Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis

Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that genetics also shape the gut microbiota.It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to CIA.Here,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched B.fragilis than DBA/1J mice and RA patients.Transplantation of B.fragilis prevents CIA in DBA/1J mice.We identify that B.fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate.Fibroblast-like synoviocytes(FLSs)in RA are activated to undergo tumor-like transformation.Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of RA-FLSs.We treat CIA mice with propionate and show that propionate attenuates CIA.Moreover,a combination of propionate with anti-TNF etanercept synergistically relieves CIA.These results suggest that B.fragilis or propionate could be an alternative or complementary approach to the current therapies.

The Predictive Value of Baseline HBs Ag Level and Early Response for HBs Ag Loss in Patients with HBe Ag-positive Chronic Hepatitis B during Pegylated Interferon Alpha-2a Treatment

Objective To explore the predictive value of baseline HBs Ag level and early response for HBs Ag loss in patients with HBe Ag-positive chronic hepatitis B during pegylated interferon alpha-2a treatment. Methods A total of 121 patients with HBe Ag-positive chronic hepatitis B who achieved HBs Ag loss were enrolled; all patients were treated with PEG-IFNα-2a 180 μg/week. Serum HBV DNA and serological indicators （HBs Ag, anti-HBs, HBe Ag, and anti-HBe） were determined before and every 3 months during treatment. Results The median treatment time for HBs Ag loss was 84 weeks （7-273 weeks）, and 74.38% （90 cases） of the patients needed extended treatment （〉 48 weeks）. The correlation between baseline HBs Ag levels and the treatment time of HBs Ag loss was significant （B = 14.465, t = 2.342, P = 0.021）. Baseline HBs Ag levels together with the decline range of HBs Ag at 24 weeks significantly correlated with the treatment time of HBs Ag loss （B = 29.862, t = 4.890, P = 0.000 and B = 27.993, t = 27.993, P = 0.005）. Conclusion Baseline HBs Ag levels and extended therapy are critical steps toward HBs Ag loss. Baseline HBs Ag levels together with early response determined the treatment time of HBs Ag loss in patients with HBe Ag-positive chronic hepatitis B during pegylated interferon alpha-2a treatment.

Psychiatric side effects of pegylated interferon alfa-2b as compared to conventional interferon alfa-2b in patients with chronic hepatitis C

AIM: To assess systematically the spectrum and extent of depressive symptoms comparing patient groups receiving peginterferon or conventional interferon.METHODS: Ninety-eight patients with chronic hepatitis C and interferon-based therapy (+ribavirin) were consecutively enrolled in a longitudinal study. Patients were treated with conventional interferon alfa-2b (48/98patients; 5 MIU interferon alfa-2b thrice weekly) or peginterferon alfa-2b (50/98 patients; 80-150 μgpeginterferon alfa-2b) in combination with weight-adapted ribavirin (800-1 200 mg/d). Repeated psychometric testing was performed before, three times during and once after antiviral therapy: Depression was evaluated by the Hospital Anxiety and Depression Scale (HADS), anger/hostility by the Symptom Checklist-90 Items Revised (SCL-90-R).RESULTS: Therapy with pegylated interferon alfa-2bproduces comparable scores for depression (ANOVA:P = 0.875) as compared to conventional interferon.Maximums of depression scores were even higher and cases of clinically relevant depression were frequent during therapy with peginterferon. Scores for anger/hostility were comparable for both therapy subgroups.CONCLUSION: Our findings suggest that the extent and frequency of depressive symptoms in total are not reduced by peginterferon. Monitoring and management of neuropsychiatric toxicity especially depression have to be considered as much as in antiviral therapy with unmodified interferon.

Evolution and predictive factors of thyroid disorder due to interferon alpha in the treatment of hepatitis C

AIM： To study predictive factors of thyroid dysfunction associated with interferon-alpha （IFNa） therapy in chronic hepatitis C （CHC） and to describe its long-term evolution in a large population without previous thyroid dysfunction. METHODS： We performed a follow-up of thyroid function and detection of thyroid antibodies in 301 patients treated for CHC with IFNα from 1999 to 2004. RESULTS： Thyroid disorder developed in 30/301 （10%） patients with a mean delay of 6 ± 3.75 mo： 13 patients had hyperthyroidism, 11 had hypothyroidism, and 6 had biphasic evolution. During a mean follow-up of 41.59 ± 15.39 mo, 9 patients with hyperthyroidism, 3 with hypothyroidism, and 4 with biphasic evolution normalized thyroid function in 7.88 ± 5.46 mo. Recovery rate of dysthyroidism was not modified by treatment discontinuation, but was better for patients with negative thyroid antibodies before antiviral treatment （P = 0.02）. Women had significantly more dysthyroidism （P = 0.05）. Positive thyroid peroxidase and thyroglobulin antibodies were more frequent before antiviral treatment in patients who developed dysthyroidism （P 〈 0.0003 and P = 0.0003, respectively）. In a multivariate model, low fibrosis was found to be a predictive factor of dysthyroidism （P = 0.039）.CONCLUSION： In this monocentric population of CHC, dysthyroidism, especially hyperthyroidism, developed in 10% of patients, Low fibrosis was found to be a predictive factor of dysthyroidism, Thyroid disorder recovered in 16/30 patients （53%） and recovery was better in the non-autoimrnune form,

Hepatitis B surface antigen clearance in inactive hepatitis B surface antigen carriers treated with peginterferon alfa-2a

AIM: To examine the association between interferon(IFN) therapy and loss of hepatitis B surface antigen(HBs Ag) in inactive HBs Ag carriers. METHODS: This was a retrospective cohort study in inactive HBs Ag carriers, who were treatment-naive, with a serum HBs Ag level < 100 IU/m L and an undetectable hepatitis B virus(HBV) DNA level(< 100 IU/m L). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBs Ag, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. RESULTS: Thirteen(65.0%) of 20 treated patients achieved HBs Ag loss, 12 of whom achieved HBs Ag seroconversion. Mean HBs Ag level in treated patients decreased to 6.69 ± 13.04 IU/m L after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/m L. Serum HBV DNA level remained undetectable(< 100 IU/m L) in all treated patients during the study. HBs Ag level of the control group decreased from 25.72 ± 25.58 IU/m L at baseline to 17.11 ± 21.62 IU/m L at week 96(P = 0.108). In the control group, no patient experienced HBs Ag loss/seroconversion, and two(5.0%) developed HBV reactivation.CONCLUSION: IFN treatment results in HBs Ag loss and seroconversion in a considerable proportion of inactive HBs Ag carriers with low HBs Ag concentrations.

Combination Therapy with Pegylated Interferon alpha-2b and Adefovir Dipivoxil in HBeAg-positive Chronic Hepatitis B versus Interferon Alone: A Prospective, Randomized Study

Currently available monotherapies of oral nucleoside/nucleotide analogs or interferon are unable to achieve a sustained and effective response in most of patients with chronic hepatitis B（CHB）. The objective of the present study was to compare the efficacy and safety of pegylated interferon（Peg-IFN） alpha-2b plus adefovir dipivoxil combination therapy versus Peg-IFN alpha-2b alone. Sixty-one HBeAg-positive chronic hepatitis B patients were randomized to receive Peg-IFN alpha-2b alone（1.5 μg/kg once weekly） or Peg-IFN alpha-2b plus adefovir（10 mg daily） for up to 52 weeks. Efficacy and safety analyses were performed on all participants who received at least one dose of study medication. The rate of HBeAg seroconversion and undetectable HBV-DNA were evaluated after 52 weeks of therapy. At the end of treatment, 11 of 30（36.7%） patients receiving combination therapy achieved HBeAg seroconversion versus 8 of 31（25.8%） in the monotherapy group（P=0.36）. In contrast, the percentage of patients with undetectable serum HBV DNA was significantly higher in the combination group than in the monotherapy group（76.7% vs. 29.0%, P〈0.001）. Thyroid dysfunction was more frequent in the combination group than in the monotherapy group（P〈0.05）. In HBeAg-positive CHB, combination of Peg-IFN alpha-2b and adefovir for 52 weeks resulted, at the end of treatment, in a higher virological response but without significant impact on the rate of HBeAg seroconversion and possibly an adverse effect on thyroid function.

Effect of sustained virological response on long-term clinical outcome in 113 patients with compensated hepatitis C-related cirrhosis treated by interferon alpha and ribavirin

AIM： To assess the long-term clinical benefit of sustained virological response （SVR） in patients with hepatitis C virus （HCV） cirrhosis treated by antiviral therapy using mostly ribavirin plus interferon either standard or pegylated.METHODS： One hundred and thirteen patients with uncomplicated HCV biopsy-proven cirrhosis, treated by at least one course of antiviral treatment ≥ 3 mo and followed ≥ 30 mo were included. The occurrence of clinical events [hepatocellular carcinoma （HCC）, decompensation and death] was compared in SVR and non SVR patients.RESULTS： Seventy eight patients received bitherapy and 63 had repeat treatments. SVR was achieved in 37 patients （33%）. During a mean follow-up of 7.7 years, clinical events occurred more frequently in non SVR than in SVR patients, with a significant difference for HCC （24/76 vs 1/37, P = 0.01）. No SVR patient died while 20/76 non-SVR did （P = 0.002）, mainly in relation to HCC （45%）.CONCLUSION： In patients with HCV-related cirrhosis, $VR is associated with a significant decrease in the incidence of HCC and mortality during a follow-up period of 7.7 years. This result is a strong argument to perform and repeat antiviral treatments in patients with compensated cirrhosis.

Effect of interferon alpha2b plus ribavirin treatment on selected growth factors in respect to inflammation and fibrosis in chronic hepatitis C

AIM: Growth factors (GF) that participate in regeneration and apoptosis have an important role in chronic liver diseases. We analyzed serum GF concentration during antiviral treatment and correlated it with morphological liver failure in chronic hepatitis C. METHODS: The levels of GF were determined in sera by ELISA method in 0,16,32 and 48 wk of therapy in 40 patients treated with IFNα2b (9 MU sc/wk) and RBV (1.2 g/d) and in 25 healthy subjects. Blind liver biopsies were done before treatment with histological grading and staging examination. RESULTS: The hepatocyte growth factor (HGF) and epidermal growth factor (EGF) were markedly elevated prior the treatment and decreased during the therapy, although they did not reach the normal level. In non-responding (NR) patients, HGF and EGF were higher than that in responders (R), however differences were not significant. Before the treatment thrombopoietin (TPO) level was significantly lower in R than in NR (P<0.03). Platelet-derived growth factor (PDGF) concentration was lower in chronic hepatitis C than in healthy subjects and decreased during the treatment. A significant positive correlation was observed between inflammatory activity in the liver tissue and the concentration of HGF (in R: r= 0.4, in NR: r= 0.5), TPO (R: r= 0.6), and a significant negative correlation between this activity and EGF (R: r = -0.6) and PDGF (R: r= -0.5). Serum HGF concentration was higher in more advanced fibrosis (R: r = 0.5, P<0.05; NR: r=0.4, P<0,03). CONCLUSION: The decrease in PDGF can be an effective prognostic marker of the treatment and HCV elimination. Decreasing HGF, EGF, and PDGF can influence the inhibition of inflammatory and fibrotic processes in the liver during the antiviral treatment.

Treatment of Hepatitis C with Pegylated Interferon Alpha-2a and Ribavirin:Experience from Benin

Background: Viral hepatitis C (HCV) is common in Benin. Untreated, it can be complicated by cirrhosis and hepatocarcinoma, which are sources of death. The objectives of this work were twofold: 1) to evaluate the effectiveness and safety of treatment with classic dual interferon pegylated alpha-2a (IFN) and ribavirin therapy in Benin, and 2) to present problems related to financial accessibility to this treatment. Methods: This was a cross-sectional, descriptive and analytical study, with a retrospective collection of data from November 1, 2010 to December 31, 2015 and prospective collection from January 1, 2016 to July 31, 2016 (7 months). We included all patients treated with IFN + ribavirin for hepatitis C at CNHU/HKM. Sustained virological response (SVR) was defined as undetectable viral load C 6 months after stopping treatment. Safety was appreciated by the search for clinical and hematological adverse effects. Results: One hundred and six patients were followed for HCV, of whom 58 (54.7%) undergoing treatment (26 under standard dual therapy and 32 under direct-acting antivirals). Of the 26 patients under-conventional dual therapy, 12 (46.1%) were genotype 1, 13 (50%) genotype 2 and one (3.9%) genotype 4. In conventional dual therapy, SVR was achieved in 15 (57.7%) patients, including the genotype 4 patient, 4 out of 12 (33.3%) genotype 1 patients, and 10 out of 13 (76.9%) for genotype 2 patients. The most common side effects with this treatment were severe asthenia (23 cases), flu-like symptoms (22 cases), weight loss (21 cases) and neutropenia (22 cases), anemia and thrombocytopenia (20 of 26 cases). The overall cost of treatment per patient was 11,800,624 FCFA for genotypes 1 and 4;and 7,835,048 FCFA for genotype 2. Conclusion: The treatment of HCV with IFN + ribavirin in Benin is effective for genotype 2. But its adverse effects are manifold and its cost is high. The switch to direct-acting antivirals (more effective, better tolerated and less expensive) was therefore necessary.

Development of novel-nanobody-based lateral-flow immunochromatographic strip test for rapid detection of recombinant human interferon a2b

Recombinant human interferon a2b(rhIFNa2b)is widely used as an antiviral therapy agent for the treatment of hepatitis B and hepatitis C.The current identification test for rhIFNa2b is complex.In this study,an anti-rhIFNa2b nanobody was discovered and used for the development of a rapid lateral flow strip for the identification of rhIFNa2b.RhIFNa2b was used to immunize an alpaca,which established a phage nanobody library.After five steps of enrichment,the nanobody I22,which specifically bound rhIFNa2b,was isolated and inserted into the prokaryotic expression vector pET28a.After subsequent purification,the physicochemical properties of the nanobody were determined.A semiquantitative detection and rapid identification assay of rhIFNa2b was developed using this novel nanobody.To develop a rapid test,the nanobody I22 was coupled with a colloidal gold to produce lateral-flow test strips.The developed rhIFNa2b detection assay had a limit of detection of 1 mg/mL.The isolation of I22 and successful construction of a lateral-flow immunochromatographic test strip demonstrated the feasibility of performing ligand-binding assays on a lateral-flow test strip using recombinant protein products.The principle of this novel assay is generally applicable for the rapid testing of other commercial products,with a great potential for routine use in detecting counterfeit recombinant protein products.

Expression of bcl-2 protein in chronic hepatitis C:Effect of interferon alpha 2b with ribavirin therapy

AIM: Mechanisms responsible for persistence of HCV infection and liver damage in chronic hepatitis C are not clear. Apoptosis is an important form of host immune response against viral infections. Anti-apoptotic protein bcl-2 expression on liver tissue as well as the influence of interferon alpha 2b (IFNa2b) and ribavirin (RBV) were analyzed in patients with chronic hepatitis C. METHODS: In 30 patients with chronic hepatitis C (responders - R and non-responders - NR) treated with IFNα2b+RBV, protein bcl-2 was determined in hepatocytes and in liver associated lymphocytes before and after the treatment. RESULTS: The treatment diminished bcl-2 protein accumulation in liver cells in_patients with hepatitis C (P<0.05). Before and after the therapy, we detected bcl-2 protein in R in 87±15% and 83±20% of hepatocytes and in 28±18% and 26±10% of liver-associated lymphocytes, respectively. In NR, the values before treatment decreased from 94±32% to 88±21% of hepatocytes and 39±29% to 28±12% of lymphocytes with bcl-2 expression. There was no statistical correlation between bcl-2 expression on liver tissue with inflammatory activity, fibrosis and biochemical parameters before and after the treatment. CONCLUSION: IFNα2b+RBV treatment, by bcl-2 protein expression decrease, enables apoptosis of hepatocytes and associated liver lymphocytes, which in turn eliminate hepatitis C viruses.

Mutation in the NS5A Region of Chinese HCV-1b Isolates and Its Correlation with Efficacy of Interferon Alpha Therapy

Objective\ To study the correlation between mutations in the NS5A region of hepatitis C virus genotype 1b and the efficacy of interferon alpha (IFN α) therapy. Methods\ Twenty patients with chronic HCV 1b infection, including 10 responders and 10 non responders to standard IFN α therapy, were investigated. HCV 1b NS5A 2209 2248 region was amplified by RT PCR and the second round product was directly sequenced before treatment. Results\ In IFN α response group, 4 out of 10 HCV isolates (40%) had mutations of amino acid in NS5A 2209 2248 region, which were all intermediate types; while in IFN α non response group, none of HCV isolates (0/10,0%) had mutations, which were all wild types (P<0.05). There was no mutant type isolates in these two groups. All patients (4/4,100%) infected with intermediate type and 6 out of 16 patients(37.5%) infected with wild type of HCV 1b were responsive to IFN α therapy (P<0.05). Conclusion\ The sequences in NS5A 2209 2248 region of Chinese HCV 1b isolates were relatively conservative. There may be a correlation between the efficacy of IFN α therapy and the mutations of amino acid in NS5A 2209 2248 region of Chinese HCV 1b isolates.

Treatment of Conjunctival Malignant Melanoma with Topical Interferon Alpha-2a

Conjunctival malignant melanoma (CMM) is a potentially lethal neoplasm with a high rate of recurrence. The modality of treatment includes a wide surgical excision, cryotherapy, topical mitomycin C and Interferon alpha 2b (INF α 2b). The aim of the study is to present the treatment of a case with CMM using topical Interferon alpha 2a. We present a 38-year-old female with diffuse bulbar dark pigmentation of the conjunctiva that arises from previously primary acquired melanosis (PAM). Biopsy resulted positive for CMM and further investigations were negative for any metastasis. Treatment with topical interferon alpha 2a was started immediately and after three months melanoma disappeared. One year after follow-up there was no sign of recurrence in regional lymph nodes or distant metastasis.

Combination of "low-dose" ribavirin and interferon alfa-2a therapy followed by interferon alfa-2a monotherapy in chronic HCV-infected nonresponders and relapsers after interferon alfa-2a monotherapy

AIM To report on the efficacy, safety and tolerability of interferon alfa-2a combined with a "low dose" of ribavirin for relapsers and non responders to alpha interferon monotherapy.METHODS Thirty-four chronic hepatitis C virus-infected non-responders to interferon alfa2a monotherapy (a course of at least 3 months treatment) and 13 relapsers to interferon alfa 2a monotherapy (a dose of 3 to 6 million units three times per week for at least 20 weeks but not more than 18 months) were treated with the same dose of interferon alfa-2a used before (3 to 6 million units three times per week) and ribavirin (10 mg/ kg daily) for 6 months. In complete responders, interferon alfa-2a was administered for further 6 months at the same dose used before as monotherapy.RESULTS Seven (20.6%) of 34 non-responders stopped the combined therapy due to adverse events, including two patients with histological and clinical Child A cirrhosis. In 17/27 (63%)non-responders, the combined therapy was stopped after three months because of non-response. Ten of the 27 non-responders completed the 1;2-month treatment course. At a mean follow up of 28 months (16- 37 months)after the treatment, 4/10 (15%) previous non-responders still remained complete responders,All 13 previous relapsers completed the 12-month treatment course. At a mean follow up of 22months (9 - 36 months) after treatment, 6/13(46%) the previous relapsers were stillsustained complete responders.CONCLUSION Our treatment schedule of the combined therapy for 6 months of interferon alfa2a with a low dose of ribavirin (10 mg/kg/day)followed by 6 months of interferon alfa-2amonotherapy is able to induce a sustainedcomplete response rate in 15% of non-responders and 46% of relapsers with chronic hepatitis C virus-related liver diseases comparable to those obtained with the standarddoses of ribavirin 1000 - 1200 mg/day.Randomized prospective controlled trials using lower total amounts of ribavirin in combination with interferon should be performed.

Interferon alpha plus ribavirin combination treatment of Japanese chronic hepatitis C patients with HCV genotype 2:A project of the Kyushu University Liver Disease Study Group

AIM： To determine the efficacy of an interferon alpha and ribavirin combination treatment for Japanese patients infected with hepatitis C virus （HCV） of genotype 2, a multi-center study was retrospectively analyzed. METHODS： In total, 173 patients with HCV genotype 2 started to receive interferon-alpha subcutaneously thrice a week and 600-800 mg of ribavirin daily for 24 wk. RESULTS： The overall sustained virological response （SVR）, defined as undetectable HCV RNA in serum, 24 wk after the end of treatment, was remarkably high by 84.4%, （146/173） by an intention-to-treat analysis. A significant difference in SVR was found between patients with and without the discontinuation of ribavirin （46.9% vs 92.9 %）, but no difference was found between those with and without a dose reduction of ribavirin. A significant difference in SVR was also found between patients with less than 16 wk and patients with 16 or more weeks of ribavirin treatment （34.8 % vs 92.0 %）. CONCLUSION： The 24-wk interferon and ribavirin treatment is highly effective for Japanese patients with HCV genotype 2. The significant predictor of SVR is continuation of the ribavirin treatment for up to 16

Effect of pegylated interferon alpha 2b plus ribavirin treatment on plasma transforming growth factor-β1,metalloproteinase-1,and tissue metalloproteinase inhibitor-1 in patients with chronic hepatitis C

AIM： To evaluate the effect of antiviral treatment on plasma levels of transforming growth factor-β1 （TGF-β1）, metalloproteinase 1 （MMP-1）, and tissue inhibitor of metaUoproteinase-1 （TIMP-1） in patients with chronic hepatitis C. METHODS： TGF-β1, MMP-1, and TIMP-1 plasma concentrations were measured by an enzyme immunoassay in 28 patients, during 48 wk of treatment with pegylated interferon-alpha 2b （PEG-IFN-α2b） plus ribavirin （RBV） and after 24 wk of follow-up. Patients were divided into two groups： responders （R） and non-responders （NR） related to achieved sustained virologic response. Normal values were evaluated in plasma samples of 13 healthy volunteers. RESULTS： Baseline plasma concentrations of TGF-β1 and TIMP-1 （30.9±3.7 and 1 506±61 ng/mL respectively） measured in all subjects significantly exceeded the normal values （TGF-β1： 18.3±1.6 ng/mL and TIMP-1： 1 102±67 ng/mL）. In contrast, pretreatment MMP-1 mean level （6.5±0.9 ng/mL） was significantly lower than normal values （11.9±0.9 ng/mL）. Response to the treatment was observed in 12 patients （43%）. TGF-β1 mean concentration measured during the treatment phase decreased to the control level in both groups. However at wk 72, values of NR patients increased and became significantly higher than in R group. TIMP-1 concentrations in R group decreased during the treatment to the level similar to normal. In NR group, TIMP-1 remained significantly elevated during treatment and follow-up phase and significant difference between both groups was demonstrated at wk 48 and 72. MMP-1 levels were significantly decreased in both groups at baseline. Treatment caused rise of its concentration only in the R group, whereas values in NR group remained on the level similar to baseline. Statistically significant difference between groups was noted at wk 48 and 72. CONCLUSION： These findings support the usefulness of TGF-β1, TIMP-1, and MMP-1 in the management of chronic hepatitis C. Elevated TIMP-1 and low MMP-1 plasma concentrations during antiviral therapy may indicate medication failure.

Peginterferon and ribavirin treatment for hepatitis C virus infection

Pegylated interferon α (IFNα) in combination with ribavirin is currently recommended as a standard-of-care treatment for chronic hepatitis C virus (HCV) infection. This combination therapy has drastically improved the rate of sustained virological response, specifically in difficult-to-treat patients. Recently, individualized treatment, such as response-guided therapy, is being developed based on host-, HCV- and treatment-related factors. Furthermore, modified regimens with currently available medications, novel modified IFNα and ribavirin or combinations with specifically targeted antiviral therapy for HCV agents, are currently being investigated. The purpose of this review is to address some issues and epoch-making topics in the treatment of chronic HCV infection, and to discuss more optimal and highly individualized therapeutic strategies for HCV-infected patients.

Effect of interferon alpha and ribavirin treatment on serum levels of transforming growth factor-β1,vascular endothelial growth factor,and basic fibroblast growth factor in patients with chronic hepatitis C

AIM： To assess the role of transforming growth factor-β1 （TGF-β1）, vascular endothelial growth factor （VEGF） and basic fibroblast growth factor （bFGF） in the pathogenesis of fibrosis associated with chronic hepatitis C （CHC） and to evaluate the influence of the antiviral therapy on above parameter levels depending on the treatment results （complete response or no response）. METHODS： Study group included 100 patients with CHC, in whom fibrosis in liver specimens was assessed （Scheuer fibrosis score： 1-4 points）. Control group included 30 subjects with antibodies anti-HCV present and persistently normal ALT level, without fibrosis （Scheuer fibrosis score： 0 points）. Concentration of studied parameters was assayed in the serum by immunoenzymatic method before and after the therapy with interferon alpha-2b and ribavirin. RESULTS： TGF-β1 levels were significantly higher in the study group compared to the control group （35.89 vs 32.37 ng/mL; P= 0.023）. Such differences were not found in VEGF and bFGF levels. In patients showing complete response （negative HCV RNA and normal ALT level）, significant increase in VEGF （112.8 vs 315.03 pg/mL; P〈 0.05） and bFGF （2.51 vs 15.79 pg/mL; P=0.04） levels were found. Significant decrease in TGF-β1 level was observed both in responders （37.44 vs 30.02 ng/mL; P=0.05）, and in non-responders （38.22 vs 30.43 ng/mL; P=0.043）. bFGF levels before the treatment were significantly lower （2.51 vs 5.94 pg/mL; P=0.04）, and after the treatment significantly higher （15.79 vs 4.35 pg/mL; P=0.01） in patients with complete response response. CONCLUSION： Among the analyzed parameters TGF-β1 seems to play the most important role in the pathogenesis of fibrosis in CHC. Levels of this factor are significantly lower in subjects who do not have fibrosis developed in them. Good therapeutic effect in CHC patients is associated with significant changes in TGF-β1, VEGF, and bFGF levels, bFGF seems to have the highest usefulness in the prognosis of treatment efficacy.

Sudden hearing loss associated with peginterferon and ribavirin combination therapy during hepatitis C treatment

Adverse effects associated with peginterferon and ribavirin during hepatitis C treatment are well known. Sudden hearing loss has rarely been reported. Possible mechanisms involved include direct ototoxicity of interferon, autoimmunity, and hematological changes. Hearing loss is frequently fully resolved after discontinuation of antiviral therapy. We report a 47-year- old man with chronic hepatitis C, genotype 2 ac who developed sudden hearing loss 22 wk after starting therapy with peginterferon alpha 2a at a dose of 180 ~g per week and ribavirin 800 mg per day. Since symptoms did not worsen, antiviral therapy was continued for 2 wk, according to the patient＇s wish. Hearing loss resolved within 2 wk after the end of treatment. Serum liver alanine aminotransferase remained normal during and after the end of antiviral therapy. HCV RNA was undetectable at the end of therapy and remained negative 24 wk later. Thus, patients should be aware that hearing loss may occur with peginterferon therapy, but the decision whether to continue or to stop the treatment is based on the clinical judgment of the physician and the wishes of the patient.

Combination of pegylated interferon and lamivudine for patients with chronic hepatitis B who have failed treatment

BACKGROUND: Treatment of chronic hepatitis B (CHB) alone with interferon or lamivudine alone or in combination is effective in only a small proportion of patients. Treatment of patients in whom antiviral therapy fails is challenging. This study was made to determine the efficacy of combined pegylated interferon alpha (peg-IFN) and lamivudine in patients with CHB who had failed to respond to antiviral treatment. METHODS: Twenty patients with CHB proven by liver biopsy, with ALT levels >1.5×ULN,HBV DNA levels>141 500 copies/ml, and previous treatment failure with an adequate regimen were treated with a combination of peg-IFN 1.5μg/kg and lamivudine 100 mg/day for 52 weeks and followed up for a further 24 weeks. Biochemical response was defined as normalization of ALT and DNA response as HBV DNA<141 500 copies/ml. Secondary efficacy measures included HBsAg loss, HBeAg loss and appearance of anti-HBe (in cases of HBeAg-positive patients). RESULTS: Twenty patients were treated, of whom 16 were HBeAg positive. At 52 weeks, normal ALT was seen in 10 (50%) (8 of 16 HBeAg+ and 2 of 4 HBeAg), HBV DNA response in 5 (25%) (5 of 16 in HBeAg+ and none in HBeAg-), and HBeAg loss with appearance of anti-HBe in 5 (31.3%) of the 16 HBeAg positive patients. At 76 weeks, 8 (80%) of the 10 patients with normal ALT at 52 weeks relapsed, with normal ALT only in 2 (10%) (1 of 16 HBeAg+ and 1 of 4 HBeAg-), and all 5 patients who had a DNA response at 52 weeks relapsed at 76 weeks and had no DNA response. HBeAg loss with appearance of anti-HBe was seen in 1 (6.3%) of 16 HBeAg-positive patients. None of the patients lost HBsAg. CONCLUSIONS: The combination of peg-IFN and lamivudine for 52 weeks is not effective for treatment of CHB patients with a failed treatment. New treatment strategies need to be developed.