Evolution of hepatitis C virus quasispecies during therapy with IL2 combinated to alpha interferon and ribavirin

This study analyses the impact of interleukin 2 (IL2) combined with alpha interferon (IFN-alpha) and ribavirin on the heterogeneity of hepatitis C virus (HCV). We studied 10 patients who took part in a clinical trial that assessed the effects of retreatment with IL2, IFN-alpha and ribavirin in patients who failed to clear the virus after a previous bitherapy. The heterogeneity of HCV quasispecies was assessed by cloning and sequencing the hypervariable region 1 (HVR1) in samples obtained at baseline (W0), after 12 weeks of treatment with IFN-alpha and ribavirin (W12), after a cycle of administration of IL2 in combination with the classical bitherapy (W21 and W24) in the eight patients who failed to clear the virus under treatment. The mean viral load at W21 and at W24 was not different from that at W12. The heterogeneity of HVR1 quasispecies after the administration of IL2 was not different from that at baseline or after 12 weeks of bitherapy. Furthermore, the proportion of nonsynonymous substitutions was unchanged after the IL2 cycles. Thus, the efficacy of the tritherapy with IL2, IFN-alpha and ribavirin is similar to that of the classical bitherapy. Treatment with IL2 in combination with IFN-alpha and ribavirin had no effect on the selective pressure on HCV quasispecies. IL2 is not the best option to treat hepatitis C.     

Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies

BACKGROUND: Chronic hepatitis C virus (HCV) infection is frequent among HIV-infected patients. Clearance of serum HCV RNA 6 months after discontinuing HCV therapy is generally interpreted as a cure of HCV infection in HIV-negative subjects. However, the occurrence of liver complications (including hepatocellular carcinoma) and/or HCV relapses in coinfected patients when followed for long periods of time after HCV therapy is not well known. METHODS: All HIV-infected patients who had been treated for chronic hepatitis C at our institution and had 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. RESULTS: A total of 351 patients were retrospectively analysed. Sustained virological response (SVR) to HCV therapy had been reached by 77 (22%) of them: 22/119 (18.5%) with IFN monotherapy, 17/106 (16%) with IFN plus RBV and 38/126 (30.2%) with PEG-IFN plus RBV. Considering the HCV genotypes, SVR had been reached by 19/184 (10.3%) of patients with genotype 1, 54/138 (39.1%) with genotypes 2 or 3, and 4/29 (13.8%) of those with genotype 4. Within a total of 4466 patient-months follow-up (mean of 58 months), none of the 77 patients with SVR showed HCV-RNA rebounds, elevations in liver enzymes potentially linked to HCV, development of hepatocellular carcinoma or episodes of decompensated cirrhosis. In contrast, all 274 patients who did not reach SVR with HCV therapy showed evidence of persistent serum HCV RNA and 90% of them showed liver enzyme elevations during a total of 15344 patient-months follow-up (mean of 56 months). Moreover, 11 (4%) developed clinical complications of liver cirrhosis and two of them died of end-stage liver disease. CONCLUSIONS: HCV replication and HCV-related liver disease seem to be permanently halted in HIV/HCV-coinfected patients showing HCV-RNA clearance 6 months after completing any kind of IFN-based therapy. In contrast, complications of liver disease due to persistent HCV infection continue to occur in non-responders. The role of maintenance HCV therapy should be explored in HIV/HCV-coinfected patients.     

Influence of viral load and alanine aminotransferase on viral genetic heterogeneity in patients with chronic hepatitis C virus infection

BACKGROUND/AIM: Hepatitis C virus (HCV) populations in vivo consist of genetically different heterogeneous mixtures defined as 'quasispecies', which vary in the hypervariable region 1 (HVR1) mostly. To further address the role of quasispecies diversity in hepatitis C infection, this study aimed to evaluate the influence of ALT, viral load and genotypes on quasispecies heterogeneity in patients with HCV infection. METHODS: Thirty-six chronic hepatitis C patients with high levels of alanine aminotransferase (ALT) were studied. None of them received any antiviral therapy. HCV RNA serum levels, genotype and genetic heterogeneity were determined by branched-chain DNA assay, restriction fragment length patterns and RT-PCR single-strand conformational polymorphism analysis of HVR1, respectively. RESULTS: Twenty-eight patients had genotype 1b (28/36; 78%), 6 patients had genotype 1a (6/36; 17%), 1 patient was 2a (1/36; 3%) and genotype could not be determined in 1 patient. The patients were categorized into two groups according to the number of bands representing the dominant strains in the circulation: group A with 2 bands having 1 strain (14/36 patients; 39%) and group B with more than 2 bands indicating more than 1 strain (22/36 patients; 61%). The serum viremia and ALT levels for these groups were 11 +/- 8.8 and 5.3 +/- 4.6 mEq/ml (p < 0.05), and 79 +/- 20, and 127 +/- 80 IU/l (p < 0.05), respectively. CONCLUSION: The results of this study suggest that hepatitis C patients having 1 dominant strain in the circulation may show a relatively weaker immune response resulting in lower ALT and higher viremia levels, whereas patients with high degrees of virus quasispecies diversity have higher ALT levels and a more active immune response causing the selection of new genome variants and depressing viral replication partly.     

Sustained suppression of hepatitis C virus by high doses of interferon and ribavirin in adult hemophilic patients

BACKGROUND: In a recent randomized controlled study, only a minority (15%) of adult hemophiliacs with chronic HCV achieved a sustained virologic response to treatment with interferon (IFN) and ribavirin given at standard doses. STUDY DESIGN AND METHODS: Whether the therapeutic response might be improved in these patients by increasing the doses of IFN was evaluated. Thirty-four previously untreated, adult hemophiliacs with chronic HCV but negative for HIV were investigated. There were 33 men and 1 woman, aged 21 to 60 years (mean, 36). Twenty-three patients (68%) had genotype 1, and median serum HCV-RNA was 473 x 10(3) IU per L (range, 3.6-2145). Patients were treated with IFN at 5 million units (MU) thrice weekly for 6 months, followed by 3 mol/L for 6 additional months in combination with daily oral doses of 1 or 1.2 g of ribavirin. RESULTS: A total of 33 patients (97%) completed the study; one patient withdrew because of treatment-related symptoms. Treatment dosage had to be reduced in 20 patients (59%). By intention-to-treat analysis, 14 patients (41%) had a sustained virologic response, particularly those infected by HCV genotype 2 or 3 (70% vs. 29% with genotype 1 or 4, p < 0.05). Sustained response rates were similar in the 13 compliant patients and the 20 patients who had to reduce IFN and/or ribavirin doses (54% vs. 35%). CONCLUSIONS: High-dose IFN therapy plus ribavirin provided high rates of sustained virologic responses in adult hemophiliacs with chronic HCV, even if side-effects led to dose reduction in half of these patients.     

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.     

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.     

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.     

献血人群中丙型肝炎病毒第1高变区抗体检测及意义

目的研究丙型肝炎病毒(HCV)第一高变区(HVR1)抗体检测在献血者血液筛查中的意义。方法采用融合F4HVR1抗原检测不同血清样本中的抗-HVR1的存在情况,并与现有C、NS3、NS4、NS5抗体进行比较。结果在HCV-RNA阳性样本中,HVR1抗体的阳性率为96.8%;在90份可疑HCV感染血清中HVR1抗体的阳性率为61.1%,与C区、NS3区接近,高于NS4区、NS5区(P<0.05),共检测出4份单独HVR1抗体阳性血清。结论在现有HCV诊断试剂基础上,对献血人群进行HCV-HVR1抗体的检测可以提高血液筛查灵敏度,减少HCV的经血传播。     

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.     

Complexity of the HVR-1 quasispecies and disease activity in patients with hepatitis C

BACKGROUND: Hepatitis C virus (HCV) easily undergoes genomic changes, especially in the hypervariable region (HVR) in the N-terminus of the E2/NS1 region. The quasispecies nature of HCV may have important biological implications in relation to viral persistence; however, the relationship between disease activity of chronic HCV infection and development of the genomic complexity have yielded conflicting results. We explored the changes in the complexity of the HVR-1 in the natural course of chronic HCV infection with and without elevation of serum alanine transaminase (ALT) levels. MATERIALS AND METHODS: Ten patients with chronic hepatitis C proven by liver biopsy, who showed persistent elevation of the serum ALT levels, and 15 patients with chronic HCV infection and persistently normal serum ALT levels (PNAL) were enrolled in this study. The number of the HCV quasispecies was determined twice for each patient at an interval of mean 2.5 years by fluorescence single-strand conformation polymorphism and sequence analysis. RESULTS: There was no significant difference in the changes in the number of quasispecies during the follow-up period between chronic hepatitis C and PNAL. There was also no significant difference in the change in the number of variable nucleotides sites between the two groups. In these patients, the number of quasispecies and the diversity of HVR-1 were correlated with platelet counts and serum hyaluronic acid levels previously shown to be associated with disease progression. CONCLUSION: Our results suggested that the disease activity is not always related to the generation of the HVR-1 quasispecies complexity.     

Impact of ribavirin exposure on early virological response to hepatitis C therapy in HIV-infected patients with chronic hepatitis C

BACKGROUND: The use of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is currently the recommended treatment for chronic hepatitis C virus (HCV) infection. Coinfection with HIV is a negative predictor of response, for reasons not well understood. METHODS: We examined the virological response at weeks 4 and 12 in 198 HCV/HIV-coinfected patients enrolled in a prospective trial in which PEG-IFN alpha 2a (180 microg per week) and RBV (1000-1200 mg daily) were provided. RESULTS: In an on-treatment analysis, 52.8% of patients achieved undetectable HCV-RNA (<600 IU/ml) at week 4, while 63% and 77.2% of patients had a decline of at least 2 and 1 log10, respectively. At week 12, 73.1% of patients reached undetectable HCV-RNA, and 83.5% and 89% achieved at least a 2- and 1-log10 drop, respectively. More than 85% of HCV genotypes 2/3 cleared HCV-RNA at week 4, a proportion significantly higher when compared with genotypes 1 (33.8%) and 4 (28.6%). Multivariate logistic regression analysis identified genotype 3 and RBV exposure (mg/kg of body weight) as independent predictors of virological response at week 12 of therapy. CONCLUSION: Early virological response rates to PEG-IFN plus RBV in HCV/HIV-coinfected patients seem to be similar to those reported for HCV-monoinfected subjects. The use of suboptimal doses of RBV in most earlier trials might account for the low response rates seen in coinfected patients. To our knowledge, this is the first report demonstrating that RBV exerts a significant independent effect on early virological response. Therefore, strategies aimed at optimizing doses and adherence to RBV might help to improve responses to HCV therapy in coinfected patients.     

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.     

Long-term outcome after interferon therapy in elderly patients with chronic hepatitis C

OBJECTIVE: The purpose of this study was to elucidate the long-term outcome after interferon (IFN) therapy in chronic hepatitis C elderly patients. METHODS: We studied the incidence of hepatocellular carcinoma (HCC) and survival probability after the initiation of IFN therapy in 500 Japanese chronic hepatitis C patients >60 years. The mean age of initiation of IFN was 63 years and the mean follow-up period was 7.4 years. Cox proportional hazard regression analysis was used to evaluate the long-term outcome after initiation of IFN therapy. Sustained virological response (SVR) was defined as negative HCV-RNA by RT-nested PCR 6 months after the completion of long-term IFN therapy. Non-response (NR) was applied to patients who did not show SVR. Hepatic fibrosis was defined as the fibrosis score (score 0-4) according to Knodell et al. RESULTS: 140 patients (28%) had an SVR and 360 patients (72%) had an NR. 71 of 500 patients developed HCC during follow-up. The cumulative incidence of HCC was 9.6% at the 5th year, 17.4% at the 10th year, and 31.3% at the 15th year. HCC developed with significance when: (1) HCV was not cleared after IFN therapy (p < 0.0001), (2) sex was male (p < 0.0001), and (3) staging of liver fibrosis was >2 (p = 0.008). 53 of the patients died. The cumulative survival probability was 95.7% at the 5th year, 86.4% at the 10th year, and 78% at the 15th year. Patients achieved a long survival with significance when: (1) staging of liver fibrosis was 1 (p < 0.0001), (2) HCV was cleared after IFN therapy (p = 0.034), and (3) sex was female (p = 0.015). CONCLUSION: Chronic hepatitis C patients with clearance of HCV after IFN therapy had a significantly reduced risk of HCC appearance and achieved prolonged survival even if they are > or =60 years.     

Hepatitis C virus-RNA clearance in HIV-coinfected patients with chronic hepatitis C treated with pegylated interferon plus ribavirin

Hepatitis C virus (HCV)-RNA clearance seems to occur more slowly in HIV/HCV-coinfected patients than in HCV-monoinfected subjects treated with pegylated interferon alpha (peg-IFN) plus ribavirin (RBV). As a consequence, concern has arisen over the feasibility of following the treatment rules applied to HIV-negative patients with chronic hepatitis C. A total of 89 HIV/HCV-coinfected patients who had fully completed a course of peg-IFN plus RBV were analysed. Of these, 29 (32.6%) reached sustained virological response (SVR). Reductions >2 logs in plasma HCV-RNA occurred in 52 (58%) patients at week 12 of treatment (early virological response; EVR). None of patients who showed HCV-RNA drops <2 logs at week 12 reached SVR (negative predictive value: 100%). The positive predictive value of EVR was 56%. On the other hand, relapses occurred in 19 (39.6%) out of the 48 patients who had negative HCV-RNA at the end of treatment, and there were no differences noted when comparing patients with HCV genotypes 2/3 and 1/4. In summary, the quantitative assessment of plasma HCV-RNA at week 12 predicts the chance of SVR using peg-IFN plus RBV in HIV-positive patients with chronic hepatitis C, as it does in HIV-negative individuals. Thus, discontinuation of anti-HCV therapy, which is associated with frequent side effects, might be warranted in HIV/HCV-coinfected patients showing HCV-RNA reductions <2 logs at week 12 of treatment. On the other hand, relapses in virological responders were unexpectedly high in HIV/HCV-coinfected patients when treatment was provided following the rules applied to HIV-negative subjects. This is particularly relevant for HCV genotypes 2/3, which only rarely relapse in HIV-negative patients. Therefore, extending therapy (for 12 months in HCV genotypes 2/3 and perhaps for 18 months in HCV genotypes 1/4) might be warranted in HIV/HCV-coinfected patients showing EVR.     

Evolution of hepatitis C virus quasispecies during ribavirin and interferon-alpha-2b combination therapy and interferon-alpha-2b monotherapy

OBJECTIVE: Ribavirin and interferon combination therapy is more effective than interferon monotherapy in patients with chronic hepatitis C virus (HCV) infection. To test the hypothesis that ribavirin induces nucleotide substitutions in the viral genome and reduces viral load by forcing it into error catastrophe in the combination therapy, we investigated the molecular evolution of HCV quasispecies in 3 patients who received combination therapy and 2 patients who received interferon monotherapy. METHODS: The quasispecies were analyzed before and after therapy by sequencing at least 8 clones in five regions of the HCV genome; 5' untranslated region, EI, E2, NS5A and NS5B. RESULTS: Marked genetic drift was observed in the NS5A and NS5B regions in patients treated with combination therapy. However, genetic distances between clones obtained after therapy were closer than those obtained before therapy. CONCLUSION: Our results suggest that the combination therapy modified HCV quasispecies, but that this did not reflect the induction of error catastrophe by ribavirin. Modification of quasispecies by this therapy requires further investigation in a larger number of patients to elucidate the possible mechanism of viral resistance against the combination therapy.     

丙型肝炎病毒基因分型与治疗效果关系的研究

目的 分析丙型肝炎病毒（HCV）基因型与利巴韦林联合聚乙二醇干扰素α-2a治疗效果的关系,为临床抗HCV治疗提供依据.方法 选择179例慢性丙型肝炎初治患者进行利巴韦林联合聚乙二醇干扰素α-2a的标准方案进行治疗,采用实时荧光定量聚合酶链反应（PCR）进行HCV-RNA定量检测,采用基因测序检测进行HCV基因分型.治疗后评价持续病毒学应答（SVR）.结果 179例丙型肝炎患者中,HCV 1b型占79.3%,HCV 2a型占8.4%,HCV 3b型占5.0%,HCV 6a型占2.2%,HCV 1b、2a混合型占1.1%,其他型占4.0%.HCV 2a型患者获得SVR率明显高于HCV 1b型,差异有统计学意义（χ^2=4.956,P=0.026）.结论 该院HCV基因型主要为HCV 1b和HCV 2a型,HCV 1b型患者对标准治疗方案的疗效较2a型差.     

Percentage of hepatitis C virus-infected hepatocytes is a better predictor of response than serum viremia levels

Pegylated alpha-interferon plus ribavirin is the current therapy for chronic hepatitis C virus (HCV) infection. Serum HCV-RNA concentration before treatment has been identified as an independent predictive factor of response. We have compared the percentage of HCV-infected hepatocytes with the concentration of serum HCV-RNA in baseline samples as predictors of response. We included 97 patients with chronic HCV infection (genotype 1), treated with pegylated-interferon-alpha2b plus ribavirin. Of these 97, 38 (39%) were sustained responders and 59 (61%) were not. Statistical differences between responders and nonresponders were found regarding the percentage of infected hepatocytes (6.83+/-4.50% versus 13.44+/-10.05%; P=0.00003) but not in serum HCV-RNA concentration [1.71+/-2.70 (x10(6) IU/L) versus 1.32+/-1.86 (x10(6) IU/L); P=0.40694]. Other factors associated with response were age, gamma-glutamyl transpeptidase level, and absence of previous therapy. Logistic regression demonstrated that percentage of infected hepatocytes (odds ratio, 1.160; 95% confidence interval, 1.065-1.264) and previous therapy (odds ratio, 0.294; 95% confidence interval, 0.109-0.795) were significant predictive factors for response. Therefore, the percentage of infected hepatocytes in liver biopsy before treatment is a better predictive factor of sustained response to 48 weeks of therapy with pegylated alpha-interferon plus ribavirin than serum HCV-RNA concentration in baseline serum sample.     

HCV-HBV infection

Chronic infection of hepatitis C (HCV) and B virus (HBV) frequently causes viral hepatitis. Patients with chronic viral hepatitis are at risk for liver cirrhosis and even hepatocellular carcinoma. In patients with chronic hepatitis C, the most effective therapy is elimination of HCV with interferon (IFN). The most effective initial IFN therapy is the combination of pegylated IFN alpha-2b plus ribavirin. Forty-eight weeks of this combination therapy produces sustained viral response rates of approximately 50%. Moreover, several reports showed that long-term IFN therapy also reduced the risk of liver carcinogenesis. In patients with chronic hepatitis B, seroconversion from HBeAg to anti-HBe antibodies suppresses viral replication and attenuates the hepatitis. Twenty-four weeks of IFN therapy produces HBeAg seroconversion rates approximately 30%.     

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.     

Combined interferon and ribavirin therapy for chronic hepatitis C in Taiwan

Chronic hepatitis C virus (HCV) infection, including its sequelae, is an important healthcare problem in Taiwan. The seroprevalence of HCV infection in first-time blood donors in Taiwan is 1.2% and an estimated 2-5% in the general population, with a great geographic variation. Genotype 1b is the most prevalent HCV genotype in Taiwan, with a prevalence rate of 50-70%. An increasing incidence of hepatocellular carcinoma (HCC) is mainly attributed to HCV infection, while the declining role of HBV is observed in Taiwan. The seroprevalence of hepatitis B surface antigen among patients with HCC was 90% three decades ago, while recently, chronic HCV infection accounts for more than 30% of HCC patients in the National Taiwan University Hospital. With the advent of a combined conventional interferon (IFN)-alpha and ribavirin therapy, to which Taiwan has contributed in the early study phase, the sustained virological response rate has been greatly improved compared with IFN monotherapy. The sustained virological response rate in Taiwanese patients treated with the combination therapy for 6 months has reached up to 50-60%, which is higher than that reported in patients from the Western countries receiving a 12-month regimen. It is necessary to search for the underlying mechanisms for the better treatment outcome with IFN plus ribavirin combination therapy in Taiwanese patients. Whether long-term effects of IFN plus ribavirin therapy can reduce the incidence of HCC needs to be established.