# HIV status defines distinct immunological drivers of persistent portal hypertension after HCV cure in people with advanced cirrhosis

## TL;DR

This study shows that HIV changes how the immune system affects liver blood pressure after hepatitis C is cured, leading to different recovery patterns.

## Contribution

The study identifies distinct immune profiles in HIV-positive and HIV-negative individuals affecting portal hypertension regression after HCV cure.

## Key findings

- In HIV-negative individuals, impaired portal hypertension regression is linked to systemic inflammation and T-cell activation.
- In HIV-positive individuals, impaired regression is associated with endothelial dysfunction and T-cell exhaustion.
- HIV coinfection reshapes the immunological pathways of post-cure liver recovery.

## Abstract

The immunological drivers of portal hypertension regression after hepatitis C virus (HCV) cure are poorly understood, particularly in the context of human immunodeficiency virus (HIV) coinfection We aimed to identify baseline immune signatures predicting the evolution of the hepatic venous pressure gradient (HVPG) in people with and without HIV (PWH/PWoH).

We prospectively followed 41 individuals with advanced cirrhosis (18 PWoH, 23 PWH) who were cured of HCV with direct-acting antivirals (DAA). Baseline plasma and cellular immune markers were extensively profiled using multiplex assays and flow cytometry. We used mixed-effects modeling to test for associations between these baseline immune features and the change in HVPG over a 48-week follow-up period, with q-values controlling for false discoveries.

Two distinct immunological profiles of impaired HVPG regression emerged. In PWoH, impaired regression was linked to a broad proinflammatory profile [TNF-α (AMR = 1.13; q=0.012), IL17A (AMR = 1.28; q=0.012), and IL10 (AMR = 1.2; q=0.028)], a widespread total CD4+ T-cell activation [HLA-DR+ (AMR = 1.44; q<0.001) and CD38+HLA-DR+ (AMR = 1.3; q=0.007)], and robust activation across central memory (CM) and effector memory (EM) subsets. Conversely, in PWH, impaired HVPG regression was associated with sVCAM-1 (AMR = 1.58; q=0.096), and a more focused activation within EM (HLA-DR+, AMR = 1.08; q=0.030) and TemRA (CD38+HLA-DR+, AMR = 1.12; q=0.030) CD4+ T-cells.

HIV coinfection fundamentally reshapes the immunological landscape of post-cure portal hypertension recovery. The shift from systemic inflammation in PWoH to endothelial dysfunction and T-cell exhaustion in PWH reveals distinct pathological pathways. Understanding these signatures is a crucial step toward developing targeted therapies to promote complete hepatic recovery.