Abstract

Background: Treatment of CHB with JNJ-3989 and NA ± JNJ-6379 has shown profound reductions in serum hepatitis B viral (HBV) markers. The INSIGHT study aims to assess intrahepatic changes in virological and immunological markers with JNJ-3989 based treatment in CHB patients.

Methods: INSIGHT is a phase 2 multicenter study in CHB patients who are hepatitis B e-antigen positive (HBeAg+) and not currently treated (NCT; Group 1) or HBeAg-negative (HBeAg-) and virologically suppressed (VS) by NA (Group 2). Patients received 48 weeks of JNJ-3989 + NA (± JNJ-6379 withdrawn from study). Paired percutaneous core liver biopsies and fine needle aspiration biopsies (FNABs) were collected using standardized procedures at baseline and week 40 to investigate changes in intrahepatic viral and immune markers.

Results: Levels of viral serum markers were higher for participants in Group 1 versus Group 2 at BL. JNJ-3989 treatment resulted in a mean (SE) hepatitis B surface antigen (HBsAg) change from BL of -3.78 (0.481) log₁₀ IU/mL for Group 1 and -2.40 (0.160) for Group 2 at Week 40. One out of nine (11.1%) patients in Group 1 reached HBsAg seroclearance at W40. The estimated mean percentage of HBsAg positive hepatocytes decreased by W40 in both groups while the mean percentage of HBcAg+ cells decreased only in Group 1 (Table). In Group 1, the percentage of HBV RNA+ hepatocytes declined from min 90.2 to max 100% at BL to 4.4-28.4% at W40 (n=4 patients in each group with samples profiled at BL and W40) and in Group 2 from 8.6-31.6% at BL to 5.6-15% at W40 (n=4 pairs). The percentage of cccDNA–/HBV RNA– cells increased during JNJ-3989 treatment in both groups, from 0-1.2% at BL in Group 1 and 31.3-64.8% in Group 2; to 48.1-68.9% in Group 1 (n=4 pairs) and 51.1-66.7% in Group 2 (n=4 pairs) at W40. Profiling of FNABs identified enrichment in early activated CD8+ T cells by W40 in Group 1 and depletion of CD8+ exhausted T cells, CD8+ effector memory T cells, and CD8+ memory stem cells in Group 2.

Conclusion: Treatment of CHB patients with JNJ-3989 resulted in reduction of HBsAg+ hepatocytes at week 40 with an increased fraction of non- infected hepatocytes. Changes during treatment were seen in intrahepatic CD8+ T cells (increase of early activated CD8+ T cells in Group1 and depletion of exhausted T cells in Group 2), suggesting that JNJ-3989 + NA treatment combination leads to activation of intrahepatic adaptive immunity.