CROI 2019 Abstract eBook

Abstract eBook

Oral Abstracts

90 HIV VIREMIA AND LOW CD4+ INCREASE HCC RISK IN THOSE WITHOUT ADVANCED LIVER FIBROSIS Jessie Torgersen 1 , Michael J. Kallan 1 , Dena M. Carbonari 1 , Jason A. Roy 2 , Lesley S. Park 3 , Tamar Taddei 4 , Rajni Mehta 4 , Kathyrn D’Addeo 4 , Joseph Lim 4 , Matthew B. Goetz 5 , Janet Tate 4 , Norbert Bräu 6 , Amy C. Justice 4 , Vincent Lo Re 1 1 University of Pennsylvania, Philadelphia, PA, USA, 2 Rutgers University, Piscataway, NJ, USA, 3 Stanford University, Stanford, CA, USA, 4 Yale University, New Haven, CT, USA, 5 University of California Los Angeles, Los Angeles, CA, USA, 6 James J. Peters VA Medical Center, Bronx, NY, USA Background: Despite rising incidence of hepatocellular carcinoma (HCC) in HIV+ patients, few studies have evaluated determinants of HCC during the antiretroviral therapy era. We evaluated HIV-related and traditional risk factors for HCC in a large cohort of HIV+ patients. Methods: We conducted a retrospective cohort study among HIV+ patients in the Veterans Aging Cohort Study from 1999-2015. Patients had HIV RNA and CD4+ cell count simultaneously assessed in the Veterans Affairs (VA) system, and follow-up began on this date. Incident HCC was determined using the VA Cancer Registry. We used multivariable Cox regression to determine adjusted hazard ratios (HR [95% confidence interval]) of HCC associated with cumulative unsuppressed HIV RNA (≥500 copies/mL), time-updated lower CD4+ count, older age, male sex, race/ethnicity, morbid obesity (body mass index ≥35 kg/m²), time-updated diabetes status, alcohol use disorder, hepatitis B virus (HBV), and hepatitis C virus (HCV) coinfection. The analysis was repeated substituting time-updated HIV RNA for cumulative unsuppressed HIV RNA. Since advanced hepatic fibrosis/cirrhosis is the strongest determinant of HCC and may overwhelm other risk factors, we stratified analyses by low and high baseline FIB-4 (<3.25 versus ≥3.25, respectively), a commonly used fibrosis index. Results: Among 36,525 HIV+ patients, 275 (0.8%) developed incident HCC. Overall, baseline FIB-4 ≥3.25 was the strongest factor associated with HCC (HR 15.1 [9.7-23.5]). However, 36.4% of HCC events occurred among those with FIB-4 <3.25. Among these patients, older age (HR 1.4 [1.2-1.7] per 10 years), morbid obesity (HR 2.6 [1.2-5.3]), diabetes (HR 1.5 [1.1-2.1]), ≥12 months of unsuppressed HIV RNA (HR 2.0 [1.4-2.9]), lower CD4+ count (200-349 cells/ mm³: HR 1.5 [1.1-2.2]; <200 cells/mm³: HR 1.6 [1.0-2.4] versus ≥500 cells/mm³), HBV coinfection (HR 5.2 [3.7-7.3]), and HCV coinfection (HR 6.1 [4.1-9.0]) were independently associated with incident HCC. The risk of HCC was also increased with higher HIV RNA level (HR 1.3 [1.1-1.4] per 1.0 log 10 copies/mL). Conclusion: Among HIV+ patients without advanced liver fibrosis, higher HIV RNA and longer duration of HIV viremia, greater immunosuppression, morbid obesity, and diabetes, in addition to HBV and HCV coinfection, increased the risk of HCC. Addressing these factors before development of advanced fibrosis could help reduce the incidence of HCC in HIV+ patients. 91LB SINGLE HEPATOCYTE ANALYSIS IN HIV-HBV COINFECTION SHOWS HBV TRANSCRIPTION SILENCING Ashwin Balagopal 1 , Hyon S. Hwang 1 , Tanner Grudda 1 , Jeffrey Quinn 1 , Richard K. Sterling 2 , Mark Sulkowski 1 , Chloe Thio 1 1 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Virginia Commonwealth University, Richmond, VA, USA Background: Hepatitis B virus (HBV) is a leading cause of liver failure and hepatocellular carcinoma worldwide. Due to shared modes of transmission, ~10% of people living with HIV also have chronic HBV infection. HBV cannot be cured because the long-lived covalently closed circular DNA (cccDNA) resides in every infected hepatocyte. However, little is known about HBV replication in human livers. Methods: Here, we used single-cell laser capture microdissection (scLCM) and droplet digital PCR (ddPCR) to characterize the HBV replication landscape in situ in humans. We quantified cccDNA, total HBV DNA, and pre-genomic RNA (pgRNA) in each hepatocyte, adjusting for intracellular cytoplasmic RNA 7SL. Results: We examined a median (range; total) 255 (52 – 290; 1100) hepatocytes that were individually isolated from five HIV/HBV co-infected persons with increasing exposure to dually-active antiretroviral therapy (DAART) against HIV and HBV (HB1-5; no exposure to >7 years of exposure). Total HBV DNA, cccDNA, and pgRNA were quantified in each cell. The proportion of infected hepatocytes (cccDNA positive) decreased with longer DAART exposure from 100% (HB1) to 33% (HB5)(Table). The median (range) total HBV DNA per cell was 1 cp/cell (0-112 cp/cell); of cccDNA was 1 cp/cell, (0-31 cp/cell); and of pgRNA was 38 cp/cell, (0-1919 cp/cell). The amounts of cccDNA, total HBV DNA, and pgRNA significantly decreased in infected cells with longer DAART

Oral Abstracts

89 INTRAHEPATIC HEPATITIS C KINETICS WITH DIRECT-ACTING ANTIVIRALS IN HIV COINFECTION Ashwin Balagopal 1 , Laura M. Smeaton 2 , Vincent Vu 2 , Charles S. Venuto 3 , Gene D. Morse 4 , Beverly Alston-Smith 5 , Daniel E. Cohen 6 , Jorge L. Santana 7 , Donald D. Anthony 8 , Mark Sulkowski 1 , David L. Wyles 9 , Andrew H. Talal 4 , for the ACTG A5335S Substudy Team 1 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Harvard University, Boston, MA, USA, 3 University of Rochester, Rochester, NY, USA, 4 University at Buffalo, Buffalo, NY, USA, 5 NIH, Rockville, MD, USA, 6 AbbVie, Inc, North Chicago, IL, USA, 7 University of Puerto Rico, San Juan, Puerto Rico, 8 Case Western Reserve University, Cleveland, OH, USA, 9 University of Colorado Denver, Denver, CO, USA Background: Direct-acting antivirals (DAA) target hepatitis C virus (HCV) proteins, dramatically improving treatment in HIV/HCV co-infection. The DAA effect in liver, however, is not well understood. We examined intrahepatic clearance of HCV. Methods: A5335S, a substudy of trial A5329 (Paritaprevir/Ritonavir, Ombitasvir, Dasabuvir, with Ribavirin) enrolled persons co-infected with HIV, suppressed HIV RNA on antiretrovirals, and chronic genotype 1 HCV without cirrhosis. Core liver biopsies were performed before and 7 days after DAA initiation, with frequent blood sampling to measure plasma HCV RNA and plasma IP-10. In liver, single-cell laser capture microdissection was used to estimate HCV-infected cells and interferon-stimulated genes (ISG) expressing cells in percentages. Plasma and liver concentrations were assessed at 2nd biopsy for all DAAs. Results: Five (3 men, 2 women; ages 40-61, 3 black, 2 Hispanic; all from US) of six enrollees completed A5335S; all were HCV treatment-naïve. Due to anemia, participant 5 delayed 2nd biopsy until treatment day 50. Mean baseline plasma HCV RNA = 6.7 log10 IU/mL; mean decrease in plasma HCV RNA after starting DAAs was -3.0 log10 IU/mL in 24 hours and -4.1 log10 IU/mL in 7 days. At 1st biopsy, HCV-infected cells were mean (range) = 27% (13-51%), and positively correlated with baseline plasma HCV RNA (Spearman rank correlation r=0.9, p<0.05; Table). At 2nd biopsy HCV-infected cells had mean (range) = 0.9% (0.4- 1.7%). The mean (range) absolute decline was 26.6% (12.4-50.1%), representing clearance of >93% of infected hepatocytes. Hepatocyte ISG expression was abundant pre-DAA [means: ISG15 22%; IFITM3 46%; IFI27 24%; IFI6 27%]: IFI27 and IFI6 decreased after DAA initiation in all participants; IFITM3 increased in 2 participants, and ISG15 increased in 1 participant. Plasma IP-10 levels rapidly declined frommean baseline = 427 pg/mL thru day 4; mean 1-week change from baseline was -296 pg/mL. Pre-dose paritaprevir concentrations from liver and plasma ranged from 1788–4228 ng/g and 6–194 ng/mL, respectively (other DAAs not shown). Conclusion: In this intensive substudy, the burden of HCV-infected hepatocytes declined rapidly, and within the first week of DAA therapy fewer than 2%were infected. Hepatocyte innate immune signals did not diminish uniformly after DAA initiation. Given assumptions of adherence, we extrapolate that HCV could theoretically be eradicated from the liver in this study sample within 63 days.

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CROI 2019