Circulating sCD14 is associated with virological response to pegylated-interferon-alpha/ribavirin treatment in HIV/HCV co-infected patients

Abstract

Objectives: Microbial translocation (MT) through the gut accounts for immune activation and CD4+ loss in HIV and may influence HCV disease progression in HIV/HCV co-infection. We asked whether increased MT and immune activation may hamper anti-HCV response in HIV/HCV patients.

Methods: 98 HIV/HCV patients who received pegylated-alpha-interferon (peg-INF-alpha)/ribavirin were retrospectively analyzed. Baseline MT (lipopolysaccharide, LPS), host response to MT (sCD14), CD38+HLA-DR+CD4+/CD8+, HCV genotype, severity of liver disease were assessed according to Early Virological Response (EVR: HCV-RNA <50 IU/mL at week 12 of therapy or ≥2 log(10) reduction from baseline after 12 weeks of therapy) and Sustained Virological Response (SVR: HCV-RNA <50 IU/mL 24 weeks after end of therapy). Mann-Whitney/Chi-square test and Pearson's correlation were used. Multivariable regression was performed to determine factors associated with EVR/SVR.

Results: 71 patients displayed EVR; 41 SVR. Patients with HCV genotypes 1-4 and cirrhosis presented a trend to higher sCD14, compared to patients with genotypes 2-3 (p = 0.053) and no cirrhosis (p = 0.052). EVR and SVR patients showed lower levels of circulating sCD14 (p = 0.0001, p = 0.026, respectively), but similar T-cell activation compared to Non-EVR (Null Responders, NR) and Non-SVR (N-SVR) subjects. sCD14 resulted the main predictive factor of EVR (0.145 for each sCD14 unit more, 95%CI 0.031-0.688, p = 0.015). SVR was associated only with HCV genotypes 2-3 (AOR 0.022 for genotypes 1-4 vs 2-3, 95%CI 0.001-0.469, p = 0.014).

Conclusions: In HIV/HCV patients sCD14 correlates with the severity of liver disease and predicts early response to peg-INF-alpha/ribavirin, suggesting MT-driven immune activation as pathway of HIV/HCV co-infection and response to therapy.

Figure 1. Higher microbial translocation is associated with HCV genotypes 1–4 and cirrhosis.

a)-b) sCD14 and LPS were compared between patients with advanced fibrosis (AF) and non advanced fibrosis (N-AF). c)-d) sCD14 and LPS were compared between patients with cirrhosis and absence of cirrhosis (N-Cirrhosis). e)-f) sCD14 and LPS were compared between patients with HCV genotypes 1–4 and genotypes 2–3. Each point represents the value from one subject's plasma. sCD14 and LPS were measured in plasma samples; sCD14 µg/mL, LPS pg/mL. AF = advanced fibrosis – N-AF = non advanced fibrosis. p-values were assessed by Mann Whitney U test. p>0.05 was considered non significant (NS).

Figure 2. Activated HLA-DR+CD4+ and CD8+ T-cells according to liver fibrosis, cirrhosis and HCV genotypes.

a)-b) Activated HLA-DR+CD4+ and CD8+ T-cells were compared between patients with advanced fibrosis (AF) and non advanced fibrosis (N-AF). c)-d) Activated HLA-DR+CD4+ and CD8+ T-cells were compared between patients with cirrhosis and absence of cirrhosis (N-Cirrhosis). e)-f) Activated HLA-DR+CD4+ and CD8+ T-cells were compared between patients with HCV genotypes 1–4 and genotypes 2–3. Each point represents the value from one subject's plasma. Activated HLA-DR+CD4+ and CD8+ T-cells % values are presented. AF = advanced fibrosis – N-AF = non advanced fibrosis. p-values were assessed by Mann Whitney U test. p>0.05 was considered non significant (NS).

Figure 3. Activated HLA-DR+CD4+ and CD8+ T-cells according to EVR and SVR.

a)-b) Activated HLA-DR+CD4+ and CD8+ T-cells were compared between patients with early virological response [EVR, i.e. undetectable serum HCV-RNA (<50 IU/mL) or ≥2 log₁₀ reduction from baseline after 12 weeks of therapy], and Null Responders (NR) (i.e. serum HCV-RNA ≥50 IU/mL and <2 log₁₀ reduction from baseline). c)-d) Activated HLA-DR+CD4+ and CD8+ T-cells were compared between patients with sustained virological response [SVR, i.e. undetectable serum HCV-RNA (<50 IU/mL) 24 weeks after the end of a full course of 48 or 72 weeks of anti-HCV treatment, according to genotype], and N-SVR subjects. Each point represents the value from one subject's plasma. Activated HLA-DR+CD4+ and CD8+ T-cells % values are presented. p-values were assessed by Mann Whitney U test. p>0.05 was considered non significant (NS).

Figure 4. Circulating sCD14 and LPS levels are higher in NR and in N-SVR patients.

a)-b) sCD14 and LPS were compared between patients with early virological response [EVR, i.e. undetectable serum HCV-RNA (<50 IU/mL) or ≥2 log₁₀ reduction from baseline after 12 weeks of therapy], and Null Responders (NR) (i.e. serum HCV-RNA ≥50 IU/mL and <2 log₁₀ reduction from baseline). c)-d) sCD14 and LPS were compared between patients with sustained virological response [SVR, i.e. undetectable serum HCV-RNA (<50 IU/mL) 24 weeks after the end of a full course of 48 or 72 weeks of anti-HCV treatment, according to genotype], and N-SVR subjects. Each point represents the value from one subject's plasma. sCD14 and LPS were measured in plasma samples; sCD14 µg/mL, LPS pg/mL. p-values were assessed by Mann Whitney U test. p>0.05 was considered non significant (NS).