CROI 2019 Abstract eBook

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Poster Abstracts

University of Cincinnati, Cincinnati, OH, USA Background: The US is in the midst of a major drug epidemic fueled in large part by the widespread recreational use of synthetic opioids such as fentanyl. Unfortunately, medications approved for the treatment of opioid use disorders (OUD) are underutilized and/or not offered in many settings. Thus, persons with OUD are at significant risk for transmission of the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). Moreover, commonly abused substances can antagonize immune responses and promote viral replication. However, the impact of synthetic opioids on virus replication has never been explored. Methods: We evaluated the impact of fentanyl using in vitro systems that replicate infectious viruses. Fentanyl was available as a highly purified analytical reference standard and used at concentrations of 1 ng, 100 ng, and 10 ug. Viral protein synthesis was quantified by ELISA, while apoptosis and cell death were measured by M30 or MTT assays, respectively. HCV replicative fitness was evaluated in a luciferase-based system. RNAseq was conducted to evaluate cellular gene regulation in the presence of fentanyl. Results: Low dose fentanyl had no impact on HCV replication in Huh7.5 ... JFH1 hepatocytes; however, higher doses significantly enhanced HCV replication. In the HepG2.2.15 hepatocyte cell line, fentanyl caused a dose-dependent increase in HBV replication, although the same low dose that caused increased HCV replication had a minimal effect on HBV. A dose-dependent increase in HCV replicative fitness was observed in the presence of fentanyl. Similarly, fentanyl increased HIV replication in two lymphocyte cell lines. Addition of fentanyl resulted in significant accumulation of soluble caspase-cleaved keratin 18 – a product of apoptosis – in two hepatocyte cell lines. Cell death was minimal at low drug concentrations. RNAseq identified a number of hepatocyte genes that were up or down regulated after fentanyl exposure including those related to apoptosis, viral gene expression, hepatocarcinogenesis, and NFΚB. Conclusion: Collectively, these preliminary data suggest that synthetic opioids promote viral replication but may have distinct effects depending on the drug dose and the viral target. As higher viral loads are associated with pathogenesis and virus transmission, additional research is essential to an enhanced understanding of opioid-virus pathogenesis and for the development of new and optimized treatment strategies. 619 A DECISION-TREE ANALYSIS FOR HEPATITIS A IMMUNITY AMONG HIV- INFECTED MSM IN TOKYO Tomohiko Koibuchi 1 , Michiko Koga 1 , Tadashi Kikuchi 2 , Lay Ahyoung Lim 1 , Hidenori Sato 1 , Eisuke Adachi 1 , Takeya Tsutsumi 1 , Hiroshi Yotsuyanagi 1 1 University of Tokyo Institute of Medical Science, Tokyo, Japan, 2 National Institute of Infectious Diseases, Tokyo, Japan Background: Japan has very low endemicity for hepatitis A virus (HAV), and the prevalence of anti-HAV among general population aged < 50 years is < 5 %. However, the level of HAV immunity among HIV-infected patients in Japan is unknown. The epidemiology of HAV infection among HIV-infected men who have sex with men (MSM) is essential for an HAV vaccination program. Methods: We examined the presence of IgG-HA antibody among HIV-infected patients from January 2017 to December 2017 in IMSUT Hospital, the University of Tokyo. Epidemiological data, including age, sex, mode of HIV transmission, year of HIV diagnosis, HAV vaccine status, previous HAV infection and other infectious disease status (hepatitis B, hepatis C and syphilis), were recorded. A decision tree algorithm (data-mining technique) was used to reveal factors and profiles most relevant to the prevalence of anti-HAV for further investigation. Results: In total 468 HIV-infected patients were examined for the presence of IgG-HA antibody. Of these, 459 patients (male, 438; female; 21) had both HAV vaccine status and previous HAV infection. The mode of HIV transmission among male patients were as follows: MSM, 378; heterosexual, 47; contaminated blood (hemophilia), 4; unknown, 9. After excluding 24 MSM patients who were receiving HAV vaccine, data from 354 MSM patients were used for analysis (median age, 45 years. IQR, 39-51). Of 354 MSM patients, 60 (16.9 %) were IgG-HA antibody positive. Median age was significantly higher in the HA positive group than in the negative group (50 vs. 44 years; P< 0.001). The prevalences of hepatitis B core antibody and treponemal antibody were significantly higher in the HA positive group than in the negative group (71.7% vs. 57.1%; P=0.037 and 75.0% vs. 57.8%; P=0.013, respectively). Patient age > 63.5 years was the first variable in the initial classification of the decision-tree algorithm, and year of HIV diagnosis was the second-division variable for HAV immunity (Figure).

617 FENTANYL USE AND LIVER DISEASE IN THE MIAMI ADULT STUDIES ON HIV (MASH) COHORT Marianna K. Baum 1 , Kenneth E. Sherman 2 , Qingyun Liu 1 , Gustavo G. Zarini 1 , Sabrina S. Martinez 1 , Leslie Seminario 1 , Jupshy Jasmin 1 , Jacqueline Hernandez 1 , Colby Teeman 1 , Javier Tamargo 1 , Nathalie Jaspar 1 , Priscilla K. Clayton 1 , Pedro J. Greer 1 , Jag H. Khalsa 3 , Adriana Campa 1 1 Florida International University, Miami, FL, USA, 2 University of Cincinnati, Cincinnati, OH, USA, 3 National Institute on Drug Abuse, Rockville, MD, USA Background: Human immunodeficiency virus (HIV) infection continues to be associated with liver disease, one of the major causes of morbidity and mortality in these patients. Substance abuse decreases adherence to antiretroviral therapy and increases risk for liver injury. Fentanyl is a synthetic opioid clinically used in anesthesia and management of chronic pain, recently mixed with heroin and cocaine, and ingested unintentionally. Fentanyl overdose leads to respiratory depression, brain damage and death; its effect on liver is not known. Methods: Participants from the Miami Adult Studies on HIV (MASH) cohort were tested for fentanyl using BNTX Rapid Response TM fentanyl urine strip tests at a detection level of 40 ng/ml norfentanyl. Cocaine and heroin use were determined with questionnaires and confirmed with urine toxicology. Alcohol consumption was determined with Alcohol Use Disorders Identification Test (AUDIT). HIV infection, lack of hepatitis B and C coinfections, CD4 count and HIV viral load were documented frommedical charts. FIB-4, a non-invasive measure of liver fibrosis, was calculated, and FIB-4 value of >1.45 was used as the cutoff to determine presence or absence of meaningful (moderate-severe) hepatic fibrosis. Statistical analyses included descriptive statistics and logistic regression performed with SAS 9.4. Models were adjusted for age, gender, BMI, AUDIT score>8, and HIV infection. Results: Data were analyzed on a subsample of MASH cohort participants who were HIV infected (N=305, CD4 count mean 610.21cells/μL±362.06 SD, mean HIV viral load =2.58 log 10 ±1.24 SD) or HIV uninfected (N=267). Mean age was 54.05years±8.28 SD; 60.03%were males, 62.16% Black and 22.93% Hispanic. Logistic regression indicated a significant association between the use of fentanyl and liver fibrosis (FIB-4>1.45), adjusted OR= 5.195 (95% CI 2.051,13.159, p=0.0005). When participants who were frequent users of cocaine and heroin were removed from the analyses, fentanyl continued to be associated with liver fibrosis (FIB-4>1.45), adjusted OR=4.76 (95% CI 1.67-13.56, P=0.0035). In addition, HIV infection status was significantly associated with FIB-4>1.45, adjusted OR=2.25 (95% CI 1.27-3.98, P=0.0056). Conclusion: These data indicate that misuse of fentanyl among substance users in the MASH cohort may be associated with development of hepatic fibrosis. Strategies to identify risk and understanding of aberrant drug-related behaviors and treatments are needed. 618 THE SYNTHETIC OPIOID FENTANYL ENHANCES VIRAL REPLICATION IN VITRO Jason T. Blackard , Susan D. Rouster, Mohamed Tarek M. Shata, Kenneth E. Sherman, Ling Kong

Poster Abstracts

CROI 2019 234