Early prediction of sustained virological response at day 3 of treatment with albinterferon‐α‐2b in patients with genotype 2/3 chronic hepatitis C

Background: Albinterferon‐α‐2b (albIFN) is a long‐acting fusion polypeptide composed of albumin and IFN‐α‐2b. In a phase 2 study of albIFN 1500 μg q2wk or q4wk in patients with genotype 2/3 chronic hepatitis C, albIFN demonstrated sustained virological response (SVR) rates of 62–77% (intent‐to‐treat population). Aims: To assess the association of initial viral kinetics during albIFN therapy with baseline factors and SVR prediction. Methods: In all, 43 patients were treated with albIFN 1500 μg (q2wk/q4wk) plus ribavirin (RBV) 800 mg/day for 24 weeks. Hepatitis C virus (HCV)‐RNA levels were measured by real‐time polymerase chain reaction, insulin resistance by homeostasis model assessment of insulin resistance (HOMA‐IR) and serum albIFN levels by enyzme‐linked immunosorbent assay. Prediction analysis was performed in a per protocol 28‐patient subset who were ≥80% adherent to albIFN/RBV and had HCV‐RNA levels measured at treatment day 3. Results: Day‐3 HCV‐RNA level and first‐phase viral decline as well as second‐phase slope of viral decline were significantly associated with SVR. In adherent patients, 82.1% had a day‐3 viral load <4.2 log₁₀ IU/ml or first‐phase decline >1.25 log₁₀ IU/ml, which was predictive of SVR, both positively (95.7%; sensitivity: 100%) and negatively (100%; specificity: 83.3%). As low first‐phase decline was associated with a high pretreatment HOMA‐IR index (P=0.004) and a low day‐3 serum albIFN level (P=0.01). Conclusions: First‐phase viral decline with albIFN/RBV was predictive of SVR in this study and may be modulated in part by IR.     

Hepatitis C virus‐specific CD8+ T cell frequencies are associated with the responses of pegylated interferon‐α and ribavirin combination therapy in patients with chronic hepatitis C virus infection

Aim: Hepatitis C virus (HCV)‐specific cytotoxic T lymphocytes (CTLs) play critical roles in elimination of the HCV‐infected hepatocytes. However, the mechanism of HCV elimination by pegylated interferon‐α (peg‐IFNα) plus ribavirin is not fully understood. We examined HCV‐specific CTL responses during this combination therapy. Methods: CD8+ T cells were isolated from 16 HCV infected patients treated by this combination therapy and were subjected to IFN‐γ enzyme‐linked immunospot (ELISPOT) assay. Results: The numbers of IFN‐γ spots against HCV Core or NS3 protein‐derived peptides in HCV patients before treatment were similar to those in healthy donors, and those in HCV patients significantly increased 4 weeks after the initiation of combination therapy. All HCV Core or NS3 proteins‐derived peptides specific CD8+ T cells responses in pre‐treated patients were not associated with ALT levels and HCV viral loads of HCV patients before treatment. And those in pre‐treated patients were similar between sustained virologic responder (SVR) patients and non‐SVR patients. Significant increase of HCV Core or NS3 proteins‐derived peptides specific CD8+ T cells responses between before and 4 weeks after this combination therapy were observed in SVR patients, but not in non‐SVR patients. Conclusions: These results demonstrated that significant increase of HCV‐specific CD8+ T cells at 4 weeks after the initiation of IFN treatment might be associated with the elimination of HCV. Our findings suggest that the reactivity against HCV Core and NS3 proteins‐derived peptides might be useful in predicting the clinical outcome of the combination therapy of peg‐IFNα and ribavirin.     

The role of IL‐1β in reduced IL‐7 production by stromal and epithelial cells: a model for impaired T‐cell numbers in the gut during HIV‐1 infection

Abstract. Thang PH, Ruffin N, Brodin D, Rethi B, Cam PD, Hien NT, Lopalco L, Vivar N, Chiodi F (Karolinska Institutet, Stockholm, Sweden; National Institute of Hygiene and Epidemiology, Hanoi, Vietnam; San Raffaele Scientific Institute, Milan, Italy). The role of IL‐1β in reduced IL‐7 production by stromal and epithelial cells: a model for impaired T‐cell numbers in the gut during HIV‐1 infection. J Intern Med 2010; 268 : 181–193. Objectives. Interleukin (IL)‐7 is a key cytokine in T‐cell homeostasis. Stromal cells, intestinal epithelial cells and keratinocytes are known to produce this cytokine. The mechanisms and cellular factors regulating IL‐7 production are still unclear. We assessed whether IL‐1β and interferon (IFN)‐γ, cytokines produced during inflammatory conditions, may impact on IL‐7 production. Design. We used human intestinal epithelial cells (DLD‐1 cell line) and bone marrow stromal cells (HS27 cell line), known to produce IL‐7; IL‐7 production was evaluated at the mRNA and protein levels. To assess whether treatment of HS27 cells with IL‐1β and/or IFN‐γ leads to changes in the gene expression of cytokines, Toll‐like receptors (TLRs) and chemokines, we analysed gene expression profiles using the whole‐genome microarray Human Gene 1.0 ST. Results. We found that IFN‐γ enhanced the expression of IL‐7 mRNA (P < 0.001) in both cell lines. IL‐1β treatment led to a significant down‐regulation (P < 0.001) of IL‐7 mRNA expression in both cell lines. The IL‐7 concentration in supernatants collected from treated DLD‐1 and HS27 cell cultures reflected the trend of IL‐7 mRNA levels. The gene profiles revealed dramatic changes in expression of cytokines and their receptors (IL‐7/IL‐7Rα; IL‐1α,IL‐1β/IL‐1R1; IFN‐γ/IFN‐γR1), of IFN regulatory factors (IRF‐1 and 2), of TLRs and of important chemo‐attractants for T cells. The microarray results were verified by additional methods. Conclusions. Our results are discussed in the setting of inflammation and T‐cell survival in the gut compartment during HIV‐1 infection where stromal and epithelial cells may produce factors that contribute to impaired IL‐7 homeostasis and homing of T cells.     

CD81 expression in peripheral blood lymphocytes before and after treatment with interferon and ribavirin in HIV/HCV coinfected patients

Background

CD81 is expressed on lymphocytes and confers HCV viral infectivity support. The aim of our study was to quantify CD81 expression in peripheral blood B‐ and T‐cells of HCV/HIV‐coinfected patients and healthy subjects to examine its association with several HCV virological characteristics and the therapeutic responsiveness to HCV antiviral treatment.

Methods

We carried out a cross‐sectional study on 122 naïve patients. For a duration of 48 weeks, 24 out of 122 patients underwent HCV antiviral therapy with interferon (IFN)‐α and ribavirin. T‐ and B‐cell subsets were analysed by flow cytometry.

Results

We found that HIV/HCV coinfected patients with HCV‐RNA ≥850 000 IU/mL had lower values of %CD19+CD81‐CD62L+ and %CD19+CD62L+; and higher values of CD19+CD81+CD62L− and CD19+CD81+ percentages and absolute counts than patients with HCV‐RNA <850 000 IU/mL. Similarly, HIV/HCV coinfected patients with the genotype 1 had lower values of %CD19+CD81−CD62L+ and higher values of CD3+CD81+CD62L− and CD3+CD81+ percentages and absolute counts than patients without genotype 1. Moreover, we found that HIV/HCV coinfected patients had higher values of %CD19+HLA‐DR+CD25+, %CD19+CD40+CD25+ and %CD19+CD25+ than healthy control patients. When we studied the B‐ and T‐cell subset kinetics of 24 HIV/HCV coinfected patients on HCV antiviral therapy, we found a significant decrease in CD3+CD81+and CD3+CD81+CD62L− subsets and a significant increase in CD3+CD62L+ and CD3+CD81+CD62L+ percentages and absolute counts, but the variation in these markers disappeared several months after stopping the treatment.

Conclusions

We observed a different pattern of CD81 T‐cell and B‐cell levels in naïve HIV/HCV coinfected patients according to HCV virological status and their subsequent variations during HCV antiviral treatment. CD81 expression might influence HCV pathogenesis and response to HCV antiviral treatment.

     

Baseline sensitivity of T cells to alpha‐IFN correlates with sustained virological response to IFN‐based triple therapy in HCV infection

Chronic infection with HCV is a public health problem with approximately 170 million people infected worldwide. Interferon alpha (IFNα) sensitivity in liver and IL28B genotype has been identified as important determinants of HCV clearance in the setting of pegylated interferon/ribavirin treatment. Herein, we explored IFNα sensitivity in PBMC from 21 healthy donors and 21 HCV‐infected patients treated with pegylated interferon/ribavirin and HCV nonstructural protein‐3 inhibitors (i.e. telaprevir/boceprevir). We explored phospho‐STAT1 level as read‐out for IFN signalling pathway activation in PBMC, T cells and monocytes and correlated results with virological response. We found that PBMC from healthy donors are desensitized to IFNα after priming and challenged with IFNα, with a subsequent decrease of phospho‐STAT1 and interferon‐stimulated genes. Furthermore, we show that CD3+ T cells, but not monocytes, become desensitized after 4 weeks of treatment, with a significant decrease of phospho‐STAT1 after ex vivo IFNα stimulation. Finally, we identified baseline phospho‐STAT1 level in CD3+ T cells as a potential biomarker of sustained virological response, regardless of the IL28B genotype. In the upcoming costly era of IFN‐sparing regimen, baseline IFNα sensitivity could act as biomarker to define cost‐effectiveness strategies of treatment by identifying patients who will or will not respond to IFN‐based treatments.     

Multicenter Study of Pegylated Interferon α‐2a Monotherapy for Hepatitis C Virus‐Infected Patients on Hemodialysis: REACH Study

Many studies have reported poor vital prognosis in hepatitis C virus (HCV)‐infected dialysis patients. The rate of HCV‐infected dialysis patients in Japan is as high as 9.8%, and antiviral therapy is believed to be important for improving vital prognosis. We conducted a multicenter study to examine the administration method for pegylated interferon α‐2a (PEG‐IFNα‐2a) monotherapy in HCV‐infected dialysis. We studied 56 patients: 14 with low viral loads (HCV RNA < 5.0 log IU/mL) were treated with 90 μg PEG‐IFNα‐2a weekly, 42 with high viral loads (HCV RNA ≥ 5.0 log IU/mL) were treated with 135 μg PEG‐IFNα‐2a weekly. We examined the sustained virological response (SVR), factors affecting the SVR, and treatment safety. The overall SVR rate was 39% (22/56); that for genotype 1, genotype 2, low viral loads, and high viral loads was 29%, 67%, 93%, and 21%, respectively. From receiver operating characteristic (ROC) analysis, the HCV RNA cutoff values likely to achieve SVR for genotypes 1 and 2 were <5.7 log IU/mL (SVR rate: 64% 9/14) and <6.5 log IU/mL (SVR rate: 88% 7/8), respectively. If there was HCV RNA negativation at 4 weeks (rapid virological response), the SVR rate was 94% (16/17), whereas it was 6% (1/16) if there was HCV RNA positivity at 24 weeks. The rate of treatment discontinuation from adverse events or aggravated complications was 25% (14/56). High SVR rates can potentially be achieved with PEG‐IFN monotherapy by identifying the target patients, based on virus type and viral load before initiating treatment and by modifying therapy during treatment according to responsiveness.     

The development of systemic lupus erythematosus following interferon‐α therapy for hepatitis C infection

Interferon‐alpha (IFN‐α) therapy has been associated with de novo development of systemic lupus erythematosus (SLE), and discontinuation of IFN‐α resulted in disease resolution in most patients. Recurrence of SLE in the absence of concomitant IFN‐α therapy has not been reported. We present here a woman who developed overt clinical manifestations of SLE one year after withdrawal of IFN‐α therapy for hepatitis C virus (HCV) infection. This report highlights the importance of long‐term follow‐up for the belated development of SLE in patients who have experienced IFN‐α induced autoimmune phenomena.     

Predicting efficacy and safety outcomes in patients with hepatitis C virus genotype 1 and persistently ‘normal’ alanine aminotransferase levels treated with peginterferon α‐2a (40KD) plus ribavirin

Background: Currently, the approved dosage of ribavirin has not been studied in patients with ‘normal’ alanine aminotransferase (ALT) levels. Methods: Modelling and simulations were performed using generalised additive models (GAMs) to predict the incidence of anaemia and rate of sustained virological response (SVR) in patients with hepatitis C virus (HCV) genotype 1 and persistently ‘normal’ ALT levels treated with peginterferon α‐2a (40KD) 180 μg/week plus ribavirin 1000/1200 mg/day for 48 weeks. Results: Model‐based simulations predicted that SVR rates would increase from 39 to 48% if patients with genotype 1 and persistently ‘normal’ ALT levels had received the standard weight‐adjusted dose of ribavirin. This was similar to the predicted 49% SVR rate for genotype 1 patients with elevated ALT levels. The incidence of anaemia was predicted to increase from 13% to 23% in patients with persistently ‘normal’ ALT activity and was higher than that predicted for patients with elevated ALT levels; however, the difference appeared to be largely explained by the higher proportion of women in the former group. Conclusions: Simulations based on GAM suggest that regimens for patients with HCV genotype 1 should include the standard weight‐adjusted dose of ribavirin, as similar SVR rates are predicted to be achieved, regardless of patients' ALT status at baseline.