Advances in treatment have transformed HIV disease to a chronic illness in most individuals in the U.S. The most common central nervous system (CNS) complication of chronic HIV disease is HIV-associated neurocognitive disorder (HAND). In the U.S., HAND prevalence estimates range up to 55% of treated individuals. HAND is also common outside the U.S. For example, our current project in China identified that more than a third of nearly 150 treated HIV (+) individuals in Anhui and Yunnan provinces had HAND. Data such as these support that the benefits of antiretroviral therapy (ART) can be incomplete, with many patients not returning to normal neurocognitive performance or, worse, developing new neurocognitive impairment while taking ART. One explanation for this is the limited penetration of some antiretrovirals into the nervous system. Recent reports have identified that worse antiretroviral penetration characteristics are associated with worse control of HIV replication and worse neurocognitive performance. Most reports, however, have focused on treatment - rather than prevention - of HAND. Like many other medical conditions, prevention of HAND may be a more cost-effective public health goal than treating disease that has already occurred. We propose to build on our prior work in China by performing a phase IV, randomized, controlled clinical trial of the safety and effectiveness of ART that differs in its penetration characteristics in 250 ART-naive individuals who have normal neurocognitive performance. The primary objective will be to determine the effects of better penetrating (BP) ART (zidovudine-lamivudine-nevirapine) compared with worse penetrating (WP) ART (tenofovir-lamivudine-efavirenz) on the prevention of HAND. We hypothesize that volunteers who are randomized to BP-ART will be less likely to neurocognitively decline over 96 weeks of observation than those who are randomized to WP-ART. The secondary objective will be to assess the influence on study outcomes of two conditions: persistent immune activation and viral hepatitis. In an exploratory aim, the project will also assess the influence on study outcomes of a concise panel of drug disposition-associated genetic polymorphisms. Demonstrating that HAND can be prevented by using BP-ART should influence HIV treatment guidelines in the U.S., China, and elsewhere and ultimately lead to preservation of normal neurocognitive functioning in people afflicted with HIV/AIDS.

Public Health Relevance

The project proposes to demonstrate that HAND can be prevented by using better penetrating antiretroviral therapy, which should influence HIV treatment guidelines in the U.S., China, and elsewhere and ultimately lead to preservation of normal neurocognitive functioning in people afflicted with HIV/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH092225-02
Application #
8111860
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Colosi, Deborah
Project Start
2010-07-15
Project End
2015-03-31
Budget Start
2011-06-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$533,855
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Obermeit, Lisa C; Beltran, Jessica; Casaletto, Kaitlin B et al. (2017) Evaluating the accuracy of self-report for the diagnosis of HIV-associated neurocognitive disorder (HAND): defining ""symptomatic"" versus ""asymptomatic"" HAND. J Neurovirol 23:67-78
Curley, Paul; Rajoli, Rajith K R; Moss, Darren M et al. (2017) Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico, In Vitro, and In Vivo Investigation. Antimicrob Agents Chemother 61:
Fazeli, Pariya L; Moore, David J; Franklin, Donald R et al. (2016) Lower CSF A? is Associated with HAND in HIV-Infected Adults with a Family History of Dementia. Curr HIV Res 14:324-30
Day, Tyler R C; Smith, Davey M; Heaton, Robert K et al. (2016) Subtype associations with HIV-associated neurocognitive disorder in China. J Neurovirol 22:246-50
Ma, Qing; Vaida, Florin; Wong, Jenna et al. (2016) Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. J Neurovirol 22:170-8
Anderson, Albert M; Harezlak, Jaroslaw; Bharti, Ajay et al. (2015) Plasma and Cerebrospinal Fluid Biomarkers Predict Cerebral Injury in HIV-Infected Individuals on Stable Combination Antiretroviral Therapy. J Acquir Immune Defic Syndr 69:29-35
Hong, Suzi; Banks, William A (2015) Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications. Brain Behav Immun 45:1-12
Gupta, Saurabh; Iudicello, Jennifer E; Shi, Chuan et al. (2014) Absence of neurocognitive impairment in a large Chinese sample of HCV-infected injection drug users receiving methadone treatment. Drug Alcohol Depend 137:29-35
Tatro, Erick T; Soontornniyomkij, Benchawanna; Letendre, Scott L et al. (2014) Cytokine secretion from brain macrophages infected with human immunodeficiency virus in vitro and treated with raltegravir. BMC Infect Dis 14:386
Grant, Igor; Franklin Jr, Donald R; Deutsch, Reena et al. (2014) Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology 82:2055-62

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