Vitamin D deficiency is associated with severity of liver disease in HIV/HCV coinfected patients.

OBJECTIVE: To study the association of plasma 25-hydroxy vitamin D (25(OH)D) levels in HIV/HCV coinfected patients with severity of liver disease and virological response to hepatitis C virus (HCV) therapy with pegylated-interferon-alpha plus ribavirin (pegIFNα/RBV). METHODS: A cross-sectional study in 174 HIV/HCV coinfected patients that underwent a liver biopsy previously to start HCV therapy and a retrospective study of 125 of them. Plasma 25(OH)D levels were quantified by enzyme immunoassay. Liver biopsies were evaluated by METAVIR score. A sustained virological response (SVR) was defined as an undetectable serum HCV viral load (<10 IU/mL) up through 24 weeks after the end of HCV treatment. RESULTS: The median of plasma 25(OH)D level was 48 nmol/L (p25th: 32.5; p75th: 56.1) and 27 (15.5%) had 25(OH)D deficiency (<25 nmol/L). The percentage of 25(OH)D deficiency was higher in patients with significant fibrosis (F ≥ 2) (92.6% vs. 57.1%; p = 0.010) and moderate necroinflammatory activity grade (A ≥ 2) (85.2% vs. 60%; p = 0.043). However, adjusted logistic regression analyses showed that 25(OH)D deficiency was only associated with severity of liver disease [F ≥ 2 (OR = 8.47 (95% of confidence interval (CI) = 1.88; 38.3); p = 0.005) and A ≥ 2 (OR = 3.25 (95%CI = 1.06; 10.1); p = 0.040)]. Moreover, any significant relationship was found between 25(OH)D deficiency and SVR after HCV therapy. CONCLUSION: Plasma 25(OH)D deficiency was associated with liver disease severity in HIV/HCV coinfected patients, but it was not associated with HCV treatment failure.

Plasma IL-6 and IL-9 predict the failure of interferon-α plus ribavirin therapy in HIV/HCV-coinfected patients.

BACKGROUND: The cytokine profile plays an important role in treatment outcome of hepatitis C virus (HCV) infection, and probably modulates the immune response against HCV. The aim of this study was to evaluate which cytokines affect the response to interferon-α (IFN-α) and ribavirin therapy and how these cytokines change 72 weeks after starting anti-HCV therapy in HIV/HCV-coinfected patients. METHODS: We carried out a retrospective follow-up study of 65 patients on anti-HCV therapy. A sustained virological response (SVR) was defined as an undetectable HCV viral load up to 24 weeks after the end of treatment. Cytokines were measured using a multiplex immunoassay kit. RESULTS: On starting anti-HCV therapy, non-responder (NR) patients had higher levels of interleukin (IL)-6, IL-9, IL-10 and tumour necrosis factor (TNF)-α (P < 0.05), while IL-17A levels were increased in SVR patients (P = 0.058). However, only patients with high levels of IL-6 and IL-9 had decreased odds to achieve SVR (P < 0.05). Plasma levels of IL-6 and IL-9 had a high predictive value for SVR failure [area under the ROC curve (AUC) 0.839 (95% CI 0.733-0.945) and AUC 0.769 (95% CI 0.653-0.884)]. In addition, during anti-HCV therapy, IL-1ß showed an increase in NR patients (P = 0.015) and IL-10 decreased in SVR patients (P = 0.049). After clearing HCV infection, low levels of TNF-α, IL-6, IL-9, IL-10, IL-13 and IL-22 were found in SVR patients (P < 0.05), as well as IL-1ß, but only near statistical significance (P = 0.073). CONCLUSIONS: High plasma levels of IL-6 and IL-9 had a high predictive value for SVR failure. Furthermore, clearing of HCV infection was associated with low inflammatory and T helper (Th)2/Th9/Th22 cytokine levels.

High plasma CXCL10 levels are associated with HCV-genotype 1, and higher insulin resistance, fibrosis, and HIV viral load in HIV/HCV coinfected patients.

BACKGROUND: CXCL10 may contribute to the host immune response against the hepatitis C virus (HCV), liver disease progression, and response to HCV antiviral therapy. The aim of our study was to analyze the relationship among virological, immunological, and clinical characteristics with plasma CXCL10 levels in human immunodeficiency virus (HIV)/HCV-coinfected patients. METHODS: We carried out a cross-sectional study on 144 patients. CXCL10 and insulin were measured using an immunoassay kit. The degree of insulin resistance was estimated for each patient using the homeostatic model assessment (HOMA) method. Insulin resistance was defined as a HOMA index higher than or equal to 3.8. Aspartate aminotransferase (AST) to platelet ratio (APRI), FIB-4, Forns index, HGM1, and HGM2 were calculated. RESULTS: The variables associated with log(10) CXCL10 levels by univariate analysis were age (b=0.013; p=0.023), prior AIDS-defining condition (b=0.127; p=0.045), detectable plasma HIV viral load (b=0.092; p=0.006), log(10) HOMA (b=0.216; p=0.002), HCV-genotype 1 (b=0.114; p=0.071), and liver fibrosis assessed by all non-invasive indexes (log(10) APRI (b=0.296; p=0.001), log(10) FIB-4 (b=0.436; p<0.001), log(10) Forns index (b=0.591; p<0.001), log(10) HGM1 (b=0.351; p=0.021), and log(10) HGM2 (b=0.215; p=0.018)). However, in multivariate analysis, CXCL10 levels were only associated with HOMA, detectable plasma HIV viral load, HCV-genotype 1 and FIB-4 (R-square=0.235; p<0.001). CONCLUSION: Plasma CXCL10 levels were influenced by several characteristics of patients related to HIV and HCV infections, insulin resistance, and liver fibrosis, indicating that CXCL10 may play an important role in the pathogenesis of both HCV and HIV infections.

Sustained virological response to interferon-α plus ribavirin decreases inflammation and endothelial dysfunction markers in HIV/HCV co-infected patients.

OBJECTIVES: Hepatitis C virus (HCV) antiviral therapy might lead to decreased chronic immune activation and endothelial dysfunction associated with cardiovascular risk. The aim was to evaluate the effect of HCV eradication on serum markers of inflammation and endothelial dysfunction markers in HIV/HCV co-infected patients. METHODS: We carried out a retrospective study of 69 HIV/HCV co-infected patients on interferon (IFN)-α plus ribavirin. In addition, 47 HIV-infected subjects were selected as a control group. A sustained virological response (SVR) was defined as an undetectable HCV viral load up to 24 weeks after the end of treatment. Tumour necrosis factor (TNF) receptor-1 (TNF-R1), soluble E-selectin (sE-selectin), soluble P-selectin (sP-selectin), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured using a multiplex immunoassay kit. RESULTS: HIV/HCV co-infected patients had higher values of soluble TNF-R1 (sTNF-R1), sE-selectin and sICAM-1 than HIV mono-infected patients (P < 0.05). SVR patients had a decrease in sTNF-R1, sP-selectin, sE-selectin and sICAM-1 during anti-HCV treatment (P < 0.05) and, at the end of treatment, SVR patients had lower values of sTNF-R1, sE-selectin and sVCAM-1 than non-responder patients (P < 0.05), although the values of sTNF-R1, sP-selectin, sE-selectin and sICAM-1 remained higher than in HIV mono-infected patients (P < 0.05). Moreover, we found a significant positive relationship between an increase in sTNF-R1 and increases in sP-selectin, sE-selectin and sICAM-1 during anti-HCV therapy. CONCLUSIONS: Chronic hepatitis C infection induces alterations of markers of inflammation and endothelial dysfunction. Eradication of HCV, following IFN-α and ribavirin therapy, reduces immune activation as well as markers of inflammation and endothelial dysfunction.

An artificial neural network improves the non-invasive diagnosis of significant fibrosis in HIV/HCV coinfected patients.

OBJECTIVE: To develop an artificial neural network to predict significant fibrosis (F≥2) (ANN-SF) in HIV/Hepatitis C (HCV) coinfected patients using clinical data derived from peripheral blood. METHODS: Patients were randomly divided into an estimation group (217 cases) used to generate the ANN and a test group (145 cases) used to confirm its power to predict F≥2. Liver fibrosis was estimated according to the METAVIR score. RESULTS: The values of the area under the receiver operating characteristic curve (AUC-ROC) of the ANN-SF were 0.868 in the estimation set and 0.846 in the test set. In the estimation set, with a cut-off value of <0.35 to predict the absence of F≥2, the sensitivity (Se), specificity (Sp), and positive (PPV) and negative predictive values (NPV) were 94.1%, 41.8%, 66.3% and 85.4% respectively. Furthermore, with a cut-off value of >0.75 to predict the presence of F≥2, the ANN-SF provided Se, Sp, PPV and NPV of 53.8%, 94.9%, 92.8% and 62.8% respectively. In the test set, with a cut-off value of <0.35 to predict the absence of F≥2, the Se, Sp, PPV and NPV were 91.8%, 51.7%, 72.9% and 81.6% respectively. Furthermore, with a cut-off value of >0.75 to predict the presence of F≥2, the ANN-SF provided Se, Sp, PPV and NPV of 43.5%, 96.7%, 94.9% and 54.7% respectively. CONCLUSION: The ANN-SF accurately predicted significant fibrosis and outperformed other simple non-invasive indices for HIV/HCV coinfected patients. Our data suggest that ANN may be a helpful tool for guiding therapeutic decisions in clinical practice concerning HIV/HCV coinfection.

Can serum hyaluronic acid replace simple non-invasive indexes to predict liver fibrosis in HIV/Hepatitis C coinfected patients?

BACKGROUND: Hyaluronic acid (HA) serum levels correlate with the histological stages of liver fibrosis in hepatitis C virus (HCV) monoinfected patients, and HA alone has shown very good diagnostic accuracy as a non-invasive assessment of fibrosis and cirrhosis. The aim of this study was to evaluate serum HA levels as a simple non-invasive diagnostic test to predict hepatic fibrosis in HIV/HCV-coinfected patients and to compare its diagnostic performance with other previously published simple non-invasive indexes consisting of routine parameters (HGM-1, HGM-2, Forns, APRI, and FIB-4). METHODS: We carried out a cross-sectional study on 201 patients who all underwent liver biopsies and had not previously received interferon therapy. Liver fibrosis was determined via METAVIR score. The diagnostic accuracy of HA was assessed by area under the receiver operating characteristic curves (AUROCs). RESULTS: The distribution of liver fibrosis in our cohort was 58.2% with significant fibrosis (F≥2), 31.8% with advanced fibrosis (F≥3), and 11.4% with cirrhosis (F4). Values for the AUROC of HA levels corresponding to significant fibrosis (F≥2), advanced fibrosis (F≥3) and cirrhosis (F4) were 0.676, 0.772, and 0.863, respectively. The AUROC values for HA were similar to those for HGM-1, HGM-2, FIB-4, APRI, and Forns indexes. The best diagnostic accuracy of HA was found for the diagnosis of cirrhosis (F4): the value of HA at the low cut-off (1182 ng/mL) excluded cirrhosis (F4) with a negative predictive value of 99% and at the high cut-off (2400 ng/mL) confirmed cirrhosis (F4) with a positive predictive value of 55%. By utilizing these low and high cut-off points for cirrhosis, biopsies could have theoretically been avoided in 52.2% (111/201) of the patients. CONCLUSIONS: The diagnostic accuracy of serum HA levels increases gradually with the hepatic fibrosis stage. However, HA is better than other simple non-invasive indexes using parameters easily available in routine clinical practice only for the diagnosing of cirrhosis.

Association between exposure to nevirapine and reduced liver fibrosis progression in patients with HIV and hepatitis C virus coinfection.

BACKGROUND: We analyzed the effect of exposure to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) on the progression of liver fibrosis in patients with human immunodeficiency virus (HIV) and hepatitis C virus coinfection. METHODS: We analyzed data and liver biopsy findings for 201 coinfected patients. Fibrosis was scored following the French METAVIR Cooperative Study Group. We used multinomial logistic regression analysis and the fibrosis progression rate to assess the association between cumulative exposure to antiretroviral drugs and stage of fibrosis. RESULTS: The adjusted odds ratio (AOR) and 95% confidence interval (CI) of having a fibrosis stage score of 0 or 1, compared with 3 or 4, increased with each additional year of exposure to HAART (AOR, 1.32; 95% CI, 1.04-1,67), to NNRTIs as a class (AOR, 1.64; 95% CI, 1.18-2.27), to efavirenz (AOR, 1.54; 95% CI, 1.03-2.30), and to nevirapine (AOR, 1.72; 95% CI, 1.15-2.78). This effect was not found with PIs as a class. The AOR (95% CI) of having a fibrosis stage score of 2 versus 3 or 4 increased with each additional year of exposure to NNRTIs (AOR, 1.51; 95% CI, 1.08-2.10) and nevirapine (AOR, 1.58; 95% CI, 1.06-2.37). This effect was not found with highly active antiretroviral therapy, PIs, or efavirenz. The AOR (95% CI) of having a fibrosis progression rate < or = 0.1 versus > 0.1 increased with each additional year of exposure to highly active antiretroviral therapy (AOR, 1.31; 95% CI, 1.07-1.60), to NNRTIs (AOR, 1.33; 95% CI, 1.03-1.70), and to nevirapine (AOR, 1.44; 95% CI, 1.07-1.95). This effect was not found with PIs or with efavirenz. CONCLUSIONS: In contrast with previous studies, we found that exposure to NNRTIs was clearly associated with a reduction in fibrosis progression, whereas exposure to PIs was not. Of note, exposure to nevirapine was more consistently associated with a reduction in fibrosis progression than was exposure to efavirenz. Prospective work is needed in this area.

Liver biopsy findings for HIV-infected patients with chronic hepatitis C and persistently normal levels of alanine aminotransferase.

BACKGROUND: Severe liver fibrosis is common in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who have a high alanine aminotransferase (ALT) level. However, little is known about the frequency, liver biopsy findings, and significance of a persistently normal ALT level in coinfected patients. METHODS: We analyzed clinical data and histological findings for 256 patients coinfected with HIV and HCV, 24 (9.4%) of whom had an ALT level within the normal range on > or =2 separate occasions within a 6-month period. RESULTS: The proportion of patients demonstrating advanced stages of fibrosis (F3 and F4) was 78 (33.7%) of 232 patients in the high ALT level group, compared with 0 (0%) of 24 patients in the persistently normal ALT level group (P<.001). Among patients with persistently normal ALT levels, 23 (96%) had any grade of fibrosis, and 7 (29%) had stage F2 of fibrosis. No differences were found between both groups with respect to age, sex, HIV transmission category, Centers for Disease Control and Prevention clinical category, CD4+ cell count (both nadir and baseline values), type of antiretroviral therapy, years since onset of HCV infection, alcohol use, or HCV load. However, the proportion of patients infected with HCV genotype 3 was significantly higher among patients with high ALT levels than in patients with persistently normal ALT levels (61 [26.9%] of 232 patients vs. 1 [4.2%] of 24 patients; P=.04). CONCLUSIONS: Histological abnormalities are significantly milder in patients coinfected with HIV and HCV who have persistently normal ALT levels than those found in patients with high ALT levels. However, a subgroup of patients with persistently normal ALT levels may have significant cases of fibrosis. Liver biopsy may be recommendable in patients coinfected with HIV and HCV who have persistently normal ALT levels, to determine the extent of liver fibrosis and, consequently, to assess suitability for treatment.