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Principal Investigator: JASON T BLACKARD
Organization: UNIVERSITY OF CINCINNATI
Fiscal Year: 2024
Award: $697,172
Funding agency: National Institute on Alcohol Abuse and Alcoholism
Abstract
HIV/AIDS continues to be a major global health issue, and chronic liver disease has become a major cause of
HIV-mortality. Several contributing factors are recognized including hepatotoxicity of anti-HIV drugs,
coinfection of hepatitis viruses and widespread alcohol use. The likelihood of concurrent use of other addictive
substances such
as fentanyl is high. Excessive alcohol use has been linked directly to increased HIV viral
load, engagement in HIV-risk behaviors, and poor adherence in HIV prevention interventions. In addition,
alcohol and fentanyl are known to alter the functionality of drug metabolizing enzymes and transporters, critical
determinants for the efficacy and safety of anti-HIV drugs. Indeed, we have shown that ethanol (alcohol)
exposure decreased the hydrolysis of
tenofovir alafenamide fumarate (TAF) and produced a new metabolite:
ethyl TAF. This metabolite is a hybrid molecule with part from TAF and part from ethanol. TAF is a new
version of TDF (tenofovir disoproxil fumarate) with decreased organ toxicity, and both tenofovir prodrugs are
hydrolyzed and followed by phosphorylation to produce therapeutically active metabolite. TAF is hydrolyzed by
carboxylesterase-1 (CES1), while TDF is hydrolyzed predominantly by CES2. TAF and TDF are listed in
~75% anti-HIV regimens used for both pre-exposure prophylaxis
(PrEP) and treatment as prevention
(TasP). Our Preliminary Study has also shown that fentanyl increased the expression of chemokine co-
receptors and led to increased HIV infection. The central hypothesis of this project is that metabolism-based
interactions of tenofovir drugs with alcohol +/- fentanyl produce signature changes that reliably indicate efficacy
and safety of tenofovir regimens and serve as a foundation for developing adherence-monitoring and
PrEP/TasP intervention strategies. The Specific Aims are: (1) to characterize metabolite signatures and
mechanistic biomarkers, and (2) to ascertain the significance of alcohol +/- fentanyl-altered metabolism. To
determine the metabolite signatures specific to alcohol +/- fentanyl, human primary hepatocytes and peripheral
blood mononuclear cells (PBMCs)
will be treated with a tenofovir-regimen in the presence or absence of
alcohol (+/- fentanyl); the metabolite signatures will be determined by LC-MS/MS. The altered metabolite
signatures will be ascertained by in vivo studies. Transcriptome analysis will be performed at both tissue (e.g.,
PBMC) and single cell level (selected samples) to identify mechanistic biomarkers. To establish the
significance, hepatocytes and PBMCs will be incubated with a tenofovir-regimen with or without alcohol +/-
fentanyl, and viral load and cytotoxicity will be monitored. The connection of metabolite signatures and
biomarkers with efficacy and safety will be ascertained in vivo. Finally, PBMCs from HIV-negative patients
exposed to PrEP, PrEP+alcohol or PrEP+alcohol/fentanyl will be tested against HIV infection ex vivo. The
combination of in vitro, ex vivo, and in vivo study design ensures high scientific rigor.
Terms: <AIDS><AIDS Virus><AIDS drugs><AIDS prevention><AIDS/HIV><Absolute ethanol><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Actiq><Adherence><Alcohol Chemical Class><Alcohol Drinking><Alcohol abuse><Alcohol consumption><Alcohols><Ali-esterase><Anti-AIDS Agents><Anti-AIDS Drugs><Anti-HIV Agents><Anti-HIV Drugs><Anti-Human Immunodeficiency Virus Agents><Anti-viral Response><Apoptosis><Apoptosis Pathway><B-esterase><Behavior><Behavioral><Biological Markers><Body Tissues><CAP-hydrolyzing Enzyme><CES1><Capsaicin-Hydrolyzing Enzyme><Carboxyesterase><Carboxylate Esterase><Carboxylester Lipase><Carboxylesterase 1><Carboxylesterase B><Carboxylesterases><Carboxylic Ester Hydrolase><Carboxylic Ester Hydrolases><Cell Body><Cells><Cessation of life><Chemotactic Cytokines><Death><Diphosphates><Drug Precursors><Drugs><Duragesic><ETOH><Ensure><Enzyme Gene><Enzymes><Epidemic><Esterification><EtOH abuse><EtOH drinking><EtOH use><Ethanol><Ethyl Alcohol><Exposure to><Fentanest><Fentanyl><Fentyl><Foundations><Free Radicals><Fumarates><General Population><General Public><Goals><Grain Alcohol><HIV><HIV Infections><HIV Prevention><HIV Seronegativities><HIV Seronegativity><HIV negative><HIV risk><HIV/AIDS><HIV/AIDS prevention><HTLV-III Infections><HTLV-III Seronegativities><HTLV-III Seronegativity><HTLV-III-LAV Infections><Health><Hepatic Cells><Hepatic Parenchymal Cell><Hepatitis Viruses><Hepatocyte><Hepatotoxic effect><Hepatotoxicity><Homologous Chemotactic Cytokines><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Hybrids><Hydrolysis><In Vitro><Incubated><Individual><Injections><Intercrines><Intermediary Metabolism><Intervention><Intervention Strategies><Isocarboxazid amidase><LAV-HTLV-III><Link><Liver Cells><Liver Toxicity><Lymphadenopathy-Associated Virus><Lytotoxicity><Medication><Medicine><Metabolic Processes><Metabolism><Methylcarbinol><Modern Man><Monitor><Naproxen Esterase><Non-specific Carboxylesterase><Non-specific Esterase><Nonspecific Esterase><Ohio><Organ><Oxidative Stress><PBMC><Patients><Peripheral Blood Mononuclear Cell><Persons><Pharmaceutical Preparations><Phentanyl><Phosphorylation><PrEP><Prevalence><Preventative intervention><Prevention><Pro-Drugs><Procaine Esterase><Prodrugs><Programmed Cell Death><Protein Phosphorylation><Pyrophosphates><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Regimen><Research Design><Risk><Risk Behaviors><Risky Behavior><SIS cytokines><Safety><Sampling><Study Type><Technology><Tenofovir><Testing><Therapeutic><Time><Tissues><Toxic effect><Toxic effect on liver cells><Toxicities><Viral Burden><Viral Load><Viral Load result><Viral hepatitis><Viread><Virus-HIV><alcohol co-abuse><alcohol ingestion><alcohol intake><alcohol problem><alcohol product use><alcohol use><alcohol use disorder><alcoholic beverage consumption><alcoholic drink intake><antiAIDS agent><at risk behavior><bio-markers><biologic marker><biomarker><biomarker validation><carboxylesterase><chemoattractant cytokine><chemokine><chronic hepatic disease><chronic hepatic disorder><chronic liver disease><chronic liver disorder><co-infection><coinfection><cytotoxicity><design><designing><drug metabolism><drug/agent><ethanol abuse><ethanol consumption><ethanol drinking><ethanol ingestion><ethanol intake><ethanol product use><ethanol use><ethanol use disorder><global gene expression><global health><global transcription profile><hazardous alcohol use><hepatic toxicity><hepatitis virus infection><hepatoxicity><high risk><in vivo><intervention for prevention><interventional strategy><marker validation><mortality><multidisciplinary><opiate deaths><opiate mortality><opioid deaths><opioid mortality><opioid overdose death><opioid related death><originality><pre-exposure prophylaxis><prevention intervention><preventional intervention strategy><preventive intervention><problem alcohol use><problem drinking><problematic alcohol consumption><problematic alcohol use><receptor><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><stem><study design><substance use><substance using><synthetic opiate><synthetic opioid><transcriptome><transcriptome sequencing><transcriptomic sequencing><transcriptomics><treatment adherence><treatment as prevention><treatment compliance><treatment-based prevention><virology>