Improving immunotherapy response with direct-acting antiviral therapy in patients with advanced hepatocellular carcinoma and chronic hepatitis C virus infection.

e16181 Background: Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) carries a poor prognosis. Immune checkpoint therapy (ICT) enhances antitumor activity through CD8⁺ T-cell proliferation. Direct-acting antivirals (DAAs) have been associated with a remarkable HCV cure rate and have been shown to enhance hepatic and systemic immune responses by reversing the exhaustion of the HCV-specific CD8 + T-cell response. HCV guidelines do not address the optimal timing of DAAs in patients with advanced HCC undergoing ICT. We conducted a phase IV clinical trial in patients with HCV-associated HCC to determine whether clearing HCV with early DAA therapy improves ICT response and enhances the immune response against liver cancer cells by reversing T-cell exhaustion. Methods: In this open-label single-arm clinical trial (NCT05717400), patients with HCV-related HCC received atezolizumab plus bevacizumab and DAAs (sofosbuvir/velpatasvir [SV] or SV/voxilaprevir [SVV]). Peripheral blood samples were collected at baseline and at weeks 4 (W4) and 12 (W12) after DAA initiation for high-dimensional flow cytometry. Tumor biopsies were obtained before and after DAA therapy. Multiplex immunofluorescence quantified intertumoral CD8⁺ T-cell densities and immune-cell phenotypes. Primary endpoints were objective response rate (ORR), disease control rate (DCR), and sustained virological response (SVR). Results: Between March 17, 2023, and August 28, 2024, 11 patients were screened, and 2 were enrolled. Patient 1 was a 74-year-old Black man with metastatic HCC and HCV genotype 2 treated with SV. Patient 2 was a 64-year-old White man with stage IIIB HCC and HCV genotype 1a treated with SVV after initial DAA failure. Both were ICT-naïve, started DAAs within weeks of ICT initiation, experienced no grade 3 or 4 adverse events, had stable disease as their overall best response (DCR 100%; ORR 0%), and had SVR. In both patients, CD4⁺ and CD8⁺ T-cell frequencies increased over time, whereas monocyte frequencies decreased. At all times, both patients had high CD4:CD8 ratios but low natural killer (NK) cell frequencies. We observed no changes in proliferation or in the expression of the activation markers 41BB, OX40, ICOS, or CD69 on T-cell subsets or NK cells. The expression of inhibitory markers in T and NK cell subsets is shown. At W12, patient 1 had increased T-cell densities, while patient 2 had pronounced tumor infiltration by cytotoxic T lymphocytes (CD3⁺CD8⁺) and macrophages (CD68⁺). Conclusions: Early DAA therapy after ICT in patients with advanced HCC was safe and resulted in enhanced CD4⁺ and CD8⁺ T-cell responses with excellent virologic control but did not impact tumor response. Larger clinical trials are warranted to determine whether HCV clearance with DAA therapy enhances ICT response in patients with HCV-related HCC. Clinical trial information: NCT05717400 .