Society: AASLD

LIVE STREAM SESSION

Background:
The clinical course of HBV in individuals with HIV coinfection is marked by accelerated disease progression. A tenofovir-containing anti-retroviral regimen is recommended in most people with HIV-1/HBV-coinfection but there have not been randomized studies of TDF vs TAF in treatment-naïve HIV-1/HBV-coinfected individuals. We report primary endpoint results from a phase 3 study comparing B/F/TAF vs DTG+F/TDF at Week (W) 48 in participants initiating treatment for both viruses.
Methods:
Adults with HIV-1/HBV coinfection were randomized 1:1 to initiate blinded treatment with B/F/TAF or DTG+F/TDF (with placebo). Primary endpoints were proportion of participants with HIV-1 RNA <50 copies/mL (FDA Snapshot) and plasma HBV DNA <29 IU/mL (missing=failure) at Week 48. Noninferiority was assessed with 95% CI (12% margin). Secondary and other endpoints included change from baseline CD4 count, proportion with HBsAg and HBeAg loss/seroconversion, and ALT normalization (AASLD criteria).
Results:
243 participants were randomized and treated (121 B/F/TAF, 122 DTG+F/TDF) from 11 countries in Asia, Europe, North and Latin America. Baseline characteristics were median age 32 years, 4.5% female, 88% Asian, 30% HIV-1 RNA >100,000 c/mL, 40% CD4 <200 cells/μL, median HBV DNA 8.1 log10 IU/mL, 78% HBeAg+. At W48, B/F/TAF was noninferior to DTG+F/TDF at achieving HIV-1 RNA <50 copies/mL (95% vs 91%, difference 4.1%; 95% CI -2.5% to 10.8%, p=0.21), with mean CD4 gains of +200 and +175 cells/μL, respectively. B/F/TAF was superior to DTG+F/TDF at achieving HBV DNA <29 IU/mL (63% vs 43%, difference 16.6%; 95% CI 5.9% to 27.3%, p=0.0023). Participants treated with B/F/TAF vs DTG+F/TDF had numerically higher HBsAg loss (13%, 6%, p=0.059), HBeAg loss (26%, 14%, p=0.055), HBeAg seroconversion (23%, 11%, p=0.031), and ALT normalization (73%, 55%, p=0.066). Most frequent AEs were upper respiratory tract infection (17%, 11%), COVID-19 (13%, 11%), pyrexia (9%, 12%), ALT increase (7%, 11%), and nasopharyngitis (11%, 4%). ALT flares (elevations at ≥2 consecutive post-baseline visits) occurred in 11 participants (7 B/F/TAF, 4 DTG+F/TDF) which resolved.
Conclusions:
In adults with HIV-1/HBV-coinfection starting antiviral therapy, both B/F/TAF and DTG+F/TDF had high HIV-1 suppression at year 1, with B/F/TAF resulting in superior HBV DNA suppression and significantly more HBeAg seroconversion. Safety findings were similar between groups.

Background and Aims: Non-alcoholic steatohepatitis (NASH) is a major cause of cirrhosis and the effect of alcohol use on NASH progression and fibrosis/cirrhosis remains to be explored. While common elements in the pathogenesis of NASH and alcohol- associated liver disease (ALD) have been described the combined effects of NASH and ALD remain obscure. We hypothesized that repeated alcohol binges in a high fat-cholesterol-sugar diet (NASH diet) -induced model of NASH accelerates liver damage and fibrosis through inflammatory pathways activation and neutrophil recruitment.
Methods: 8-10 weeks old male C57BL/6 mice received either chow or NASH diet for 3 months with or without weekly alcohol binges. Liver mRNA was analyzed for fibrosis and inflammation markers. Hepatic fibrosis and inflammation were further tested by immunohistochemistry (IHC), qPCR and western blotting. Neutrophil infiltration and neutrophil extracellular traps (NETs) were examined.
Results: Liver transcriptome screen revealed major increase in genes involved in leukocyte migration, inflammatory response and extracellular matrix reorganization in mice that received weekly alcohol binges (EtOH) plus NASH diet compared to either of the diets alone. NASH diet and EtOH binges, respectively, resulted in increased serum ALT compared to chow diet, and EtOH plus NASH diet caused the greatest liver damage compared to all groups. Fibrosis markers, including Sirius red staining, a-SMA and vimentin protein levels, were highest in the NASH diet plus EtOH group compared to NASH diet and EtOH alone. We found an increase in the Ly6G⁺ neutrophils in the liver after EtOH binges that was even higher in mice with NASH plus EtOH. Increased citrullinated histone and neutrophil elastase levels in NASH plus EtOH mice, but not in NASH mice indicated the presence of neutrophil extracellular traps (NETs) in the liver. In vitro, cell-free NETs caused robust hepatic stellate cell activation (HSCs), indicated by increased smooth muscle actin and collagen protein production that was abrogated by DNase treatment. HSCs sensed NETs via NLRP3 inflammasome, as NLRP3 inhibition attenuated their activation. Interestingly, neutrophil infiltration and NETs production were partially regulated by NLRP3. Inhibition of NLRP3 by in vivo administration of MCC950, an NLRP3 inflammasome inhibitor, or NLRP3 KO mice significantly attenuated liver damage, neutrophil infiltration and NETs formation in NASH plus EtOH binge fed mice.
Conclusion: Alcohol binges in NASH accelerate liver damage and fibrosis. NETs directly induce a pro-fibrotic stellate cell phenotype via NLRP3. Inhibition of NLRP3 attenuates NET formation and in vivo NLRP3 inhibition may represent a target to attenuate the pro-fibrotic effect of alcohol in NASH fibrosis.

Prashanth Thevkar Nagesh

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