Hepatitis C Virus (HCV) Clearance After Treatment With Direct-Acting Antivirals in Human Immunodeficiency Virus (HIV)-HCV Coinfection Modulates Systemic Immune Activation and HIV Transcription on Antiretroviral Therapy

Abstract

Background: Hepatitis C virus (HCV) coinfection among people with human immunodeficiency virus (HIV) might perturb immune function and HIV persistence. We aimed to evaluate the impact of HCV clearance with direct-acting antivirals (DAAs) on immune activation and HIV persistence in HIV/HCV-coinfected individuals on antiretroviral therapy (ART).

Methods: In a prospective observational study, ART-treated participants with HIV/HCV coinfection received sofosbuvir/daclatasvir ± ribavirin (n = 19). Blood samples were collected before DAA therapy, at the end of treatment, and 12 months after DAA termination (12MPT). T- and natural killer (NK)-cell phenotype, soluble plasma factors, cell-associated (CA)-HIV deoxyribonucleic acid (DNA) forms (total, integrated, 2LTR), CA-unspliced (US) and multiple-spliced ribonucleic acid (RNA), and plasma HIV RNA were evaluated.

Results: Hepatitis C virus clearance was associated with (1) a downmodulation of activation and exhaustion markers in CD4⁺, CD8⁺ T, and NK cells together with (2) decreased plasma levels of Interferon gamma-induced protein 10 (IP10), interleukin-8 (IL-8), soluble (s)CD163 and soluble intercellular adhesion molecule (sICAM). Cell-associated US HIV RNA was significantly higher at 12MPT compared to baseline, with no change in HIV DNA or plasma RNA.

Conclusions: Elimination of HCV in HIV/HCV-coinfected individuals alters immune function and the transcriptional activity of latently infected cells. This report provides insights into the effects of HCV coinfection in HIV persistence and regards coinfected subjects as a population in which HIV remission might prove to be more challenging.

Keywords: HIV reservoir; direct antiviral agents; hepatitis C; immune activation.

Figure 1.

Human immunodeficiency virus (HIV) reservoir dynamics in HIV/hepatitis C virus-coinfected individuals treated with direct-acting antivirals (DAA). Cell-associated (CA) HIV deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), as well as plasma HIV RNA were evaluated in coinfected individuals before treatment initiation (baseline [BSL]), at the end of treatment (EOT), and 12 months after finalizing DAA therapy (12MPT). The CA total HIV DNA, integrated DNA and 2LTR (A), CA multiple-spliced (MS)-RNA, unspliced (US)-RNA, and plasma RNA (B), and US-RNA/integrated DNA, US-RNA/total HIV DNA, and MS/US-RNA ratios (C) are shown. Viral DNA and RNA copies were calculated relative to 10⁶ cell equivalents (CE). Individual values, median and 25th and 75th percentiles, are indicated. Statistical comparisons were performed using Wilcoxon test, P < 0.05.

Figure 2.

Association analysis between cell-associated (CA) unspliced (US) and plasma human immunodeficiency virus (HIV) ribonucleic acid (RNA) in HIV/hepatitis C virus-coinfected individuals treated with direct-acting antivirals (DAA). The CA US-RNA as well as plasma HIV RNA were evaluated in coinfected individuals before treatment initiation (baseline [BSL]), at the end of treatment (EOT), and 12 months after finalizing DAA therapy (12MPT). Relationship between variables was measured by applying a generalized linear mixed-effects model with plasma RNA as the independent variable and CA US-RNA and time as fixed-effect predictors; P value for the CA US-RNA coefficient is shown. White, gray, and black filled dots represent individual measures belonging to BSL, EOT, and 12MPT subgroups, respectively.

Figure 3.

Correlation analyses between cellular and soluble markers of immune activation and inflammation, and human immunodeficiency virus (HIV) reservoirs in HIV/hepatitis C virus-coinfected individuals treated with direct-acting antivirals (DAA). Heat map representation of Spearman rank correlation coefficients computed for the expression of CD8⁺ T-cell immune markers at 12 months after finalizing DAA therapy (12MPT) (A) and plasma levels of soluble factors of immune activation and inflammation at 12MPT (B) versus HIV unspliced (US)-ribonucleic acid (RNA) at 12MPT (US-RNA 12 MPT), US-RNA fold up between 12MPT and baseline (BSL) (Fold-up US-RNA 12MPT/BSL), and differences between US-RNA at 12MPT minus levels at BSL (Delta US-RNA 12MPT-BSL). The colors denote both the correlation direction and strength of association, ranging from −1 (blue) to 1 (red). Statistical significant associations are further shown below each panel in individual × vs y plots. Spermans’s r and P values are shown. ICAM, intercellular adhesion molecule; IL, interleukin; IP-10, interferon-inducible protein 10; TNF, tumor necrosis factor.