The Candidate: This is an application for a K01 award for Dr. Ana-Claire Meyer, a neurologist at theUniversity of California, San Francisco. Dr. Meyer is establishing herself as a young investigator focused onpatient-oriented clinical research on infectious diseases of the nervous system in resource-limited settings. Dr.Meyer will obtain additional research training through coursework, tutorials and practical experience in thefollowing areas: applying state-of-the-art research and laboratory methods in tropical medicine,neurophysiology, neuropsychology and neurovirology to global health settings; designing and implementingclinical trials; and additional training in implementation science and global health. With this award, she willobtain the didactic training and mentored clinical research experience she needs to establish herself as anindependent researcher and successfully compete for R01 funding. This K01 award will enable Dr. Meyer totake the next steps to achieve her long-term career goal: to become a leading researcher developing,evaluating, and implementing innovative and cost-effective interventions to diagnose and treat neurologicconditions in resource limited settings such as sub-Saharan Africa. The Environment: To support her career objectives and research plan, Dr. Meyer has assembled amultidisciplinary mentoring committee comprised of senior clinical investigators who will provide addedexpertise in conducting clinical, epidemiological, and translational research on HIV-associated neurocognitivedisorders within an international collaborative. Her primary mentor is Dr. Richard W. Price, and her co-mentorsare Drs. Gretchen Birbeck and Craig Cohen. Her developing country mentor will be Dr. Elizabeth Bukusi. Her home institution, the University of California San Francisco (UCSF), is considered one of thenation's premier health sciences, training, and research centers and has a well-established reputation inbiomedical research. The Department of Neurology is a leading academic center dedicated to excellence inpatient care, education and research. The HIV Neurology Research Program conducts clinical and basicscience research on the effects of HIV on the nervous system and includes active collaborations with clinicalHIV, virology and immunology programs. Her international collaborative site, Family AIDS Care and EducationServices (FACES), is an HIV/AIDS care and treatment program based in Kenya. FACES currently providesHIV care in 83 facilities in Nyanza Province and Nairobi. As of December 31, 2010, FACES had 96,821patients cumulatively enrolled with 37,310 patients on ART. FACES clinical sites have previous experiencewith research studies. In addition, FACES sites are staffed by well-trained clinicians and ancillary staff andhave the necessary infrastructure and oversight to complete this study. Research Plan: We estimate that HIV-associated neurocognitive disorders (HAND) may affect nearly188,000 individuals in Nyanza Province, Kenya, 5.5 million across sub-Saharan Africa, and 8.25 millionworldwide. HAND has been associated with poor adherence to antiretroviral therapy (ART) and with highermortality. Combination ART is the most effective treatment for HAND to date and some studies havesuggested that ART with higher penetration into the central nervous system (CNS) lead to improved neurologicoutcomes. However, these studies have important limitations and thus there is insufficient evidence torecommend ART with high CNS penetration effectiveness (CPE) for the treatment of HAND. The objective ofthis application is to determine whether it is important to treat HIV-infected individuals with neurocognitivedisorders with ART with high CPE. Because of limited ART choices in Kenya, we will be able to directlycompare the effects of specific ART regimens thus avoiding the limitations of prior studies. The centralhypothesis is that, among individuals with HAND, ART with high CPE lead to improved neurologic outcomes ascompared to ART with low CPE. We will enroll a prospective observational cohort of 200 HIV-infected ART-na ve adults with HIV-associated cognitive impairment.
Aim 1 : To determine the effect of common ART regimens with different CNS pharmacokinetics on theneuro-psychological performance of ART-na ve HIV infected adults with cognitive impairment in western KenyaOver a follow-up period of 48 weeks, we will determine the effect of four ART regimens on three NP measures:a composite score, the QNPZ-4, and level of impairment using common diagnostic criteria.
Aim 2 : To determine the effect of common ART regimens with different CNS pharmacokinetics on viralreplication and inflammation in the cerebrospinal fluid (CSF) of ART-na ve HIV infected adults with cognitiveimpairment in western KenyaIn a sub-sample of 100 individuals, we will determine the effect of ART regimens on: (1) CSF HIV-1 RNA; (2)CSF:plasma HIV-1 RNA ratio; (3) CSF WBC count; (4) CSF neopterin. We will also create a unique repositoryof samples for future collaborative studies.
Aim 3 : To determine whether there is a practice effect on the neuropsychological test batteryWe will re-administer our NP battery to 100 HIV un-infected individuals who we have previously studied.
These specific aims logically build toward an R01 to determine the effect of ART on combined systemic andneurologic outcomes in cognitively impaired individuals in a randomized controlled trial.

Public Health Relevance

A better understanding of which antiretroviral therapies lead to the greatest improvementsin cognition among individuals with HIV-associated neurocognitive disorders could help physicians better tailorantiretroviral therapy. Ultimately; this could lead to improved cognition; functional status and health forindividuals with HIV-associated neurocognitive disorders.

National Institute of Health (NIH)
Fogarty International Center (FIC)
Research Scientist Development Award - Research & Training (K01)
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Special Emphasis Panel (ZRG1-AARR-H (55))
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Jessup, Christine
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Yale University
New Haven
United States
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Meyer, Ana-Claire (2014) Neurology and the Global HIV Epidemic. Semin Neurol 34:70-7
Meyer, Ana-Claire; Jacobson, Mark (2013) Asymptomatic cryptococcemia in resource-limited settings. Curr HIV/AIDS Rep 10:254-63
Kendi, Caroline; Penner, Jeremy; Koech, Julius et al. (2013) Predictors of outcome in routine care for Cryptococcal meningitis in Western Kenya: lessons for HIV outpatient care in resource-limited settings. Postgrad Med J 89:73-7
Meyer, A-C L; Kendi, C K; Penner, J A et al. (2013) The impact of routine cryptococcal antigen screening on survival among HIV-infected individuals with advanced immunosuppression in Kenya. Trop Med Int Health 18:495-503