Longitudinal evolution of vertically HIV/HCV–co‐infected vs HCV–mono‐infected children

HIV co‐infection has been suggested to play a deleterious role on the pathogenesis of liver fibrosis among vertically HCV‐infected children. The aim of this study was to describe the longitudinal evolution of vertically acquired HIV/HCV co‐infection in youths, in comparison with HCV infection alone. This was a retrospective, multicentre study including vertically HIV/HCV–co‐infected patients and age‐ and sex‐matched vertically HCV–mono‐infected patients. Progression to advanced liver fibrosis, defined as F3 or more by elastography or METAVIR biopsy staging, and response to treatment were compared by means of univariate and multivariate regression analyses and Cox regression models. Sixty‐seven co‐infected patients were compared with 67 matched HCV–mono‐infected patients. No progression to advanced liver disease was observed during the first decade. At a median age of 20.0 [19.0, 22.0] years, 26.7% co‐infected vs 20% mono‐infected had progressed to advanced fibrosis (P = .617). Peg‐IFN/RBV for HCV treatment was given to 37.9% vs 86.6% (P‐value < .001). At treatment initiation, co‐infected patients were older (16.9 ± 4.1 vs 11.7 ± 4.5 years, P < .001), and 47.1% vs 7.1% showed advanced fibrosis (P < .003), with no differences in hard‐to‐treat genotype distribution. Sustained viral response was comparable between groups (43.5% vs 44.0%, P = .122). In vertically HIV/HCV–co‐infected patients, the progression to liver fibrosis was rare during childhood. At the end of adolescence, over 25% of patients displayed advanced liver disease. Response to Peg‐IFN/RBV was poor and comparable in both groups, supporting the need for fast access to early treatment with direct‐acting antivirals against HCV for vertically co‐infected patients.     

Correlates of high hepatitis C virus RNA load in a cohort of HIV‐negative and HIV‐positive individuals with haemophilia

Summary. Hepatitis C virus (HCV) treatment failure and disease progression are more likely with high HCV‐RNA load. Correlates of high HCV‐RNA load in individuals with haemophilia are largely unknown. Among 1266 interferon naïve HCV‐infected individuals with haemophilia, we compared those with high (>2 × 10⁶ HCV‐RNA copies/mL) to lower viral load, overall and stratifying on HIV co‐infection status using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Overall, high HCV load was independently associated with longer duration of HCV infection (P_trend = 0.0001), body mass index ≥25 kg/m² (OR = 1.4, 95% CI = 1.1–1.9), and HIV co‐infection (OR = 1.4, 95% CI = 1.0–1.8). Among 795 HIV‐negative participants, high HCV‐RNA load was associated with older age at HCV acquisition (OR = 1.9 for >15 years vs≤2 years, P_trend = 0.008), and lower AST/platelet ratio (P_trend = 0.01), in addition to longer duration of HCV infection (P_trend = 0.0008), and body mass index ≥25 kg/m² (OR = 1.6, P = 0.005). Among 471 HIV‐positive individuals, anti‐retroviral therapy (ART) was the only variable associated with high HCV‐RNA load (OR = 1.8, CI = 1.1–2.9 for combination ART; OR = 1.8, CI = 0.9–3.4, for other ART vs no treatment). High HCV‐RNA load with haemophilia is more likely with longer duration of infection, older age at infection, higher body mass index, and antiretroviral therapy. These findings may help identify individuals at increased risk of HCV treatment failure and progression to end‐stage liver disease.     

Efficacy and safety of pegylated interferon alpha‐2a therapy for chronic hepatitis C in HIV‐infected patients with haemophilia

Summary. The objective of this study was to evaluate the efficacy and safety of pegylated interferon (PEG‐IFN) alpha‐2a monotherapy in a cohort of Chinese haemophilic patients co‐infected with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) and undergoing highly active antiretroviral drugs therapy. Twenty‐two (n = 22) patients with CD4 lymphocyte counts over 200 cells μL^?1 were treated with 180 μg of PEG‐IFN alpha‐2a subcutaneously once in a week for 48 weeks. HCV load (HCV RNA), HIV load (HIV RNA) and CD4 lymphocyte counts were measured at baseline and 4, 12, 24, 48 and 72 weeks after initiation of anti‐HCV therapy. Efficacy and safety were analysed according to baseline CD4 status (≥350 cells μL^?1). Significant HCV‐RNA decreases (>1 log₁₀ copies mL^?1) were observed through week 72 after PEG‐INF alpha‐2a monotherapy across both CD4 strata. CD4 status was not associated with treatment outcomes as evaluated using rapid viral response rate (P = 0.655), early viral response rate (P = 0.387), end‐of‐treatment viral response rate (P = 1.000) or sustained viral response rate (SVR, P = 0.674). A sustained virological response was achieved in nine patients (41%), five with genotype 2a (83%) and four with genotype 1b (25%, P = 0.023). SVR was HCV genotype dependent. Eleven patients required a dose reduction in PEG‐IFN alpha‐2a. PEG‐IFN alpha‐2a monotherapy could be considered as a safe and effective option for the treatment of HCV infection in HIV patients with haemophilia, particularly in resource‐limited settings. While higher CD4 lymphocyte counts resulted in greater HCV‐RNA reduction, HCV genotype was a predictor for sustained virological response.     

Memory re‐differentiation and reduced lymphocyte activation in chronic HCV‐infected patients receiving direct‐acting antivirals

Recently, the treatment of HCV has advanced significantly due to the introduction of direct‐acting antivirals (DAAs). Studies using interferon (IFN)‐containing regimens failed to consistently show restoration of immunologic responses. Therefore, IFN‐free DAA formulations provide a unique opportunity to dissect the immunologic effect of HCV cure. This study investigates the restoration of the immune compartment as a consequence of rapid viral clearance in patients successfully treated with DAAs and in the absence of IFN and ribavirin. Here, we evaluate the immunologic changes that occurred following DAA‐mediated HCV cure. Peripheral blood from nineteen previously treatment‐naïve patients with chronic HCV genotype 1a/1b who received an IFN and ribavirin‐free regimen of daclatasvir, asunaprevir and BMS‐791325 was evaluated. Immune reconstitution occurs in patients in whom HCV was successfully eradicated via DAA therapy. Restoration of the CD4⁺ T‐cell compartment in the peripheral blood and a re‐differentiation of the T lymphocyte memory compartment resulted in a more effector memory cell population and a reduction in expression in the co‐inhibitory molecule TIGIT in bulk T lymphocytes. Furthermore, we observed a partial reversal of the exhausted phenotype in HCV‐specific CD8⁺ T cells and a dampening of the activation state in peripheral NK cells. Collectively, our data provide the groundwork for dissecting the effect of DAA therapy on the immune system and identifying novel mechanisms by which chronic HCV infection exerts immunosuppressive effects on T cells through the recently described co‐inhibitory molecule TIGIT.     

Schistosome infection aggravates HCV‐related liver disease and induces changes in the regulatory T‐cell phenotype

Schistosome infections are renowned for their ability to induce regulatory networks such as regulatory T cells (Treg) that control immune responses against homologous and heterologous antigens such as allergies. However, in the case of co‐infections with hepatitis C virus (HCV), schistosomes accentuate disease progression and we hypothesized that expanding schistosome‐induced Treg populations change their phenotype and could thereby suppress beneficial anti‐HCV responses. We therefore analysed effector T cells and n/iTreg subsets applying the markers Granzyme B (GrzB) and Helios in Egyptian cohorts of HCV mono‐infected (HCV), schistosome‐co‐infected (Sm/HCV) and infection‐free individuals. Interestingly, viral load and liver transaminases were significantly elevated in Sm/HCV individuals when compared to HCV patients. Moreover, overall Treg frequencies and Helios^posTreg were not elevated in Sm/HCV individuals, but frequencies of GrzB⁺Treg were significantly increased. Simultaneously, GrzB⁺ CD8⁺ T cells were not suppressed in co‐infected individuals. This study demonstrates that in Sm/HCV co‐infected cohorts, liver disease is aggravated with enhanced virus replication and Treg do not expand but rather change their phenotype with GrzB possibly being a more reliable marker than Helios for iTreg. Therefore, curing concurrent schistosome disease could be an important prerequisite for successful HCV treatment as co‐infected individuals respond poorly to interferon therapy.     

Hepatic compartmentalization of exhausted and regulatory cells in HIV/HCV‐coinfected patients

Accelerated intrahepatic hepatitis C virus (HCV) pathogenesis is likely the result of dysregulation within both the innate and adaptive immune compartments, but the exact contribution of peripheral blood and liver lymphocyte subsets remains unclear. Prolonged activation and expansion of immunoregulatory cells have been thought to play a role. We determined immune cell subset frequency in contemporaneous liver and peripheral blood samples from chronic HCV‐infected and HIV/HCV‐coinfected individuals. Peripheral blood mononuclear cells (PBMC) and biopsy‐derived liver‐infiltrating lymphocytes from 26 HIV/HCV‐coinfected, 10 chronic HCV‐infected and 10 HIV‐infected individuals were assessed for various subsets of T and B lymphocytes, dendritic cell, natural killer (NK) cell and NK T‐cell frequency by flow cytometry. CD8⁺ T cells expressing the exhaustion marker PD‐1 were increased in HCV‐infected individuals compared with uninfected individuals (P = 0.02), and HIV coinfection enhanced this effect (P = 0.005). In the liver, regulatory CD4⁺CD25⁺Foxp3⁺ T cells, as well as CD4⁺CD25⁺PD1⁺ T cells, were more frequent in HIV/HCV‐coinfected than in HCV‐monoinfected samples (P < 0.001). HCV was associated with increased regulatory T cells, PD‐1⁺ T cells and decreased memory B cells, regardless of HIV infection (P ≤ 0.005 for all). Low CD8⁺ expression was observed only in PD‐1⁺CD8⁺ T cells from HCV‐infected individuals and healthy controls (P = 0.002) and was associated with enhanced expansion of exhausted CD8⁺ T cells when exposed in vitro to PHA or CMV peptides. In conclusion, in HIV/HCV coinfection, ongoing HCV replication is associated with increased regulatory and exhausted T cells in the periphery and liver that may impact control of HCV. Simultaneous characterization of liver and peripheral blood highlights the disproportionate intrahepatic compartmentalization of immunoregulatory T cells, which may contribute to establishment of chronicity and hepatic fibrogenesis in HIV coinfection.     

Stronger hepatitis C virus‐specific CD8+ T‐cell responses in HIV coinfection

Summary. Hepatitis C virus (HCV) is a widespread chronic infection that shares routes of transmission with human immunodeficiency virus (HIV). Thus, coinfection with these viruses is a relatively common and growing problem. In general, liver disease develops over years with HIV coinfection, when compared to decades in HCV monoinfection. The role of the immune system in the accelerated pathogenesis of liver disease in HIV/HCV coinfection is not clear. In this study, we compared the frequency, magnitude, breadth and specificity of peripheral blood CD4⁺ and CD8⁺ T‐cell responses between HCV‐monoinfected and HCV/HIV‐coinfected individuals and between HIV/HCV‐coinfected subgroups distinguished by anti‐HCV antibody and HCV RNA status. While HIV coinfection tended to reduce the frequency and breadth of anti‐HCV CD8⁺ T‐cell responses in general, responses that were present were substantially stronger than in monoinfection. In all groups, HCV‐specific CD4⁺ T‐cell responses were rare and weak, independent of either nadir or concurrent CD4⁺ T‐cell counts of HIV‐infected individuals. Subgroup analysis demonstrated restricted breadth of CD8⁺ HCV‐specific T‐cell responses and lower B‐cell counts in HIV/HCV‐coinfected individuals without anti‐HCV antibodies. The greatest difference between HIV/HCV‐coinfected and HCV‐monoinfected groups was substantially stronger HCV‐specific CD8⁺ T‐cell responses in the HIV‐coinfected group, which may relate to accelerated liver disease in this setting.     

T-lymphocyte populations in hepatitis C and HIV co-infected patients treated with interferon-alfa-2a and ribavirin

Objective

The effects on T‐lymphocyte populations of two interferon‐alfa‐2a (IFN) regimens associated with ribavirin were evaluated in 36 HCV‐HIV co‐infected patients with chronic hepatitis C, T‐CD4 cell count > 250 cells/µL and a plasma viral load of < 10 000 HIV RNA copies/mL.

Methods

Patients were given IFN for 48 weeks. Group A (18 patients) received 6 mega units (MU) subcutaneously three times a week for 24 weeks, then 3 MU three times a week for the last 24 weeks. Group B (18 patients) received 9 MU daily for 2 weeks, 3 MU daily for 22 weeks, then 3 MU three times a week for the last 24 weeks. Serum HCV RNA was evaluated at weeks 12 and 72. Ribavirin was added at week 16 for virologic nonresponders at week 12. CD3, CD3 CD4, CD3 CD8, CD3 CD4 human leucocyte antigen (HLA)‐DR and CD3 CD8 HLA‐DR lymphocyte subsets were evaluated before, during and after treatment by cytofluorometry. Controls were healthy and HCV mono‐infected patients.

Results

CD3 CD4 and CD3 CD8 T‐cells counts were both impaired during anti‐HCV therapy, but returned to baseline value after treatment completion. Lymphopenia concerned mainly CD8 T‐cells, the percentage of which decreased, whereas that of CD4 increased. Three patients displayed reversible CD4 lymphopenia < 200 cells/µL. HIV infection at inclusion was responsible for higher CD3 CD8 HLA‐DR T‐cell percentages in co‐infected patients than in healthy and HCV mono‐infected subjects. T‐cell sequestration in lymphoid tissues and enhanced apoptosis may account for lymphopenia.

Conclusion

High‐dosed IFN anti‐HCV therapy induced only moderate and transient CD4 lymphopenia in HIV co‐infected patients.

     

Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa‐2a/ribavirin

Summary. It is unclear whether the current threshold for ‘high’ hepatitis C virus (HCV) RNA level (800 000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono‐infected and 176 HIV–HCV co‐infected patients treated with peginterferon alfa‐2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono‐infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70%vs 43%) when 400 000 IU/mL was used and 16% (59%vs 43%) when 800 000 IU/mL was used. In HIV–HCV genotype 1 co‐infected patients, the difference was 51% (71%vs 20%) when 400 000 IU/mL was used and 43% (61%vs 18%) when 800 000 IU/mL was used. A lower threshold (200 000 IU/mL) was identified for genotype 1 mono‐infected patients with ‘normal’ alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400 000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1‐infected individuals with elevated ALT.     

HIV–HCV co‐infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension

Summary. Patients co‐infected with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) are fraught with a rapid fibrosis progression rate and with complications of portal hypertension (PHT) We aimed to assess the influence of immune function [Centers of Disease Control and Prevention (CDC) stage] on development of PHT and disease progression in HIV–HCV co‐infection. Data of 74 interferon‐naïve HIV–HCV co‐infected patients undergoing liver biopsy, measurement of portal pressure and of liver stiffness and routine laboratory tests (including CD4+ cell count, HIV and HCV viral load) were analysed. Time of initial exposure (risk behaviour) was used to assess fibrosis progression. Fibrosis progression, time to cirrhosis and portal pressure were correlated with HIV status (CDC stage). HIV–HCV patients had rapid progression of fibrosis [0.201 ± 0.088 METAVIR fibrosis units/year (FU/y)] and accelerated time to cirrhosis (24 ± 13 years), high HCV viral loads (4.83 × 10⁶ IU/mL) and a mean HVPG at the upper limit of normal (5 mmHg). With moderate or severe immunodeficiency, fibrosis progression was even higher (CDC‐2 = 0.177 FU/y; CDC‐3 = 0.248 FU/y) compared with patients with higher CD4+ nadirs (CDC‐1 = 0.120 FU/y; P = 0.0001). An indirect correlation between CD4+ cell count and rate of fibrosis progression (R = ?0.6654; P < 0.001) could be demonstrated. Hepatic venous pressure gradient (HVPG) showed early elevation of portal pressure with median values of 4, 8 and 12 mmHg after 10, 15 and 20 years of HCV infection for CDC‐3 patients. Patients treated with highly active anti‐retroviral therapy (HAART) had similar rates of progression and portal pressure values than patients without HAART. Progression of HCV disease is accelerated in HIV–HCV co‐infection, being more pronounced in patients with low CD4+ cell count. A history of a CD4+ cell nadir <200/μL is a risk factor for rapid development of cirrhosis and PHT. Thus, HCV treatment should be considered early in patients with HIV–HCV co‐infection and largely preserved CD4+ cell counts.     

Acute and chronic immune biomarker changes during interferon/ribavirin treatment in HIV/HCV co‐infected patients

Chronic viral infections lead to persistent immune activation, which is alleviated by eradicating or suppressing the infection. To understand the effects of interferon treatment on immune system activation by chronic infections, we evaluated kinetic patterns of a broad spectrum of serum biomarkers during HCV treatment in HIV/HCV co‐infected patients. HCV viral load and 50 biomarkers were analysed at baseline and 27 time points during pegylated interferon‐alpha and ribavirin (IFN/RBV) treatment of 12 HIV/HCV co‐infected patients. We evaluated biomarker changes from baseline for each time point and biomarker correlations with clinical parameters, treatment response and liver histopathology. IL‐1α, IL‐12p40, IL‐1RA, IP‐10, MIG, MIP‐1α/1β, HGF, sCD40L, TRAIL and leptin increased in the first day. IL‐12p70, IL‐17A, IL‐10, GROα, IL‐8, MCP‐3, IL‐4 and M‐CSF peaked later during week 1. IL‐1α, HGF, IP‐10, MIP‐1α, TRAIL, sCD40L, IL‐10, IL‐12p70, MCP‐3, FGFb, ENA‐78, TGF‐β, IL‐2, IFN‐γ, IL‐6, IL‐15, IL‐7 and PDGF‐BB decreased below baseline over the course of treatment. Higher BMI, baseline HCV viral load and leptin levels were associated with lack of sustained virologic response. ENA‐78 was associated with sustained viral response. Positive correlations were found between liver inflammation and baseline CD4 count, sVCAM and HGF; fibrosis stage and HGF; liver steatosis, BMI and leptin. Our findings suggest IFN/RBV treatment initially increases levels of several biomarkers, but eventually leads to a decline in many immune markers. These findings shed light on the relationship between IFN treatment and immune activation by chronic viral infections, such as HCV.     

The individual and combined influence of HIV and hepatitis C virus on dyslipidaemia in a high-risk Hispanic population

Objectives

To assess the effects of chronic hepatitis C (HCV) and HIV infection on dyslipidaemia in a Hispanic population at high risk of insulin resistance.

Methods

We compared serum lipids and C‐reactive protein (CRP) in 257 Hispanic adults including 47 HIV‐ mono‐infected, 43 HCV‐mono‐infected and 59 HIV/HCV‐co‐infected individuals as well as 108 healthy controls. We also assessed the effect of HCV on lipid alterations associated with antiretroviral therapy (ART), and the impact of HCV and HIV on the associations among insulin resistance, triglycerides and cholesterol.

Results

HCV infection was associated with lower total and low‐density lipoprotein (LDL) cholesterol, but not high‐density lipoprotein (HDL) cholesterol or triglycerides compared with healthy controls. HIV infection was associated with higher triglycerides and lower HDL, but not total or LDL cholesterol. HCV mitigated the elevation of triglycerides associated with ART. In healthy Hispanic adults, insulin resistance was significantly correlated with higher triglycerides, CRP and lower HDL. HIV infection nullified the association of insulin resistance with triglycerides and HDL, and the association of triglycerides with LDL. HCV infection nullified the association of insulin resistance with triglycerides, HDL and CRP.

Conclusions

HCV co‐infection alters the profile of HIV‐associated dyslipidaemia. The clinical significance of these findings for cardiovascular complications in HIV merits further study.     

The impact of HIV/HCV co‐infection on health care utilization and disability: results of the ACTG Longitudinal Linked Randomized Trials (ALLRT) Cohort

Summary. HIV/hepatitis C virus (HCV) co‐infection places a growing burden on the HIV/AIDS care delivery system. Evidence‐based estimates of health services utilization among HIV/HCV co‐infected patients can inform efficient planning. We analyzed data from the ACTG Longitudinal Linked Randomized Trials (ALLRT) cohort to estimate resource utilization and disability among HIV/HCV co‐infected patients and compare them to rates seen in HIV mono‐infected patients. The analysis included HIV‐infected subjects enrolled in the ALLRT cohort between 2000 and 2007 who had at least one CD4 count measured and completed at least one resource utilization data collection form (N = 3143). Primary outcomes included the relative risk of hospital nights, emergency department (ED) visits, and disability days for HIV/HCV co‐infected vs HIV mono‐infected subjects. When controlling for age, sex, race, history of AIDS‐defining events, current CD4 count and current HIV RNA, the relative risk of hospitalization, ED visits, and disability days for subjects with HIV/HCV co‐infection compared to those with HIV mono‐infection were 1.8 (95% CI: 1.3–2.5), 1.7 (95% CI: 1.4–2.1), and 1.6 (95% CI: 1.3–1.9) respectively. Programs serving HIV/HCV co‐infected patients can expect approximately 70% higher rates of utilization than expected from a similar cohort of HIV mono‐infected patients.     

Eradication of hepatitis C virus could improve immunological status and pyoderma gangrenosum‐like lesions

Hepatitis C virus (HCV) can affect immune cells and induce various kinds of immune‐related diseases including pyoderma gangrenosum. We experienced a difficult‐to‐treat case of pyoderma gangrenosum‐like lesions in a patient with HCV infection. The patient was treated with pegylated interferon (PEG IFN)‐α‐2b and ribavirin (RBV) therapy and achieved a sustained virological response. Before the eradication of HCV, the frequency of T‐helper 17 cells was remarkably high in comparison to chronic hepatitis C patients without extrahepatic immune‐related diseases. Moreover, we could detect negative and positive strand‐specific HCV RNA in the CD19⁺ B lymphocytes and CD4⁺ T lymphocytes. However, after the eradication of HCV, the immunological status became normal and the pyoderma gangrenosum‐like lesions became stable without immunosuppressive therapy. Here, we report a sequential immunological analysis during PEG IFN/RBV therapy and the beneficial effect of HCV eradication in difficult‐to‐treat pyoderma gangrenosum‐like lesions.     

Effect of hepatitis C virus on immunological and virological responses in HIV‐infected patients initiating highly active antiretroviral therapy: a meta‐analysis

Co‐infection of human immunodeficiency virus (HIV) with hepatitis C virus (HCV) is rather common. In the era of highly active antiretroviral therapy (HAART), viral hepatitis could result in adverse outcomes in HIV+ patients. The current meta‐analysis aims to evaluate the impact of HCV on immunological and virological responses after HAART initiation in HIV/HCV co‐infected individuals by synthesizing the existing scientific evidence. A comprehensive search of electronic databases was performed. Eligible studies were analysed using univariate and multivariate meta‐analytic methods. Totally, 21 studies involving 22533 individuals were eligible. The estimated summary difference in CD4 cell counts increase between HIV and HIV/HCV co‐infected subjects after 3–12 months on HAART was 34.86 cells/mm³ [95% confidence interval (CI): 16.82–52.89]. The difference was more prominent in patients with baseline CD4 counts below 350 cells/mm³ (38.97, 95% CI: 20.00–57.93) and attenuated 2 years later (13.43, 95% CI: 0.83–26.04). The analysis of ratio measures yielded similar findings. The virological control remained unaffected by the presence of HCV (adjusted Hazard Ratio for co‐infected patients vs those with HIV alone: 0.99, 95% CI: 0.91–1.07). The bivariate meta‐analytic method confirmed the results of the univariate approaches. This meta‐analysis supports the adverse effect of HCV on immune recovery of HIV+ patients initiating HAART, especially of those with initially impaired immunologic status. Although this effect diminishes over time, early administration of HAART in the setting of co‐infection seems to be justified.     

THIS ARTICLE HAS BEEN RETRACTED: Haemodynamic derangement in human immunodeficiency virus‐infected patients with hepatitis C virus‐related cirrhosis: the role of bacterial translocation

Background and aims: Analysis of the influence of the effects of increased intestinal permeability on haemodynamic alterations in human immunodeficiency virus (HIV)‐infected patients with decompensated hepatitis C virus (HCV)‐related liver disease. Methods: Forty HIV/HCV co‐infected patients and 40 HCV mono‐infected patients, 20 of them with compensated cirrhosis and 20 with a previous decompensation, and 20 healthy controls, were studied. Intestinal permeability was determined by serum levels of lipopolysaccharide‐binding protein (LBP). Monocyte expression of toll‐like receptor 4 (TLR‐4), serum levels of interleukin (IL)‐6 and soluble receptors of tumour necrosis factor (sTNFRI) were analysed. Cardiac index, systemic vascular resistance (SVR), plasma renin activity (PRA) and aldosterone concentration were also determined in cirrhotic patients. Results: Serum levels of LBP, TLR‐4, IL‐6 and sTNFRI were significantly higher in HIV–HCV co‐infected and HCV mono‐infected patients with decompensated cirrhosis compared with those with compensated liver disease. Significantly lower values of SVR and higher values of cardiac index, PRA and aldosterone concentration were observed in patients with decompensated cirrhosis compared with those with compensated liver disease, particularly in those with elevated levels of IL‐6. There were no significant differences between HIV/HCV co‐infected and HCV mono‐infected patients. Conclusions: Higher intestinal permeability and consequent macrophage activation is observed in patients with cirrhosis; this permeability is even higher in those with portal hypertension. Serum values of IL‐6 are associated with the characteristic haemodynamic derangement observed in advanced phases of cirrhosis. HIV/HCV co‐infected cirrhotic patients present inflammatory and systemic haemodynamic alterations similar to those observed in HCV mono‐infected patients.     

Characteristics of regulatory T‐cell function in patients with chronic hepatitis B and C coinfection

Regulatory T cells (Tregs) affect the pathogenesis and disease progression of chronic viral hepatitis. This study evaluated the frequency and function of Tregs in patients with chronic HBV/HCV coinfection. Seventy‐four untreated HBV/HCV co‐infected patients were enrolled in this study. These subjects were divided into four subgroups: HBV‐active/HCV‐active (BACA), HBV‐inactive/HCV‐active (BICA), HBV‐active/HCV‐inactive (BACI) and HBV‐inactive/HCV‐inactive (BICI). Treg frequency was calculated as the fraction of CD4⁺Foxp3⁺T cells among CD4⁺T cells. Treg‐mediated inhibition was measured as percent of inhibition of T‐cell proliferation. The expression of interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α and interleukin (IL)‐10 with/without Treg inhibition was also studied. Among the patients, there were 8 cases of BACA (10.8%), 38 of BICA (51.4%), 14 of BACI (18.9%) and 14 of BICI (18.9%). The frequency of CD4⁺Foxp3⁺T cells was comparable between the four groups. The inhibitory function of Tregs among the patients in the BACA and BICA was higher than that in the BICI (BACA vs BICI, P = .0210; BICA vs BICI, P = .0301). Patients in the BACA and BICA had higher fibrosis‐4 (FIB‐4) scores and serum ALT levels and lower serum albumin levels than those of the other groups. ALT abnormality was significantly and independently associated with a higher Treg immunosuppressive ability. The IFN‐γ expression of the effector T cells in the BACA was higher than that of the other groups. In conclusion, the inhibitory function of Tregs is higher among the HBV/HCV co‐infected patients with active HCV infection. ALT abnormality plays a dominant role in Treg function.     

HCV RNA decline in chronic HCV genotype 2 and 3 during standard of care treatment according to IL28B polymorphism

The IL28 gene is highly associated with sustained viral response (SVR) in patients infected with genotype 1 after standard of care (SOC) treatment with peg‐IFN and ribavirin. It is also associated with a steeper first phase HCV RNA decline during treatment. In genotype 2 and 3 infections, these correlations are less obvious. We studied the IL28B association to rapid viral response (RVR), SVR, first and second phase HCV RNA decline during treatment in 100 HCV mono‐infected and 13 HCV/HIV co‐infected patients. We found a significantly higher mean baseline HCV RNA level in IL28B SNP CC than non‐CC mono‐infected patients, 6.99 vs 6.30 log₁₀ IU/mL (P = 0.02), and a significantly larger median 1st phase decline in patients with CC than non‐CC genotype, 2.03 vs 1.37 log₁₀ IU/mL, respectively. The overall SVR rate in HCV mono‐infected patients was 87% vs 77% in HCV/HIV co‐infected patients, with no correlation to IL28B SNP. In mono‐infected patients with RVR, the SVR rate was high and independent of IL28B genotype. In mono‐infected patients who failed to achieve RVR who had IL28B CC and non‐CC genotype, 64% and 67% achieved SVR, respectively. In genotype 2 and 3 infected patients, the 1st phase HCV RNA decline was steeper in patients with IL28B CC vs non‐CC genotype during SOC treatment. This did not translate into a higher frequency of RVR or SVR. Hence, the clinical relevance of pretreatment analysis of IL28B polymorphisms in genotype 2 and 3 infected patients can be questioned in patients with expected high SVR rate.     

A multicentre,randomized study to evaluate the safety and efficacy of histamine dihydrochloride and interferon-alpha-2b for the treatment of chronic hepatitis C

summary . Interferon‐ (IFN‐)α is currently the standard of care treatment for patients with chronic hepatitis C virus (HCV) infection. A significant part of the benefit of IFN‐α in chronic hepatitis C is believed to be related to the activation of lymphocytes such as T cells and natural killer (NK) cells, which participate in the elimination of infected cells. Histamine dihydrochloride (HDC) has been shown to potentiate the IFN‐α‐induced activation of T cells and NK cells by a mechanism that involves the protection of these lymphocytes against oxygen radical‐induced functional inhibition and apoptosis. This study was designed to examine the efficacy and safety of HDC in combination with IFN‐α‐2b in treatment‐naïve patients with chronic HCV infection. All patients received IFN‐α‐2b, 3 MIU, three times weekly via subcutaneous injection, and were randomized to one of four HDC regimens (1 mg of either: once a day, three times a week; once a day, five times a week; twice a day, three times a week or; twice a day, five times a week). The doses of HDC in combination with IFN‐α‐2b resulted in sustained viral response rates ranging from 31% to 38%. Sustained biochemical response rates ranged from 28% to 41% across the four treatment groups. Patients infected with HCV genotype 1, and those with high baseline viral levels, which are characteristics associated with poor prognosis, had sustained virologic response rates ranging from 18% to 42% and 15% to 39%, respectively. Combination treatment was generally well tolerated. We propose that the potential benefit of HDC + IFN therapy for chronic HCV infection should be the focus of further investigation.     

Circulating CD56dim natural killer cells and CD56+ T cells that produce interferon‐γ or interleukin‐10 are expanded in asymptomatic,E antigen‐negative patients with persistent hepatitis B virus infection

Infection with hepatitis B virus (HBV) can result in spontaneous resolution or chronic infection, which can remain asymptomatic or can progress to cirrhosis and/or hepatocellular carcinoma. The host immune response is thought to be a major determinant of the outcome of HBV infection and virus‐specific cytotoxic T lymphocytes (CTL) can mediate immunity against the virus and cause liver pathology. Antigen‐nonspecific innate lymphocytes may also contribute to HBV infection and liver disease, therefore, we examined the frequencies, phenotypes, cytolytic activities and cytokine profiles of circulating natural killer (NK) cells, CD1d‐restricted invariant natural killer T (iNKT) cells and CD56⁺ T cells in 102 asymptomatic HBV‐infected patients and compared them with those in 66 uninfected control subjects. NK cells expressing low levels of CD56 (CD56^dim) and CD56⁺ T cells were significantly expanded in the circulation of HBV‐infected patients compared with control subjects. CD1d expression and iNKT cell frequencies were similar in both groups. Despite these expansions, we did not detect augmented natural or cytokine‐induced cytotoxicity in the HBV‐infected subjects. All lymphocyte populations studied produced interferon‐γ (IFN‐γ) significantly more frequently when taken from HBV‐infected patients compared with when taken from healthy controls. Additionally, NK cells from the patients more frequently produced interleukin‐10. As our HBV‐infected cohort consisted of asymptomatic patients with low viral loads, we propose that CD56^dim NK cells and CD56⁺ T cells control HBV infection by noncytolytic mechanisms.