-1 Assay® will be used for the HCV viral load assay. Both the LYNX and the Savanna platforms have been designed for use in limited resource settings. They are inexpensive, easy to operate and robust. All reagents are provided with the test kits and no refrigeration is required. The analytical and clinical performance of these assays will be demonstrated in both laboratory and clinical validation studies at the Jos University Teaching Hospital in Jos, Nigeria. The tests will be transferred to their respective manufacturers, and regulatory approval for will be sought. The impact of earlier detection and improved monitoring of viral hepatitis will prompt earlier treatment resulting in prevention of carcinogenesis and/or earlier stage diagnosis with improved outcomes in patients in low and middle income countries.
Hepatocellular carcinoma (HCC) is a highly lethal cancer with over 80% of the cases occurring in the developing world. Chronic hepatitis C (HCV) infection is a major risk factors for HCC development. The goal of this proposal is to develop diagnostic tests for HCV infections for use in low and middle income countries to identify patients at risk for HCC and to monitor treatment of the viral infection.
The University of Sciences, Techniques and Technologies of Bamako (USTTB, formerly University of Bamako) Project Research Laboratory was formed as a collaborative venture between the National Institutes for Health (NIH)/National Institutes of Allergy and Infectious Diseases (NIAID) and the Faculty of Medicine, Pharmacy and Dentistry at USTTB in Mali. Together they have developed state of the art retrovirology and mycobacteriology laboratories and the Malians have received training in clinical and laboratory research. Northwestern University has had a formal affiliation with USTTB since 2008 as a major partner of the Northwestern AIDS International Training and Research Program (AITRP) funded by NIH/Fogarty International Center and has trained Malian researchers in Bioethics, Molecular Virology, Clinical Microbiology and Clinical Investigation. The aims of this project are to:
- transition the existing laboratory and research programs supported by NIH/NIAID intramural funding to an extramural program associated with Northwestern University
- further develop the research retrovirology and tuberculosis laboratory capabilities at SEREFO
- enhance the overall research capacity at USTTB to the point they will have a sustainable and independently funded research portfolio within the next five years.
Significance & Background
The WHO estimates that the incidence of pulmonary TB in Mali is 320 cases per 100,000 inhabitants, including 138 cases per 100,000 with pulmonary plus mediastienal involvement. While the countrywide HIV prevalence is a relatively low 1.5%, in patients with TB who are co-infected with HIV it is 11 fold greater, 16.2%. HIV co-infection with tuberculosis (TB) is a major concern worldwide including Mali, a West African Francophone country with over 15 million inhabitants (1,2). Co-infection with HIV interferes with early diagnosis and complicates disease management. When these infections occur together, they are associated with overall higher morbidity and mortality than when they present alone (3,4). Co-infection rates in Mali vary considerably by region ranging from 0% in Gao, 11.1% in Dioila, 23.1% in Mopti, 23.5% in Sikasso, 25% in the capital of Bamako and 27.8% in Segou (1,2,5).
The HIV epidemic in Mali is feminized, with women disproportionately infected compared to men. UNAIDS has estimated that women account for 60% of all adult infections. Prevalence in pregnant women ranges between 3.0-4.5%. Only 13.4% of pregnant women received any form of antiretroviral treatment for prevention of mother to child transmission (PMTCT) in 2007, but that was actually an improvement over the 8.6% rate noted in 2006. The AIDS epidemic has already orphaned 44,000 children and 9,400 children were living with HIV/AIDS as of 2007. As a result of these factors and others, HIV, TB and HIV/TB co-infection presents a major challenge to the treatment of both diseases and is of great concern (1).
SEREFO provides all facilities in order to successfully diagnose and monitor both HIV and tuberculosis, such as a fully operational and certified BSL-3 laboratory. Since 2005 this laboratory has been performing TB diagnosis using traditional and modern methods, mycobacteria identification, drug susceptibility testing, and strain typing. Recently they added to their work, HIV diagnosis using rapid test, ELISA and confirmation with Western Blot. Also the lab can perform the HIV viral load using modern techniques and gene sequencing in HIV treatment failure cases. The research aims of the present project are perfectly in line with SEREFO’s mission to improve the health of the people of Mail and benefit the Malian and International community by:
- Conducting sustainable laboratory and clinical research on bacterial and viral diseases of the highest quality with an initial focus on investigations of the immunology and molecular biology of HIV and Mycobacterium tuberculosis (MTb, TB) and their interaction
- Developing and sustaining training programs and mentorship for nascent researchers
- Promote scientific collaborations both nationally and internationally
- Providing scientific support to Malian public health institutions
- Creating and sustaining a research infrastructure to enable SEREFO scientists to successfully compete for national and international funding
- USAID. Mali: HIV/AIDS Health Profile. September 2010.1-4.
- US Department of State. About PEPFAR>Operational Plans>Fiscal Year 2009 Operational Plan - February 2010>Section IV Other PEPFAR Country Narrative>Africa. http://www.pepfar.gov/about/129111.htm. Accessed 13 May 2011.
- Corbett EL, Marston B, Churchyard GJ, De Cock KM. Tuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment. Lancet. Mar 18 2006;367(9514):926-937.
- Martinson NA, Hoffmann CJ, Chaisson RE. Epidemiology of Tuberculosis and HIV: Recent Advances in Understanding and Responses. Proc Am Thorac Soc. Jun;8(3):288-293.
- WHO. Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 Global Health Surveillance and Response. 2010 (ISBN 978 92 4 159919 1)
University of Bamako/SEREFO
Robert L. Murphy, MD
Anatole Tounkara, MD, PhD - Dean of the Medical School and Founding Director of SEREFO
Ousmane Koita, PharmD, PhD - Co-Director of the SEREFO Laboratory
Prime Awardee: The University of Sciences, Techniques and Technologies of Bamako (USTTB, formerly University of Bamako)
Subcontractor: Northwestern University
Tuberculosis (TB) remains a public health problem in resource limited settings such as Mali. Tuberculosis is caused by a slow-growing acid-fast bacillus; the initial acute infection being typically followed by a period of latency in about 95% of the cases and only a few will develop active disease. So far efforts to control TB are hampered by difficulties with prevention, diagnosis, and treatment. The immune response to TB is complex and not yet characterized completely which is making difficult the development of new vaccines and drugs. The innate immune system is a key factor in disease outcome. Although advantages of infection could be attributed to intrinsic characteristics of the pathogen, the host response needs to be defined to understand the outcome of the disease. Interferons (IFNs) are proteins made and released by host cells in response to the presence of pathogens such as bacteria, viruses, parasites or tumor cells. They activated immune cells such as natural killer cells and macrophages. Human monocytes derived from PBMCs are key cell components of the innate immune system that encounter the mycobacteria and are involved in the formation of Granuloma. To better understand responses due to host-pathogen interaction related to the outcome of TB disease, we will investigate the secretion of inflammatory cytokines.
Recently, we identified by spoligotyping that Maf and Mtb are the most prevalent strains, respectively accounting for 27.8 and 71.4% of TB cases in Mali. Since its description by Castets et al. In 1968, Maf is an important cause of human tuberculosis (up to 40% of pulmonary tuberculosis) in West-Africa. M.africanum causes TB almost exclusively in countries between and including the Gambia and Cameroon. Although studies performed in and around West African countries about Maf have shown variable prevalence’s, all suggested that it is less common among drug resistant isolates and retreatment cases. Our preliminary report suggests that MAF is less likely to be resistant to TB first line drugs and less likely to be associated with treatment/retreatment failure than is MTB.
There are an estimated 1.2 million HIV-infected persons living in the United States; however, only approximately 40% of are retained in care. This has profound impact on patient and population level HIV prevention and treatment outcomes. Furthermore, due to the growing numbers of persons living with HIV, the demand for HIV care providers is greater than ever, though the HIV workforce appears to be declining. Accordingly, part of the National HIV/AIDS Strategy calls for innovative strategies to diversify and strengthen the HIV provider workforce in order to meet the growing unmet need while improving access to HIV care for those infected. This is of particular importance in communities disproportionately affected by HIV, especially those in medically underserved urban and rural settings. Through provision of pharmaceutical care, pharmacists have long played a key role in optimizing treatment and care for HIV-infected individuals, most often in the setting of specialty HIV clinics. A novel approach to expand the role of pharmacists in the community setting is to develop a patient-centered HIV care model in which community pharmacists provide HIV medication therapy management (MTM) in partnership with medical clinical sites.
This three-year project, initiated through a public-private partnership between the Centers for Disease Control and Prevention (CDC) and Walgreens and led by Dr. Patrick Clay at the University of North Texas Health Science Center, will follow 1,000 HIV-infected participants nationwide, of which at least 15 percent are from rural communities. These participants will be recruited from at least 10 HIV primary care clinics, each of which has partnered with select Walgreens pharmacies where specially trained pharmacists will provide individualized care known as MTM. In addition to standard HIV care by their medical provider, patients enrolled in the study will also receive regularly scheduled MTM visits with the pharmacists over 18-24 months. Pharmacists and medical providers will collaborate to provide HIV treatment and care.
Through development and implementation of this novel patient-centered HIV care model, the project team aims to identify optimal communication patterns between pharmacists and medical providers that increase retention in HIV care, adherence to HIV and non-HIV medication therapy, and HIV viral load suppression, as well as decrease medical care costs.
The project team also includes collaborators from HealthHIV, Northwestern University, University of Nebraska Medical Center, University of Minnesota, University of Kentucky, and the American Pharmacists Association.
Project PI (@UNTHSC):
Patrick Clay, PharmD, FCCP, CCTI
Kristin Darin, PharmD
Approximately 2-4 million of the 33 million people living with HIV worldwide are co-infected with chronic Hepatitis B (HBV)1. In Nigeria and other parts of sub-Saharan Africa, where HBV is endemic, prevalence rates of HBV among HIV infected individuals range from 6-20%2, 3, 4. HIV and HBV have an uneasy co-existence. In developed countries, patients with HIV/HBV co-infection have been shown to have higher rates of liver-related complications than patients with HBV and HIV mono-infection5, 6 and liver disease secondary to viral hepatitis is now the leading cause of morbidity and mortality among HIV-infected individuals7, 8.
This study, entitled “An Assessment of Liver Disease in HIV/HBV Co-Infected Nigerians,” is a National Institutes for Health Fogarty supplement and will be assessing the prevalence of liver fibrosis and cirrhosis among ART naïve, HIV-infected individuals with and without Hepatitis B co-infection who are enrolled in an HIV Care and Treatment Program in Jos University Teaching Hospital (JUTH) in Nigeria. Nigeria has a high prevalence of HIV and Hepatitis B and subsequent liver disease, making this a vital area of study. The study will be the first of its kind to use the Fibroscan® technique to assess the degree of liver damage. The Fibroscan® uses pulse-echo ultrasound to follow propagation of an elastic shear wave through the liver tissue, and measures liver stiffness in a volume of liver that is much greater than that obtained from liver biopsy. The technique, performed much like an ultrasound is easily learned, quick to perform, and acceptable to patients. Fibroscan® has shown excellent diagnostic accuracy when compared to liver biopsy for hepatic fibrosis and cirrhosis and has been proposed as an alternative to liver biopsy making it a highly attractive for resource-limited settings.
1 Report UG. http://data.unaids.org/pub/Report/2009/jc1736_2008_ annual_report_en.pdf (12 October 2009, date last accessed
2 Lai CL, Ratziu V, Yuen MF, et al. Viral hepatitis B. Lancet 2003;362:2089-94.
3 Harania RS, Karuru J, Nelson M, et al. HIV, hepatitis B and hepatitis C co-infection in Kenya. AIDS 2008; 22:1221-2.
4 Hoffman CJ Charalambous S, Martin DJ, et al. Hepatitis B virus infection and response to antiretroviral therapy (ART) in a South African ART program. Clin Infect Dis. 2008; 47:1479-85.
5 Puoti M, Torti C, Bruno R, et al. Natural history of chronic hepatitis B in co-infected patients. J Hepatol 2006; 44:S65-70.
6 Sulkowski MS, Thomas DL, Chaisson RE, et al. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000; 283:74-80
7 Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 32:492-7.
8 Palella Jr FJ, Baker RK, Moorman AC, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006; 43:27-34.
Jos University Teaching Hospital (JUTH)
Dr. Rob Murphy
Dr. Claudia Hawkins (Northwestern University)
Dr. Oche Agbaji (JUTH)
Northwestern University’s Center for Global Health participates on the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) in Nigeria and Tanzania, which is funded by the U.S. Department of Health and Human Services (DHHS) through a grant awarded to the Harvard School for Public Health. The Center’s role in the PEPFAR project involves:
- Education and training
- Supply chain management
- Clinical oversight
Education & Training
Human capacity building activities are an important aspect of all development projects. The goal is to enhance the skills of the host-country health workers, enabling them to better serve the people of their country. Faculty and staff from the Center for Global Health collaborate with the in-country clinical team to conduct approximately eight workshops per year in Nigeria, each lasting 3-5 days. The topics of these trainings are dependent on the needs of the partner institutions. Examples of past trainings include Basic and Advanced Antiretroviral Training, Basic and Advanced Pharmacy Training, HIV-TB co-infection, HIV-Hepatitis co-infection, Neurologic manifestations in patients infected with HIV, Prevention of Mother to Child Transmission (PMTCT) and Pediatrics. To ensure the effectiveness of trainings, the Center administers pre- and post-tests to determine whether participants are retaining the information and whether a participant can move to the next level of training. Ultimately, the participants of such trainings return to their home institution and provide step-down training to their colleagues.
Supply Chain Management
The Center for Global Health liaises with in-country personnel to conduct supply chain management activities for all HIV drugs and capacity building in this area. There are approximately 55,000 adult and pediatric patients that currently receive antiretroviral therapy at one the host-country clinics affiliated with this PEPFAR program. Two of the Center for Global Health’s pharmacologists, Dr. Kristin Darin and Dr. Kim Scarsi, project out drug needs, coordinate the ordering of these drugs, and monitor their effective delivery. They also conduct clinical oversight to ensure that prescriptions are accurately prescribed and administered according to program clinical guidelines.
As Clinical Consultant to the MDH HIV Care and Treatment Program in Tanzania, Dr. Claudia Hawkins provides clinical and technical oversight to program, advising specifically in the areas of ART, PMTCT/Pediatrics, TB/HIV and Quality Improvement. She facilitates regularly in National ART Trainings and Advanced level and specialty trainings.
The Center for Global Health conducts retrospective analyses and operational research on antiretroviral therapies and regimen comparisons in both Nigeria and Tanzania. The databases that the Center uses arebuilt and implemented by the Harvard School of Public Health, the prime awardee of the PEPFAR project in Nigeria. The Center for Global Health analyzes this data to study health outcomes for different drugs and regimens.
See the posters that were presented at the 2010 International AIDS Conference in Vienna:
- Clinical and virologic outcomes of six first-line regimens in a large ART program in Nigeria
- TDF-3TC-NVP is Inferior to AZT-3TC-NVP in a Large ART Program in Nigeria
President's Emergency Plan for AIDS Relief (PEPFAR) initiative funded through the Department of Health and Human Services (DHHS).
Nigeria and Tanzania
Harvard School of Public Health (HSPH)
Key Partner in Nigeria:
AIDS Prevention Initiative in Nigeria (APIN)
Key Partner in Tanzania:
Management for Development and Health (MDH)
Dr. Phyllis Kanki, HSPH
Dr. Robert L. Murphy
- Dr. Babafemi Taiwo
- Dr. Chad Achenbach
- Dr. Kristin Darin
- Dr. Claudia Hawkins
- Dr. Kim Scarsi