Immune Biomarker Differences and Changes Comparing HCV Mono-Infected, HIV/HCV Co-Infected, and HCV Spontaneously Cleared Patients

<div><p>Background</p><p>Immune biomarkers are implicated in HCV treatment response, fibrosis, and accelerated pathogenesis of comorbidities, though only D-dimer and C-reactive protein have been consistently studied. Few studies have evaluated HIV/HCV co-infection, and little longitudinal data exists describing a broader antiviral cytokine response</p> <p>Methods</p><p>Fifty immune biomarkers were analyzed at baseline(BL) and HCV end of treatment follow-up(FU) time point using the Luminex 50-plex assay in plasma samples from 15 HCV-cleared, 24 HCV mono- and 49 HIV/HCV co-infected patients receiving antiretroviral treatment, who either did or did not receive pegylated-interferon/ribavirin HCV treatment. Biomarker levels were compared among spontaneous clearance patients, mono- and co-infected, untreated and HCV-treated, and sustained virologic responders (SVR) and non-responders (NR) at BL and FU using nonparametric analyses. A Bonferroni correction, adjusting for tests of 50 biomarkers, was used to reduce Type I error</p> <p>Results</p><p>Compared to HCV patients at BL, HIV/HCV patients had 22 significantly higher and 4 significantly lower biomarker levels, following correction for multiple testing. There were no significantly different BL levels when comparing SVR and NR in mono- or co-infected patients; however, FU levels changed considerably in co-infected patients, with seven becoming significantly higher and eight becoming significantly lower in SVR patients. Longitudinally between BL and FU, 13 markers significantly changed in co-infected SVR patients, while none significantly changed in co-infected NR patients. There were also no significant changes in longitudinal analyses of mono-infected patients achieving SVR or mono-infected and co-infected groups deferring treatment</p> <p>Conclusions</p><p>Clear differences exist in pattern and quantity of plasma immune biomarkers among HCV mono-infected, HIV/HCV co-infected, and HCV-cleared patients; and with SVR in co-infected patients treated for HCV. Though >90% of patients were male and co-infected had a larger percentage of African American patients, our findings may have implications for better understanding HCV pathogenesis, treatment outcomes, and future therapeutic targets</p> </div

Comparison of Baseline and Follow-up in HCV/HIV Co-infected Patients with Sustained Virologic Response (SVR).

<p>Median biomarker levels (pg/ml) are divided into 3 panels A) Inflammatory, chemokines; B) anti-inflammatory, adaptive, anti-viral, growth factors; and C) hematopoietic, adipose-derived, other, and cellular adhesion molecular (CAMs). Blue bar = baseline (BL), red bar = follow-up (FU). Concentrations are actual values, unless otherwise noted (†actual values 10x and †††actual values 1000x). *p<0.001. **IL-1RA is “anti-inflammatory”, but graphed with “Others” for scale.</p

Biomarkers of Significance Grouped by Comparisons between HCV and HIV/HCV Co-Infected and HCV Spontaneously Cleared Cohorts.

<p>Note: Results for each analysis were considered statistically significant if p<0.001. BL: baseline; FU: follow-up; C-SVR: co-infected sustained virologic responders; C-NR: co-infected non-responders; CDT: co-infected deferring treatment; MST-SVR: mono-infected starting treatment with sustained virologic response; MDT: mono-infected deferring treatment.</p

Comparison of HCV Mono-infected Patients and Patients who Spontaneously Cleared HCV Infection at Baseline.

<p>Median biomarker levels (pg/ml) are divided into 3 panels A) Inflammatory, chemokines; B) anti-inflammatory, adaptive, anti-viral, growth factors; and C) hematopoietic, adipose-derived, other, and cellular adhesion molecular (CAMs). Blue bar = HCV mono-infected (Mono-infected), red bar = spontaneously cleared HCV infection (HCV SC). Concentrations are actual values, unless otherwise noted (†actual values 10x, ††actual values 100x, and †††actual values 1000x). *p<0.001. **IL-1RA is “anti-inflammatory”, but graphed with “Others” for scale.</p

Comparison of Spontaneous Clearance Group to all Patients with Sustained Virologic Response (SVR) at Baseline.

<p>Median biomarker levels (pg/ml) are divided into 3 panels A) Inflammatory, chemokines; B) anti-inflammatory, adaptive, anti-viral, growth factors; and C) hematopoietic, adipose-derived, other, and cellular adhesion molecular (CAMs). Blue bar = HCV spontaneous clearance (HCV SC), red bar = HCV mono-infected and HIV/HCV co-infected patients with SVR (Combined SVR-BL). Concentrations are actual values, unless otherwise noted (†actual values 10x, ††actual values 100x and †††actual values 1000x). *p<0.001. **IL-1RA is “anti-inflammatory”, but graphed with “Others” for scale.</p

Comparison of HCV/HIV Co-infected Patients with Sustained Virologic Response (SVR) versus Nonresponse (NR) to HCV Treatment.

<p>Median biomarker levels (pg/ml) are divided into 3 panels A) Inflammatory, chemokines; B) anti-inflammatory, adaptive, anti-viral, growth factors; and C) hematopoietic, adipose-derived, other, and cellular adhesion molecular (CAMs). Blue bar = HCV/HIV co-infected SVR (C-SVR), red bar = HCV/HIV co-infected nonresponse (C-NR). Concentrations are actual values, unless otherwise noted (†actual values 10x and †††actual values 1000x). *p<0.001. **IL-1RA is “anti-inflammatory”, but graphed with “Others” for scale.</p

Comparison of Spontaneous Clearance Group to all Patients with Sustained Virologic Response (SVR) at Follow-up.

<p>Median biomarker levels (pg/ml) are divided into 3 panels A) Inflammatory, chemokines; B) anti-inflammatory, adaptive, anti-viral, growth factors; and C) hematopoietic, adipose-derived, other, and cellular adhesion molecular (CAMs). Blue bar = HCV spontaneous clearance (HCV SC), red bar = HCV mono-infected and HIV/HCV co-infected patients with SVR (Combined SVR-FU). Concentrations are actual values, unless otherwise noted (†actual values 10x, ††actual values 100x). *p<0.001. **IL-1RA is “anti-inflammatory”, but graphed with “Others” for scale.</p

Comparison of HCV/HIV co-infected Patients and Patients who Spontaneously Cleared HCV Infection at Baseline.

<p>Median biomarker levels (pg/ml) are divided into 3 panels A) Inflammatory, chemokines; B) anti-inflammatory, adaptive, anti-viral, growth factors; and C) hematopoietic, adipose-derived, other, and cellular adhesion molecular (CAMs). Blue bar = HCV/HIV co-infected (Co-infected), red bar = spontaneously cleared HCV infection (HCV SC). Concentrations are actual values, unless otherwise noted (†actual values 10x, ††actual values 100x, and †††actual values 1000x). *p<0.001. **IL-1RA is “anti-inflammatory”, but graphed with “Others” for scale.</p

Summary of Patient Demographics.

<p>Note: Data listed as total number of patients, unless otherwise noted. C-SVR: co-infected sustained virologic responders; C-NR: co-infected non-responders; CDT: co-infected deferring treatment; MST: mono-infected starting treatment; MDT: mono-infected deferring treatment; BMI: body mass index; NSAID: Non-Steroidal Anti-inflammatory drug; und: undetectable or below the lower limit of detection (LLOD).</p>1<p>LLOD is <615 IU/mL;</p>2<p>LLOD is <20 IU/mL.</p>†<p>One patient in this group had an HCV RNA level of 673 IU/mL at follow-up, but still achieved SVR.</p>‡<p>Excludes steroids administered topically or intranasally.</p>*<p>Fisher’s exact p-value.</p

Impact of NTM on TB sputum smears or cultures.

<p><i>NTM: Nontuberculous mycobacteria</i>; <i>MTBC: Mycobacterium tuberculosis</i> complex;</p>*<p><i>Pos: positive in at least two occasions</i>;</p>#<p><i>Neg: negative in three occasions</i>.</p