Dariela Micheloud

Long-term effects of highly active antiretroviral therapy in pretreated, vertically HIV type 1-infected children : 6 years of follow-up

BACKGROUND Several studies of children with human immunodeficiency virus (HIV) type 1 infection have demonstrated sustained increases in CD4+ cell count, even when virological failure has occurred after receipt of highly active antiretroviral therapy (HAART), but these studies were of limited duration. Moreover, the CD4+ cell count threshold at which antiretroviral treatment should be initiated is still unsettled. The aim of this study was to define the long-term impact of HAART on CD4+ cell percentage and viral load according to CD4+ cell percentages before HAART was initiated. METHODS We conducted a retrospective study of 113 pretreated HIV-1-infected children stratified by pre-HAART CD4+ cell percentage (<5%, 5%-15%, 15%-25%, and >25%). The inclusion criteria were as follows: initiating HAART with a protease inhibitor, having 6 years of follow-up after starting HAART, having a CD4+ cell count or viral load recorded before initiation of HAART, and having received mono- or dual-nucleoside therapy before starting HAART. RESULTS During the first 2 years of HAART, HIV-1-infected children experienced a significant increase in CD4+ cell percentage and a decrease in viral load (P<.05). During their last 4 years of receiving HAART, we found a significant decrease in viral load but not an increase in CD4+ cell percentage, because the CD4+ cell percentage reached a plateau after the second year of HAART. Moreover, children with CD4+ cell percentages of <5% at baseline did not achieve CD4+ cell percentages of >25% after 6 years of HAART. Children with CD4+ cell percentages of 5%-25% at baseline had a strong negative association with achieving CD4+ cell percentages of >30% for at least 6 and 12 months but not with achieving CD4+ cell percentages of >30% for at least 24 months. CONCLUSIONS Long-term HAART allowed for restoration of CD4+ cell counts and control of viral loads in HIV-1-infected children. However, initiating HAART after severe immunosuppression has occurred is detrimental for the restoration of the CD4+ cell count.

Clinical Outcomes Improve with Highly Active Antiretroviral Therapy in Vertically HIV Type-1–Infected Children

Background. Use of antiretroviral therapy has resulted in a decrease in morbidity and mortality rates in human immunodeficiency virus type 1 (HIV-1)-infected children.Methods. We performed a retrospective study involving 427 children to determine the effectiveness of different antiretroviral therapy protocols on clinical outcome. The follow-up period was divided into 5 calendar periods (CPs): CP1 (1980-1989), before antiretroviral therapy was administered; CP2 (1990-1993), when monotherapy was administered; CP3 (1994-1996), when combined therapy was administered; CP4 (1997-1998), when </=50% of children were receiving highly active antiretroviral therapy (HAART); and CP5 (1999-2003), when >/=60% of children were receiving HAART.Results. Children experienced a progressive increase in the CD4(+) cell count and decrease in the viral load from 1997 onwards. A lower number of AIDS cases and deaths occurred during CP5 than during the other CPs (P<.01), with a relative risk of an absence of AIDS of >20 and a relative risk of survival of >30. The AIDS rate was >50% in CP1; we observed a very strong decrease to 14% in CP2, to 16% in CP3, to 7% in CP4, and to 2% in CP5. The mortality rates in CP2 and CP3 were >6% and thereafter decreased to 0.5% in CP5. The relative risks for no hospital admission in CP4 and CP5 were >3.5. The total rates of hospital admission in CP1, CP2, and CP3 were >30%; we observed a decrease in CP4 and CP5. The duration of hospitalization decreased during the follow-up period, and it was higher in CP1 (~30 days) than in the other periods.Conclusions. We observed that HAART produces a decrease in adverse clinical outcomes (i.e., hospital admission, AIDS, and death) in children with vertical HIV-1 infection in Madrid, Spain.

Hepatitis C virus infection is associated with endothelial dysfunction in HIV/hepatitis C virus coinfected patients.

Objective:To quantify serum levels of intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) in HIV/HCV coinfected patients to examine their association with several clinical and epidemiological characteristics and the therapeutic responsiveness to interferon (IFN)-α and ribavirin therapy (IFN-α + RBV). Design:Retrospective study. Methods:We carried out a cross-sectional study with 183 IFN-α-naive patients on HAART, and 24 healthy controls. We also analyzed 30 out of 183 patients on IFN-α + RBV for the duration of 48 weeks. Results:HIV/HCV coinfected patients had higher levels of sICAM-1 and sVCAM-1 than the healthy control group (P < 0.05). Patients with HCV-genotype 1, advanced fibrosis (F≥3) or moderate to severe activity grade (A≥2) had the highest values of sICAM-1 and sVCAM-1. When we carried out a multivariate analysis, we found a significant positive relationship between both HCV-genotype 1 and advanced fibrosis (F≥3) with sICAM-1 (R = 0.549; P < 0.001); and a significant positive relationship between HCV-genotype 1 and advanced fibrosis (F≥3) with sVCAM-1 (R = 0.624; P < 0.001). We also found a positive relationship of sICAM-1 or sVCAM-1 levels with transaminases and alkaline phosphatase circulation levels (P < 0.05). Nonresponder patients had higher sICAM-1 and sVCAM-1 serum levels, and patients with sustained virologic response had significantly lower levels of sICAM-1 (P = 0.001) and sVCAM-1 (P = 0.019). Conclusion:HIV and HCV coinfection induces alterations in sICAM-1 and sVCAM-1 serum levels, which were higher in patients with HCV-genotype 1 and advanced stage of HCV infection. However, response to IFN-α + RBV may reduce these cardiovascular risk markers.

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-1β 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-1β, 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.

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

BackgroundHyaluronic 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).MethodsWe 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).ResultsThe 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.ConclusionsThe 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.

Humoral and cellular immune monitoring might be useful to identify liver transplant recipients at risk for development of infection

Abstract: Orthotopic liver transplantation (OLT) is a successful therapy for patients with end‐stage liver disease, and infection remains a significant cause of morbidity and mortality for patients undergoing this procedure. To assess humoral and cellular immunity markers as potential risk factors for development of infection, 46 consecutive liver transplant recipients (hepatitis C virus cirrhosis [n=17], alcoholic liver disease [n=15], hepatocellular carcinoma [n=9], autoimmune hepatitis [n=2], and other [n=3]) performed at a single center were prospectively studied. Maintenance therapy included tacrolimus (n=37) or cyclosporine (n=9) and prednisone. During follow‐up, 27 patients had at least 1 episode of infection (58.7%). Pre‐OLT immunoglobulin G (IgG) hypergammaglobulinemia (relative risk [RR] 2.78; 95% confidence interval [CI], 1.17–6.60, P=0.02), pre‐OLT IgA hypergammaglobulinemia (RR 2.77, CI=1.24–6.19, P=0.012), and pre‐OLT C3 hypocomplementemia (RR 3.02, CI=1.21–7.55, P=0.018) were associated with an increased risk for development of infection. Monitoring of Ig and complement levels might help to identify the risk of developing infection in OLT.

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.

Serum levels of fibrosis biomarkers measured early after liver transplantation are associated with severe hepatitis C virus recurrence.

Abstract: This prospective study analyzed the relationship between several biological markers related to liver fibrosis at 3 months and 1 year post liver transplantation in 37 patients (19 with hepatitis C virus [HCV], 18 with alcoholic liver disease). Severe HCV recurrence (HCV‐SR) was defined as fibrosis stage ≥F1 (METAVIR score) at 1 year and/or a value of hepatic venous pressure gradient ≥6 mmHg. We found HCV‐SR patients had higher values of monocyte chemotactic protein‐1 (MCP‐1), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), and hyaluronic acid (HA) than non‐severe HCV recurrence patients (P<0.05). Moreover, receiver operating characteristic curve analysis showed that interferon‐inducible protein 10 (IP‐10) (area under the curve [AUC]: 0.74; confidence interval [CI] 95%: 0.49–0.91; P=0.043), MCP‐1 (AUC: 0.78; CI 95%: 0.54–0.94; P=0.007), sVCAM‐1 (AUC: 0.89; CI 95%: 0.67–0.98; P=0.005), and HA (AUC: 0.80; CI 95%: 0.55–0.94; P=0.035) have good predictive capacity for identifying severe HCV infection. The evaluation of these biomarkers may be useful in the early identification of patients in whom a more aggressive therapeutic approach could be necessary.

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.

Epidemiologic trends of cancer diagnoses among HIV-infected children in Spain from 1997 to 2008.

Background: The introduction of highly active antiretroviral therapy (HAART) has influenced the incidence of cancer in people with human immunodeficiency virus (HIV) infection. The aim of this study was to evaluate changes in the pattern of cancer rates in HIV-infected children on HAART during over a decade of follow-up. Patients and Methods: We carried out a case-control study. Data were obtained from the records of the minimum basic data set of hospitals in Spain from 1999 to 2008. The epidemiologic trends of cancer diagnoses were evaluated through 3 calendar periods: early-period HAART: 1997–1999, midperiod HAART: 2000–2002, and late-period HAART: 2003–2008). Results: HIV-infected children had higher rates of cancer diagnosis than HIV-negative children (P < 0.001) for both acquired immunodeficiency disease syndrome (AIDS)-defining malignancies (ADM) and non-AIDS-defining malignancies (non-ADM). The highest rates of cancer diagnosis in HIV-positive children were for non-Hodgkin lymphoma, malignant neoplasm of bone and articular cartilage, and Hodgkin lymphoma. When we compared the 3 calendar periods, we found that the rate of ADM diagnoses decreased (from 9.1 to 3.6 to 1.0 cancers per 1000 HIV-children/yr; P < 0.05) and that the rate of non-ADM diagnoses increased (from 0.6 to 5.0 to 8.7 cancers per 1000 HIV-children/yr; P < 0.05). Moreover, the overall rate of cancer diagnoses (ADM plus non-ADM) did not change during the study period (9.7, 8.7, and 9.7 cancers per 1000 HIV-children/yr). Conclusions: HIV-infected children had a dramatic decrease in the rate of ADM diagnoses and an increase in the rate of non-ADM diagnoses. The overall cancer diagnosis rate has not decreased during the past decade and the incidence of cancer still remains high in HIV-infected children in Spain.