CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

HBsAg-positive individuals who had current HBV replication (>20 IU/ml) on ART and/or who were on an inadequate ART regimen. Results: Of 1.219 HIV-infected patients in active follow-up at Fann University Hospital, 873 had never been tested for HBsAg before our intervention. Their median time on ART was 9 years, and when compared with individuals previously tested, they were more likely to be female (67.7% vs. 55.5%: p<0.001) and to have a CD4 >350 cells/µL at enrollment (37.6% vs 29.5%, p=0.01). Of 449 patients tested during our intervention, 50 (11.1%) were HBsAg-positive, of whom 24 (50.0%) were female. Their median CD4 cell count at ART initiation was 153 cells/µL (interquartile range 57-234) and 2 (5.7%) had significant liver fibrosis (LSM>7 kPa). Seven (14.0%) individuals had a detectable HBV VL, of whom five were HIV suppressed. Four individuals were on ART including lamivudine and zidovudine as a backbone, and had to be switched to a TDF-containing regimen. Conclusion: In our referral HIV clinic, the majority of patients on ART had never been tested for HBV. 15% of HIV/HBV-coinfected individuals had a positive HBV VL despite HIV suppression, and 10%were not receiving a TDF-containing regimen. Considering the high risk of liver-related complication in individuals with HBV replication, HBV testing should be performed routinely during HIV clinical care. 609 LIVER FIBROSIS CHANGES OVER 3 YEARS OF TENOFOVIR-BASED ART IN HIV-HBV COINFECTION Michael J. Vinikoor 1 , Kalongo Hamusonde 2 , Shilpa Iyer 1 , Edford Sinkala 3 , Lloyd Mulenga 3 , Michael Saag 1 , Mary-Ann Davies 4 , Matthias Egger 5 , Gilles Wandeler 5 , for the IeDEA Southern Africa 1 University of Alabama at Birmingham, Birmingham, AL, USA, 2 Centre for Infectious Disease Research in Zambia, Lusaka, Zambia, 3 University of Zambia, Lusaka, Zambia, 4 Centre for Infectious Disease Epidemiology and Research, Cape Town, South Africa, 5 University of Bern, Bern, Switzerland Background: Although tenofovir-based therapy can potently reduce HBV DNA and can reverse hepatic fibrosis in HBV monoinfection, its long-term impact on clinical outcomes in HIV-HBV coinfection is not well-established and some data suggest hepatic inflammation and fibrosis persists. In Zambian HIV-HBV coinfected adults treated with antiretroviral therapy (ART), we analyzed normalization of ALT and changes in liver fibrosis, based on transient elastography (TE). Methods: We analyzed data from an active cohort of Zambian adults (18+ years) who were HIV-positive, hepatitis B surface antigen-positive, and started tenofovir-based ART. At ART start and yearly during therapy, we measured CD4, HBV DNA, ALT, and liver stiffness (LSM; based on TE). LSM were categorized as no-minimal fibrosis (<7.9 kPa; F0-1), significant fibrosis (7.9-9.5; F2-3), and cirrhosis (>9.5; F4). HBV viral suppression (VS) was defined as ≤20 IU/ml and ALT elevation was >19 U/L for women and >30 for men. We included in analysis any cohort participants with LSM at ART start and ≥1 follow-up measure. We described on-therapy HBV VS, normalization of ALT among those with baseline elevation, and regression and progression of fibrosis and cirrhosis. Results: Among 358 HIV-HBV coinfected patients enrolled, 234 were analyzed (median age, 34 years; 60.8%men). At ART start, median CD4 count was 198 cells/mm 3 , median HBV DNA was 5400 IU/ml, 81 of 183 tested (44.3%) were HBeAg-positive, 102 (47.9%) had ALT elevation, 16 (6.8%) had significant hepatic fibrosis, and 23 (9.8%) had cirrhosis. Median follow-up was 2.6 years (interquartile range, 1.7-3.8). HBV DNA suppression at 1, 2, and 3-5 years was 62.7%, 80.3%, and 84.5%. Among the 102 with ALT elevation at ART start, 50 (49.5%) had persistent elevation at their last assessment. During ART, 13 of 16 (81.2%) with significant fibrosis and 18 of 23 (78.3%) with cirrhosis experienced regression to a lower category. Five patients progressed from no-minimal to significant fibrosis (n=4) or cirrhosis (n=1) and 1 progressed from significant fibrosis to cirrhosis. The majority of patients with disease progression had evidence of both HIV and HBV VS. Conclusion: Regression of liver fibrosis and cirrhosis was common during tenofovir-based ART. Persistent ALT elevation was seen in ~20% of HIV-HBV coinfected patients, likely due to non-HIV, non-HBV-related causes such as alcohol abuse.

610 LONG-ACTING TENOFOVIR AND NITAZOXANIDE FORMULATIONS SUPPRESS HBV REPLICATION Denise A. Cobb 1 , Dhruvkumar Soni 1 , Weimin Wang 1 , Murali Ganesan 1 , Raghubendra S. Dagur 1 , Edward Makarov 1 , Yimin Sun 1 , JoEllyn McMillan 1 , Howard E. Gendelman 1 , Natalia Osna 1 , Larisa Y. Poluektova 1 , Benson Edagwa 1 1 University of Nebraska Medical Center, Omaha, NE, USA Background: To eliminate HBV infectious complete suppression of progeny virus coordinate with the elimination of infected cells must be achieved. These events can be facilitated by enhancing innate and adaptive immune responses given with antiviral therapy. We offer a new therapeutic prospective by increasing the potency of nitazoxanide (NTZ), a broad- spectrum antiviral and immune stimulating agent and tenofovir (TFV), a nucleoside reverse transcriptase inhibitor. This drug combination was transformed into hydrophobic prodrug nanocrystals, then stabilized into aqueous nanosuspensions. The modifications led to extended apparent drug half-lives, increased drug potency and improved distribution to liver cell viral compartments. Methods: NTZ and TFV prodrugs (M1NTZ and M1TAF) were synthesized and nanoformulated creating NM1NTZ and NM1TAF. Cellular drug uptake and retention was determined in human monocyte-derived macrophages (MDM). The HBV-producing human hepatocellular carcinoma HepG2.2.15 cell and humanized liver TK-NOG mice evaluated antiviral activity. HBV infected mice received a single 75 mg/kg intramuscular injection of the drugs. HBV DNA, cccDNA and HBe/sAg were monitored for 48 h and for 10 weeks in cells and animals, respectively. Results: NM1NTZ and NM1TAF had average particle sizes of 250-350 nm, polydispersity index of <0.2 and drug loading capacity of > 70%. Both formulations were taken up by MDM with sustained drug levels for 30 days; whereas native drugs were eliminated in one day. Suppression of HBV DNA release by (NM1TAF by 50%) and cccDNA pools (NM1NTZ by 88% and NM1TAF by 60%) were recorded. The combination long acting prodrug therapy reduced HBV DNA in plasma of humanized mice to undetectable levels in 2/4 animals tested at four weeks with readily detected human cells (Fig). The remaining two animals showed > log decrease in plasma viral load at equivalent times. Animals were monitored for 10 weeks to measure viral rebound. Conclusion: Long-acting TFV and NTZ prodrugs sustained antiviral activity in humanized mice for a month after a single dose. These data sets support the potential of monthly NM1TAF and NM1NTZ dosing for treatment of HBV infections.

Poster Abstracts

CROI 2020 220