DESCRIPTION (provided by applicant): The recently completed, R21 funded, Cohort of HIV-Associated Seizures and Epilepsy (CHASE) Study, enrolled 95 urban adults with HIV and new onset seizure, delineated the seizure etiology, and provided preliminary insight into the incidence of and risk factors for epilepsy development in this population. CHASE also examined the feasibility of using a cohort study design to identify the clinically relevant consequences of combining antiretroviral medications (ARVs) and the enzyme-inducing antiepileptic drugs (EI-AEDs) used in most of sub-Saharan Africa. CHASE R21 study findings have significantly contributed to the limited body of literature on this population and have informed the design of this R01 application. In this R01, we will pursue the plan delineated in the R21 to expand the CHASE cohort study to include rural and pediatric populations. We will enroll 300 additional participants (100 each; urban children, rural children and rural adults) and follow them for at least 24 months to determine the incidence of recurrent seizure and/or death. Study assessments to identify risk factors for adverse outcomes will include routine cerebrospinal fluid (CSF) evaluations, baseline neuropsychiatric screening, and CSF HIV viral load as well as CSF PCR analyses for opportunistic infections. Brain MRIs and EEGs will be obtained in the urban participants and all children will undergo quarterly neurodevelopmental assessments. In addition, an exposure-control study of people with epilepsy and HIV on ARVs and EI-AEDs will be completed to assess whether this common drug combination leads to ARV resistant HIV. Chikankata Hospital, where a dedicated Epilepsy Care Team has provided services since 2000, will serve as the headquarters for the Rural Consortium and the study site for the exposure-control study. Capacity building activities will include professional development for two junior Zambian academics (a pediatrician and a neuropsychologist), three Zambian MRI technologists, and the CHASE grants administrators. In addition, a postgraduate residency training curriculum in Radiology with a prominent Neuroradiology component will be established through clinical rotations in the US, Zambia and Malawi. A Zambian medical school graduate will complete the Radiology Residency and segue seamlessly into a Zambian faculty position during this R01 to provide expertise locally. This work will yield critical insights into the epidemiology of seizure disorders among people with HIV in a large, sub-Saharan African country as well as identify the clinically relevant consequences of the co-usage of ARVs and IE-AEDS, thus providing clinicians caring for HIV+ individuals who experience a seizure with the evidence needed to decide whether/when to initiate AEDs. The CHASE R01 will also inform policy makers regarding the need (or not) to make alternative drug regimen available to people requiring dual treatment for HIV and epilepsy. Finally, as with the R21-funded CHASE efforts, this work may identify `gaps' in care quality that inform priorities for health service improvement to benefit this population.

PUBLIC HEALTH RELEVANCE: As a consequence of the wide availability of antiretroviral therapy, HIV disease in sub-Saharan Africa is evolving from a fatal infection into a chronic condition. Caring for people with HIV/AIDS who also suffer from non-communicable disorders, such as epilepsy, is challenging because clinicians do not have sufficient knowledge to know what treatments are best when these disorders coexist. This prospective study of HIV+ Zambians will expand our R21-funded epidemiologic study of new onset seizures in urban adults to include rural and pediatric populations, provide us with important insights into when chronic treatment for seizures is needed, and examine whether combining antiretroviral medications with the older generation epilepsy medications still used in most resource poor settings increases the risk of drug resistant HIV.