A possible role of human leukocyte antigen(HLA) typing for predicting response to interferon therapy in chronic hepatitis C

Hepatitis C viral load, genotype and/or staging of liver fibrosis are known to be factors for predicting response to interferon(IFN) therapy in patients with chronic hepatitis C. The aim of this study is to investigate if human leukocyte antigen(HLA) typing is related to the response to IFN therapy. The seventy six Japanese patients were studied and categorized into two groups: 46 patients with chronic hepatitis C (Group A) and 30 with liver disease unrelated to HCV infection(Group B). In addition, 39 patients who were treated with IFN were classified into complete responders(CR) and non-complete responders (NR). There was not any differences in HLA typing between group A and B, but the frequency of HLA class I B51(5) was higher in CR than in NR patients(p = 0.045). When restricted to those who had low viral load(under 10(55) copies/ml) and genotype 2a or 2b, HLA class I CW1 was found in 7 responders(70%) and in 1 non-responder(14%) (p = 0.023). HLA class II DR9 was not found in responders but in 3 non-responders(p = 0.022). These preliminary results suggest that HLA types may be related response to IFN therapy in patients with chronic hepatitis C.     

Analysis of background factors influencing long-term prognosis of patients with chronic hepatitis C treated with interferon

OBJECTIVE: Interferon (IFN) therapy has been used as antiviral therapy for chronic hepatitis C (CH-C); however, complete response to the therapy is observed in only about 30% of patients in Japan. Background factors involved in the responsiveness to IFN therapy, and progression to liver cirrhosis (LC) and hepatocellular carcinoma (HCC) after IFN therapy have not yet been sufficiently investigated. METHODS: One hundred twenty-one patients with CH-C who received IFN therapy at Showa University Hospital between 1984 and 1999 were analyzed. RESULTS: At 6 months after the termination of IFN therapy, 53 patients achieved a complete response, 11 patients incomplete response, and 57 patients no response. During a mean follow-up of 52.7 months, 12 patients progressed to LC, and 10 patients developed HCC. Multivariate analysis showed that significant independent factors involved in progression to LC were platelet count and the efficacy of IFN therapy. The significant independent factor involved in the development of HCC was platelet count. The factor involved in the therapeutic effect at 6 months after the termination of IFN administration was the serum hepatitis C virus (HCV) RNA levels before IFN therapy. CONCLUSION: Patients with high HCV RNA levels and low platelet counts should be considered to be at high risk of progressing to LC and developing of HCC and should be carefully followed after IFN therapy using ultrasonography, CT scan and MRI.     

HCV genotype as a predictor of response to interferon therapy in patients with chronic hepatitis C

Hepatitis C virus(HCV) genotype is one of the most important predicting factors of response to interferon(IFN) therapy in patients with chronic hepatitis C. According to the molecular evolutionary analysis, HCV is classified into six major genotypes. The patients infected with genotype 1 show high HCV RNA levels and poor response to IFN therapy compared to those with genotype 2 or 3. No sufficient data are observed on response to IFN in patients with genotype 4 to 6. When PEG-IFN plus ribavirin therapy is introduced, high proportion of patients without genotype 1 must show complete response. In the near future, to predict good response to IFN therapy, it will be necessary to know whether patients have HCV genotype 1 or not.     

Predicting the therapeutic response in patients with chronic hepatitis C: the role of viral kinetic studies

A substantial proportion of patients infected with hepatitis C virus (HCV) genotype 1 still does not respond to pegylated interferon-alfa/ribavirin (IFN/RBV) therapy. Factors which identify potential non-responders are needed to limit exposure to drugs in patients unlikely to benefit from treatment and to save health care resources. Host predictive factors have a low negative predictive value. In contrast, viral factors have a high precision in predicting outcome of therapy. Viral kinetics are the basis for the study of response of therapy. The decrease in viral load within 24 h after administration of a single test dose of conventional IFN reflects the IFN-sensitivity of the virus strain and predicts the outcome of conventional IFN/RBV therapy even before treatment with a specificity of 100% and a sensitivity of 83%. In contrast to conventional IFN, the two available PEG-IFN preparations differ considerably in how they suppress viral replication, and cut-off values have to be prospectively established separately for each drug. Patients without an early virological response (HCV-RNA either undetectable or decrease by >or=2 log10 after 12 weeks) (EVR), do not achieve a sustained virological response (SVR; negative predictive value: 97-98%). Thus, in the absence of an EVR, treatment should be stopped. The outcome of PEG-IFN alfa-2a/RBV combination therapy is dependent on the rapidity of the virological response. Patients who become HCV-RNA negative after 4 weeks have the best chance of achieving an SVR. The rapidity of viral elimination may be a useful guide to tailoring the length of treatment in patients with an EVR.     

Viral dynamics and pharmacokinetics in combined interferon alfa-2b and ribavirin therapy for patients infected with hepatitis C virus of genotype 1b and high pretreatment viral load

OBJECTIVE: The aim of this study was to clarify the viral dynamics and single- and multiple-dose pharmacokinetics of ribavirin and interferon (IFN) alfa-2b in the virologic response to combination therapy with both compounds in patients infected with hepatitis C virus (HCV) genotype 1b and high viral load. METHODS: Fourteen patients received high-dose daily induction therapy followed by intermittent maintenance therapy with IFN alfa-2b and daily oral ribavirin for 24 weeks, and followed up for 24 weeks after treatment. Single- and multiple-dose pharmacokinetic studies and viral dynamics were assessed by serial measurements of serum concentrations of both compounds and HCV RNA, respectively, at weeks 1 and 24. RESULTS: During treatment, all 14 patients showed biochemical response (i.e., normalization of serum alanine transaminase activity), while 11 showed virologic response (i.e., undetectable serum HCV RNA level by qualitative polymerase chain reaction assay). Sustained biochemical and virologic response after cessation of treatment was noted in 8 and 2 patients, respectively. Serum ribavirin concentrations asymptoted by 4 weeks of treatment. Serum ribavirin concentrations in steady state, and maximum concentration and accumulation rate of ribavirin after multiple dosing were significantly higher in the presence of sustained virologic response. HCV-related parameters were not significantly associated with sustained virologic response. CONCLUSIONS: Continuous exposure and tissue accumulation of ribavirin may be necessary for sustained virologic response to combination therapy in chronic hepatitis C with genotype 1b and high viral load. Pharmacokinetic analysis of ribavirin provides information on its mechanism of action and for developing more rational treatment for IFN-resistant HCV.     

CCR5 promoter polymorphism influences the interferon response of patients with chronic hepatitis C in Japan

OBJECTIVE: Chemokines and chemokine receptors play important roles in the pathogenesis of chronic hepatitis C. Here, we explore the influence of genetic polymorphisms of chemokine and chemokine receptors such as regulated upon activation and T cell secreted (RANTES), CC chemokine receptor 5 (CCR5) and CCR2 on the outcome of interferon (IFN) monotherapy. METHODS: In a cohort of 105 patients with chronic hepatitis C as well as in 50 sustained responders and 55 nonresponders the presence of polymorphisms such as CCR5-Delta32, CCR5 59029G/A, CCR2 V64I and RANTES -403G/C was determined. RESULTS: Gender, age, liver histological staging, pretreatment ALT levels, total dose of IFN and frequencies of polymorphisms (CCR2 V64I and RANTES -403G/C) did not significantly differ between the two groups. A low viral load, hepatitis C virus (HCV) serotype 2 and CCR5 59029G/G were significantly associated with a higher probability of a sustained response (p < 0.01, p < 0.05, p < 0.05, respectively). Multiple logistic regression analysis showed that a low viral load, HCV serotype 2 and CCR5 59029G/G were independently associated with a sustained response [odds ratio 3.980 (1.647-9.621), p = 0.002; 3.584 (1.439-8.924), p = 0.006; 3.638 (1.163-11.379), p = 0.026, respectively]. CONCLUSION: These findings indicate that CCR5 59029 is a host genetic factor that is associated with responses to IFN therapy among Japanese patients with chronic hepatitis C.     

Treatment of chronic hepatitis C in southern Taiwan

Chronic hepatitis C virus (HCV) infection may lead to cirrhosis and hepatocellular carcinoma. Interferon (IFN)-alpha is effective in the treatment of chronic hepatitis C. The rate of response to IFN is enhanced by increasing the IFN dose. Extending the treatment duration can reduce the relapse rate. Addition of ribavirin to IFN increases the sustained virological response (SVR). Thus, combination therapy with IFN and ribavirin was adopted for the treatment of chronic hepatitis C in Kaohsiung Medical University Hospital in 1998. Approximately 60% of patients receiving IFN/ribavirin therapy gained SVR. IFN 6 million units three times per week combined with daily ribavirin for 6 months achieved SVR more frequently than combination therapy with 3 million units. Factors for SVR in these combination regimens were HCV genotype, viral load and early virological response. Long-term follow-up of patients treated with IFN has shown that SVR might reduce the risk of progression to cirrhosis and hepatocellular carcinoma. Pegylated (peg)-IFN has a longer half-life and better efficacy. Combination therapy with peg-IFN and ribavirin accomplished higher SVR than conventional IFN and ribavirin. A multicenter clinical trial was conducted in Taiwan to compare the efficacy of combination therapy between peg-IFN/ribavirin and conventional IFN/ribavirin for 6 months. SVR was higher in patients receiving peg-IFN and ribavirin, especially in those infected with HCV genotype 1b. Based on the results obtained, the national health insurance started to sponsor the combination therapy in October 2003, with a suggested duration for 6 months. Some small-scale studies in Taiwan have postulated higher SVR for treatment duration of 12 than of 6 months in patients with genotype 1b. Further investigation should be conducted in the near future.     

Hypervariable region 1 of hepatitis C virus genome and response to interferon therapy.

The relationship between the complexity of the hypervariable region 1 (HVR1) quasispecies of hepatitis C virus (HCV) and responsiveness to interferon-alpha (IFN) therapy was studied in patients with chronic hepatitis C. Twelve HCV-RNA-positive patients were treated daily with high dose IFN and ribavirin for 4 weeks, and then with IFN 3 MIU (Million International Units) TIW (three times per week) and ribavirin for 6 months. The HVR1 quasispecies complexity was analyzed by nested polymerase chain reaction-mediated single-strand conformation polymorphism (SSCP). The baseline HCV-RNA levels in the study group ranged from 10(6) to 10(7) copies/ml. All patients exhibited HCV genotype 1 b. Initial SSCP analysis revealed four (33.3%) patients with a low complexity pattern (SSCP bands < or =4) and eight (66.6%) patients with high complexity pattern (SSCP bands >4). After 4 weeks of IFN therapy, one patient became HCV negative, and among those remaining positive, the HCV-RNA levels decreased by 2 to 3 logs and the number of SSCP decreased by 2 to 3 bands per sample. After 6 months of IFN therapy, five (41.7%) patients became HCV-RNA-negative. Seven (58.3%) patients did not respond to IFN therapy with sustained viral load from 10(3) to 10(5) copies/ml, and high complexity SSCP patterns. Our data support the HVR quasispecies complexity to be an independent predictive factor for IFN responsiveness in patients infected with HCV.     

Sustained negativity for HCV-RNA over 24 or more months by long-term interferon therapy correlates with eradication of HCV in patients with hepatitis C virus genotype 1b and high viral load

OBJECTIVE: We assessed whether sustained negativity for HCV-RNA over 24 or more months by long-term interferon (IFN) therapy correlates with eradication of HCV in patients with hepatitis C virus genotype 1b and high viral load or not. METHODS: The number of patients with HCV-genotype 1b and high viral load exceeding 1 Meq/ml who received 6 MU of natural IFN-alpha daily for 2-8 weeks, followed by three times/week for 16-22 weeks and negativity for HCV-RNA during IFN administration was 403. Forty-one of 403 patients received 6 MU of natural IFN-alpha three times/week for more than 18 months after the initial IFN therapy (long-term-IFN-group). Three hundred and two patients did not receive any IFN treatment for 6 months after the termination of the 6-month course (6-month-IFN-group). Sustained virological response (SVR) was defined as negative HCV-RNA at both 3 and 6 months after the completion of IFN therapy. RESULTS: SVR was noted in 73.2% (30/41) of long-term-IFN-group and 18.2% (55/302) of 6-month-IFN-group. Multivariate analysis showed that long-term IFN therapy was the most significant contributor to SVR (p < 0.0001). CONCLUSION: Sustained negativity of HCV-RNA for 24 or more months by long-term IFN therapy correlated with SVR in patients with genotype 1b and high viral load.     

Interferon therapy for 2 years or longer reduces the incidence of hepatocarcinogenesis in patients with chronic hepatitis C viral infection

OBJECTIVE: The purpose of this clinical study was to determine the effect of long-term interferon (IFN) administration on the incidence of hepatocellular carcinomas (HCC) in chronic hepatitis C patients, without eradication of hepatitis C virus (HCV) by IFN therapy. METHODS: The number of patients with biopsy-proven chronic hepatitis with moderate or severe staging, HCV genotype 1b, a high viral load exceeding 1 MEq/ml (mega equivalents per milliliter), who received 6 MU of natural IFN-alpha daily for 2-8 weeks, followed by three times/week for 16-22 weeks, as initial IFN therapy, and positivity for HCV RNA during IFN administration was 131. 47 of the 131 patients continued to be treated with IFN (long-term IFN group, dose 3 or 6 MU twice or three times weekly for 1.5-10.5 years, median 4.0 years) after initial IFN therapy, while 84 patients did not receive any IFN therapy apart from the initial 6-month course (no-add-IFN group). The patients were prospectively monitored, and the cumulative incidence of HCC and risk factors for HCC were examined. RESULTS: The 5- and 10-year cumulative rates of HCC were 1.9 and 6.4% and 1.9 and 26.8% for long-term IFN and no-add-IFN groups, respectively. Cox regression analysis indicated that the relative risk of HCC in the patients of the no-add-IFN group was 8.72 times of that in patients of the long-term IFN group. CONCLUSION: Long-term IFN therapy in patients with chronic HCV infection is effective in preventing hepatocarcinogenesis.     

Prediction of treatment outcome in chronic hepatitis C patients based on early viral dynamics during high-dose induction interferon and ribavirin therapy

OBJECTIVE: In chronic hepatitis C, early viral load decline after interferon administration is dose dependent and reflects the intrinsic viral susceptibility to the antiviral action of interferon. We examined whether the augmented suppression of susceptible viral loads by high-dose induction interferon could possibly discriminate responsive patients from non-responsive patients at an early stage of treatment. METHODS: Fifty-nine chronic hepatitis C patients were randomly allocated to receive one of two treatment regimens; 3 MU interferon three times weekly plus ribavirin 1,000 mg/day for 24 weeks in the CR group (n = 30), and the same regimen as in the CR group except 10 MU interferon daily for the first week in the HR group (n = 29). Changes in viral loads during the first week of treatment were analyzed in terms of sustained virological response (SVR). RESULTS: The positive predictive values of undetectable (<100 IU/ml) or low serum HCV RNA (<2,000 IU/ml) after 1 week of treatment for SVR were 100% in both treatment groups, whereas the negative predictive values of the low viral titer were 91% in the HR group and 70% in the CR group. CONCLUSION: One-week virological response to high-dose induction interferon/ribavirin combination therapy is more predictive of SVR than conventional combination therapy in chronic hepatitis C.     

2'-,5'-Oligoadenylate synthetase response ratio predicting virological response to PEG-interferon-alpha2b plus ribavirin therapy in patients with chronic hepatitis C

OBJECTIVE: Although all the mechanisms of elimination of hepatitis C virus (HCV) by Interferon (IFN) have not been fully elucidated, the 2'-5'-oligoadenylate (2-5A) system is one of the mechanisms of the antiviral effect of IFN. Consequently, the measurement of 2'-5'-oligoadenylate synthetase (2-5AS) activity could be useful for the evaluation of IFN treatment. This retrospective study was aimed at assessing whether 2-5AS activity functions as a clinical marker of virological response to PEG-interferon-alpha2b (PEG-IFN) plus ribavirin therapy of chronic hepatitis C. METHODS: The 32 patients included in this study had high viral loads of serum HCV-RNA of genotype 1b with chronic hepatitis C. All the patients received a regimen of PEG-IFN plus ribavirin for 48 weeks, and were then divided into two groups: one group (effective group) with undetectable serum HCV-RNA levels at 24 weeks (n = 22) of therapy, the other group (ineffective group) with persistent presence of HCV-RNA in serum at 24 weeks (n = 10). The 2-5AS activity in serum was measured 2, 8 and 12 weeks before initial administration. RESULTS: The 2-5AS response ratio (measured value/measured value of baseline 2-5AS) at 2, 8 and 12 weeks after the administration in the effective group was significantly higher than that in the ineffective group. CONCLUSIONS: These results suggest that the ratio of 2-5AS is closely related to the antiviral effect, and that the measurement of 2-5AS response ratio may be a useful clinical parameter of virological response to PEG-IFN plus ribavirin therapy of chronic hepatitis C.     

Efficacy of interferon therapy in elderly patients with chronic hepatitis C

OBJECTIVE: We assessed the efficacy and safety of interferon (IFN) monotherapy in 84 elderly patients aged > or =65 years with chronic hepatitis C in a retrospective cohort study. METHODS: Twenty-two of the 84 elderly patients were treated with IFN at a dose of 6 million units daily for 6-8 weeks, 18 patients were treated 2-3 times a week for 24 weeks and 44 patients were treated daily for 2-8 weeks and 2-3 times a week for 16-24 weeks. RESULTS: A sustained virological response (SVR) occurred in 35.7% (30/84) of the patients by intention-to-treat analysis. Multivariate analysis showed that patients achieved a significant SVR when: (1) serum HCV-RNA level before IFN therapy was <100 KIU/ml (p < 0.0001) and (2) staging of liver fibrosis was mild (p = 0.040). Eleven (13.1%) patients discontinued the IFN regimen due to adverse events. Regarding factors predicting discontinuation of IFN, univariate analysis showed that patients aged >70 years were prone to drop out of therapy due to adverse events in IFN therapy (p = 0.009). CONCLUSION: Our results suggest that IFN administration is suitable for 65- to 70-year-old patients with chronic hepatitis C without genotype 1b and high virus load.     

Pegylated interferons for the treatment of chronic hepatitis C infection

BACKGROUND: Interferon (IFN) alfa is a clinically effective therapy used in a wide range of viral infections and cell-proliferative disorders. Combination therapy with IFN alfa-2b and ribavirin is the current standard of care for the treatment of chronic hepatitis C (CHC) infection. However, standard IFN alfa has the drawbacks of a short serum half-life and rapid clearance. To overcome this problem, 2 pegylated forms of IFN have been developed and tested clinically. OBJECTIVE: This article reviews the development and properties of pegylated IFN alfa-2b and pegylated IFN alfa-2a, and presents safety and efficacy data from recent clinical trials. METHODS: Relevant clinical studies were identified through a MEDLINE search from 1966 through the present using the key words hepatitis C and interferon. Studies of the pegylated IFNs in humans were then selected. RESULTS: Pegylated IFN alfa-2b is formed by covalent conjugation of a 12-kd mono-methoxy polyethylene glycol (PEG) molecule to IFN alfa-2b, and pegylated IFN alfa-2a by covalent conjugation of a 40-kd branched mono-methoxy PEG molecule to IFN alfa-2a. The 2 pegylated IFNs differ in the mixture of pegylation isomers resulting from their conjugation chemistry. Pegylated IFN alfa-2b has a prolonged serum half-life (40 hours) relative to standard IFN alfa-2b (7-9 hours). The greater polymer size of pegylated IFN alfa-2a acts to reduce glomerular filtration, markedly prolonging its serum half-life (72-96 hours) compared with standard IFN alfa-2a (6-9 hours). In clinical studies, once-weekly dosing of the pegylated IFNs was associated with a sustained virologic response in patients infected with hepatitis C virus (HCV). Once-weekly dosing with either of the pegylated IFNs was more effective than the respective thrice-weekly regimen of IFN alfa, with a comparable safety profile. The combination of once-weekly pegylated IFN and ribavirin effectively reduced HCV viral load and sustained viral suppression. CONCLUSIONS: Once-weekly dosing with either pegylated IFN alfa-2b or pegylated IFN alfa-2a has been shown to produce significantly higher rates of viral eradication than standard thrice-weekly IFN alfa therapy without compromising safety. With respect to the treatment of CHC, the greatest anti-HCV efficacy has been achieved with the combination of once-weekly pegylated IFN and ribavirin.     

老年丙型肝炎患者60例抗病毒疗效影响因素分析

目的 分析宿主因素、病毒因素、病毒应答模式以及干扰素(IFNα)种类和用药时间对老年丙型肝炎患者治疗结局的影响,寻找预测老年丙型肝炎患者持续病毒学应答(SVR)的相关因素.方法 回顾性分析2006年1月至2010年10月60例年龄≥60岁丙型肝炎患者的性别、年龄、体重指数(BMI)、HCV RNA定量及基因型、IFNα种类、病毒应答模式以及病毒阴转后用药时间等因素与SVR的关系.结果 SVR组与非SVR组性别、年龄和BMI无统计学差异;SVR组HCV RNA定量显著低于非SVR组(t=4.209,P=0.022),ALT或AST显著高于非SVR组(t=15.724,P=0.006;t=10.549,P=0.003);HCV RNA定量<1×105 IU/ml组SVR率显著高于HCV RNA定量≥1×105 IU/ml(χ2=6.801,P=0.009);基因1b型SVR率为56.8%,低于非1b型(60.9%);PEG IFNα-2a组SVR率为62.5%,普通IFNα-2a组SVR率为53.6%,两组比较无统计学差异(χ2=0.49,P=0.484);快速病毒学应答(RVR)患者95%获得SVR,早期病毒学应答(EVR)患者68.4%获得SVR;IFN治疗时间≥72周SVR率82.8%,复发率6.9%;HCV RNA定量阴转后用药≥40周患者复发率3.2%.结论 老年患者抗病毒治疗前低HCV RNA定量、ALT及AST≥2倍正常上限(ULN),HCV RNA非1b型患者可获得较高SVR.RVR比EVR患者SVR率高约30%,延长病毒阴转后用药时间可提高SVR.     

Response to interferon-based therapies in HIV-infected patients with chronic hepatitis C due to genotype 4

BACKGROUND: The hepatitis C virus (HCV) genotype is the main predictor of response to interferon (IFN)-based therapies. HCV genotype 4 is spreading among European intravenous drug users, who are frequently coinfected with HIV. Information about treatment response in this subset of patients is scarce and conflicting results have been reported. METHODS: All HIV-infected patients treated for chronic hepatitis C at our institution with a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. Treatment responses were stratified according to HCV genotype. RESULTS: A total of 390 patients were analysed. Sustained virological response (SVR) to HCV therapy had been reached by 90 (23.1%): 22/119 (18.5%) with IFN monotherapy; 17/106 (16%) with IFN plus RBV; and 51/165 (30.9%) with PEG-IFN plus RBV. SVR was significantly higher among those with HCV genotypes 2 or 3 (40.4%; 61/151) than in patients with either HCV genotype 1 (11.2%; 22/197) or HCV genotype 4 (16.7%; 7/42) (P<0.0001). In contrast, there were no significant differences in the response rate comparing HCV genotypes 1 and 4 (P=0.53). CONCLUSIONS: Response to IFN-based therapies in HIV-positive patients with hepatitis C due to HCV genotype 4 is poor, similar to that obtained for HCV genotype 1 and much lower than for HCV genotypes 2 and 3. Therefore, HIV-infected patients with hepatitis C due to genotype 4 should be considered as a particular subset of difficult-to-treat patients. New treatment strategies and drugs for these patients are eagerly awaited.     

Predictors of sustained response to alpha interferon therapy in chronic hepatitis C

OBJECTIVES: To utilize cytokine levels to predict sustained response (SR) to alpha interferon (IFN alpha) therapy in chronic hepatitis C patients, and to determine the relationship between serum tumor necrosis factor alpha (TNF alpha), interleukin (IL) IL 6, IL 8, IL 12, transforming growth factor beta (TGF beta 1) and the degree of liver damage as reflected by traditional markers. DESIGN AND METHODS: Serum cytokine levels were assessed using ELISA in 18 patients included in a controlled clinical trial of IFN alpha. RESULTS: Of the 18 patients, 27% were sustained responders (SR), 27% were response and relapse responders (RR), and 46% were non-responders (NR). Multivariate analysis showed that a low serum TNF alpha level and high serum IL 8 levels were independent factors associated with SR to IFN alpha therapy. Serum TNF alpha level highly correlated with viral load and genotype predictive values (p < 0.001). Therapy lowered the IL 6 and IL 12 profile. TGF beta 1 levels in serum are positively correlated with fibrinogenesis. CONCLUSIONS: IFN alpha therapy modulates immune response to hepatitis C virus, contributing to sustained response.     

Efficacy of interferon in immunocompromised HCV patients after liver transplantation or with HIV co-infection

Background Interferon (IFN)‐based antiviral therapy is increasingly used in immunocompromised patients with chronic hepatitis C after orthotopic liver transplantation (OLT) and HIV–HCV co‐infection. Differences in early viral kinetics have not been compared in these patients. Materials and methods We retrospectively analysed 76 patients (31 OLT, 20 HIV–HCV and 25 HCV control patients) undergoing IFN sensitivity testing before starting antiviral therapy with pegylated IFN‐α2a (180 µg week^?1) plus ribavirin (0·8–1·2 g day^?1) for 48 weeks. We compared baseline parameters, response to IFN and treatment outcome between the groups and assessed the influence of specific calcineurin inhibitors in OLT patients and immune status in HIV–HCV patients on treatment response. Results Viral loads pretherapy were higher in OLT compared to nontransplanted HCV controls (P = 0·003). The same trend was present in HIV–HCV (P = 0·09). The log‐drop after test dose was less in OLT compared to HCV (P = 0·02), while no significant difference was found between HIV–HCV and HCV. In HIV–HCV patients viral load log‐drop correlated significantly with CD4⁺ cell counts (P = 0·001). No difference in viral load pretherapy, log‐drop and treatment outcome was noted between different calcineurin inhibitors in OLT patients. Sustained virological response rates were 28% in OLT, 50% in HIV–HCV and 56% in HCV patients. Conclusions Immunosuppression results in high HCV viral loads. Initial efficacy of IFN is significantly impaired in OLT patients, but not in HIV–HCV with largely preserved CD4⁺ cell counts. Sustained virological response rates of 28% in OLT patients are suboptimal, but encouraging results are shown for HIV–HCV patients with relatively high CD4⁺ cell counts.     

Usefulness of a new immunoradiometric assay of HCV core antigen to predict virological response during PEG-IFN/RBV combination therapy for chronic hepatitis with high viral load of serum HCV RNA genotype 1b

We investigated the clinical usefulness of a new immunoradiometric (IRM) assay of hepatitis C virus (HCV) core antigen in predicting virological response during pegylated interferon plus ribavirin (PEG-IFN/RBV) combination therapy for chronic hepatitis with high viral loads of serum HCV RNA genotype 1b. Thirty-nine patients received a regimen of PEG-IFNalpha-2b (1.5 microg/kg/week s.c.) in combination with RBV (600-1,000 mg/day). Of the 39 patients, 18 (46.2%) achieved sustained virological response (SVR), 11 (28.2%) attained partial response (PR) and 10 (25.6%) showed no response (NR). Four weeks after the start of therapy, 1- and 2-log reductions in the amount of HCV core antigen were observed in 20 (2/10) and 0% (0/10) showing NR, 91 (10/11) and 63.6% (7/11) with PRs, and 88.9 (16/18) and 55.6% (10/18) of patients with SVR, respectively. The 1- and 2-log reductions 4 weeks after the start of therapy were not a defining condition for PR and SVR. The amount of HCV core antigen was significantly different between SVR and PR patients on days 1 and 7, and between patients with NR and SVR at all points of time. In conclusion, this new IRM assay is useful in predicting virological response during PEG-IFN/RBV therapy.     

Anticarcinogenic impact of interferon on patients with chronic hepatitis C: a large-scale long-term study in a single center

BACKGROUND: The anticarcinogenic capacity of interferon (IFN) was assessed in a cohort of Japanese patients with chronic hepatitis C en masse. PATIENTS AND METHODS: The rate of hepatocarcinogenesis was analyzed in 2,166 patients with chronic hepatitis C, of whom 1,654 had received IFN therapy while 512 had not. RESULTS: Crude rates of hepatocarcinogenesis in treated and untreated patients were 2.6 and 4.6% at the end of the 5th year, 5.8 and 12.7% at the 10th year and 13.9 and 23.9% at the 15th year (after completion of IFN therapy for those treated) (p < 0.001). IFN decreased the hazard ratio of carcinogenesis to 0.42 (p < 0.001) in multivariate analysis with adjustments for significant covariates including fibrotic stage, gamma-glutamyl transpeptidase level, gender, platelet count and age. Among the 1,654 patients treated with IFN, 606 (36.6%) achieved persistent loss of hepatitis C virus (HCV) RNA and an additional 266 (16.1%) gained normal levels of alanine aminotransferase without loss of HCV RNA for 6 months or longer after the completion of IFN therapy. Cumulative rates of hepatocarcinogenesis in sustained virological responders and biochemical responders were 1.4 and 2.0% at the end of the 5th year, 1.9 and 3.6% at the 10th year and 1.9 and 7.5% at the 15th year, respectively. The hazard ratio of sustained virological response was 0.10 (p < 0.001), and that of biochemical response was 0.12 (p < 0.001). Normalization of aminotransferase levels after IFN therapy without loss of serum HCV RNA decreased hepatocarcinogenesis. CONCLUSION: IFN significantly decreased the rate of hepatocarcinogenesis in patients with chronic hepatitis C as a whole in Japan, even in those who fail to clear HCV RNA from serum.