Hepatic HCV-RNA as a predictor of outcome after interferon therapy in patients with chronic hepatitis C

Measurement of serum HCV-RNA is a useful index for evaluating the antiviral effect of interferon therapy in chronic hepatitis C. In the present study, we investigated whether the detection of hepatic HCV-RNA after interferon treatment, using a polymerase chain reaction assay, predicted long-term response to therapy in patients with chronic hepatitis C. Thirty-three patients underwent liver biopsies before and after interferon therapy. Histology and clinical courses were compared after treatment. Before therapy, serum and hepatic HCV-RNA was detected in specimens from 32 (97%) and 33 (100%) patients, respectively. Serum HCV-RNA became undetectable in samples from 22 (67%) patients; however, in 10 of these patients (45%), serum HCV-RNA levels relapsed after therapy. Hepatic HCV-RNA became undetectable in 14 patients after therapy and the serum aminotransferase concentration remained within normal limits during and following (24–92 weeks) therapy in 12 of these patients (86%). All 11 patients with detectable hepatic HCV-RNA also had serum HCV-RNA and elevated aminotransferase concentrations refractory to therapy. The absence of hepatic HCV-RNA at the end of interferon treatment thus predicted a long-term complete response to therapy with a sensitivity of 100%, a specificity of 90% and an accuracy of 94%. We conclude that hepatic rather than serum HCV-RNA is a more useful index for the prediction of the long-term efficacy of interferon therapy.     

Efficacy of prolonged interferon therapy for patients with chronic hepatitis C with HCV-genotype 1b and high virus load

Background: In patients with hepatitis C virus (HCV)-genotype 1b and a high virus load, of more than 1 Meq/ml by the DNA probe assay, the clearance of HCV-RNA was achieved in only 10% with a 6-month interferon (IFN) course. We therefore assessed the efficacy of prolonged IFN therapy in patients with HCV-genotype 1b and a high virus load. Methods: A total of 51 patients with HCV genotype 1b who were given 6 million units (MU) of natural IFN-α daily for 8 weeks followed by three-times-weekly treatment with natural IFN-α for 16 weeks, were enrolled in this trial. These 51 patients were randomly assigned to one of two schedule groups at the time of termination of the first IFN therapy. The 48-week-group patients (n = 25) were given 6 MU of natural IFN-α by intramuscular injection three times weekly for 24 weeks, beginning within a week after the termination of the first IFN therapy. The 72-week-group patients (n = 26) were given 6 MU of IFN-α by intramuscular injection three times a week for 48 weeks, beginning within a week after the termination of the first IFN therapy. The therapeutic efficacy was evaluated 24 and 30 months after the initiation of the first IFN treatment. A virological response (VR) to IFN therapy was defined as the normalization of serum alanime amino transferase (ALT) level (ALT ≲ 50 IU) and HCV-RNA negativity at the two time points. Biochemical response (BR) was defined as the normalization of serum ALT, but positivity for HCV-RNA, assessed by commercial Amplicor HCV qualitative assays, at the two time points. Results: The efficacy of IFN treatment was assessed in relation to the IFN administration schedule by intention-to-treat (ITT) analysis and per-protocol analysis. With respect to the IFN regimen, VR occurred in 16.6% (4/24) of the patients in the 48-week-group with additional IFN and in 20% (5/25) in the 72-week-group with additional IFN by ITT analysis. The BR rate was 33.3% (8/24) in the 48-week group and 48% (12/25) in the 72-week group. Conclusions: We found that prolonged IFN therapy could be a worthwhile treatment strategy for patients with HCV genotype 1b and a high serum virus load. Received: March 15, 2002 / Accepted: July 26, 2002 Reprint requests to: Y. Arase Editorial on page 204     

Factors related to post-treatment relapse in chronic hepatitis B patients who lost HBeAg after lamivudine therapy

BACKGROUND AND AIM: It is uncertain if a patient's lamivudine response after HBeAg loss is durable. In Korean chronic hepatitis B patients, the relapse rate is high after termination of lamivudine therapy for patients with HBeAg loss. We evaluated the factors related to relapse in chronic hepatitis B patients with HBeAg loss after lamivudine therapy. METHODS: A total of 132 chronic hepatitis B patients, who initially had HBeAg and did not have decompensated features, were analyzed in this study. These patients lost the HBeAg after lamivudine therapy and then their therapy was stopped. Post-treatment serum alanine aminotransferase (ALT), HBeAg, anti-HBe and hepatitis B virus (HBV) DNA were monitored until relapse. RESULTS: Seventy-five patients relapsed (cumulative relapse rate: 56% at 6 months). Upon univariate analysis, the factors of age, serum total bilirubin, presence of anti-HBe after HBeAg loss, and the duration of additional lamivudine therapy after HBeAg loss were associated with relapse. Upon multivariate analysis, older age, a higher serum total bilirubin and the shorter duration of additional lamivudine therapy were significant risk factors for relapse. Patterns of relapse were the re-elevation of ALT, re-emergence of HBV DNA (69 patients) and reappearance of HBeAg (55 patients). CONCLUSIONS: To prevent relapse in patients with chronic hepatitis B infection after lamivudine therapy, age and serum bilirubin level of patients as well as a prolonged duration of additional lamivudine therapy should be considered.     

Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin

Summary.  The impact of ribavirin exposure on virologic relapse remains controversial in combination therapy with pegylated interferon (Peg-IFN) and ribavirin for patients with chronic hepatitis C (CH-C) genotype 1. The present study was conducted to investigate this. Nine hundred and eighty-four patients with CH-C genotype 1 were enrolled. The drug exposure of each medication was calculated by averaging the dose actually taken. For the 472 patients who were HCV RNA negative at week 24 and week 48, multivariate logistic regression analysis showed that the degree of fibrosis ( P  =   0.002), the timing of HCV RNA negativiation ( P  <   0.001) and the mean doses of ribavirin ( P  <   0.001) were significantly associated with relapse, but those of Peg-IFN were not. Stepwise reduction of the ribavirin dose was associated with a stepwise increase in relapse rate from 11% to 60%. For patients with complete early virologic response (c-EVR) defined as HCV RNA negativity at week 12, only 4% relapse was found in patients given ≥12 mg/kg/day of ribavirin and ribavirin exposure affected the relapse even after treatment week 12, while Peg-IFN could be reduced to 0.6 μg/kg/week after week 12 without the increase of relapse rate. Ribavirin showed dose-dependent correlation with the relapse. Maintaining as high a ribavirin dose as possible (≥12 mg/kg/day) during the full treatment period can lead to suppression of the relapse in HCV genotype 1 patients responding to Peg-IFN alpha-2b plus ribavirin, especially in c-EVR patients.     

Quantitative analysis of interferon α/β receptor mRNA in the liver of patients with chronic hepatitis C: Correlation with serum hepatitis C virus-RNA levels and response to treatment with interferon

We analysed the expression of interferon (IFN) α/β receptor mRNA in the liver of patients with chronic hepatitis C and examined the relationship between the expression of this receptor gene and the level of hepatitis C virus (HCV)-RNA as well as the response to 16 weeks of 6 × 10⁶ units IFN. The mean level of IFNα/β receptor mRNA in patients with chronic HCV infection (expressed as δ cycle; 10.8±1.9 (mean±SD); n = 39) was significantly higher than that of control subjects (9.4±0.5; n=6; P<0.01). There was a significant negative correlation between the level of IFNα/β receptor mRNA and serum HCV-RNA in 39 patients with chronic hepatitis C (R=-0.546; P<0.01). The mean level of IFNα/β receptor mRNA in six patients who showed a complete response to IFN therapy (12.3±1.6) was higher than that of 15 patients who failed to respond to therapy (10.1±1.5; P< 0.01). Our results are consistent with the suggestion that the anti-viral activity of IFN depends on the level of the IFNα/β receptor on hepatocytes in patients with chronic hepatitis C.     

The long-term efficacy of interferon alfa in chronic hepatitis C patients: A critical review

With current therapeutic regimens, sustained responses occur in no more than 25% of patients with chronic hepatitis C who are treated with interferon. Relapses occur usually within 6 months from therapy suspension, but clinical and virologic recurrencies can be observed as late as after 3 years of follow up. The rate of long-term responses seems to depend on the dosage and the period of administration of interferon, but the best therapeutic protocol remains unknown. As a direct marker of permanent recovery is not available, indirect signs of disease resolution are: (i) continuously normal alanine aminotransferase levels; (ii) clearance of HCV-RNA; (iii) disappearance of anti-C100/NS4; and (iv) significant histological improvements assessed at least 2 years after therapy withdrawal. Known baseline predictive features of long-term response are the absence of cirrhosis, low viraemic levels and infection with HCV of type III or IV genotype (Okamoto's classification). According to recent reports, the lower the heterogeneity of the hypervariable region of the envelope 2 gene of HCV, the higher the chance of a sustained remission. There is not yet any consensus on the efficacy of a second therapeutic course of interferon in inducing a permanent response, and controlled trials are needed to clarify this issue.     

Alanine aminotransferase and HCV-RNA responses following interferon therapy of HCV-RNA positive chronic hepatitis

Interferon (IFN) has been shown to be effective for chronic hepatitis C. This study investigated changes of alanine aminotransferase (ALT) and HCV-RNA in chronic hepatitis C patients treated withα-IFN. IFN was given to 73 patients with HCV-RNA positive chronic hepatitis C. The pattern of changes in ALT activity after IFN aministration was classified into five types. Type 1 was characterized by normalization of ALT (≤25 K.U) during IFN administration and sustained normalization after the IFN therapy. Type 2 involved a rebound of ALT after termination of IFN therapy and subsequent normalization. Type 3 had no ALT normalization during IFN administration, with normalization after the completion of the therapy. Type 4 involved transient normalization of ALT level during IFN therapy, with a subsequent reversion to abnormal levels after the termination of IFN therapy. Type 5 showed sustained abnormally high levels of ALT activity both during and after treatment. Twenty four patients (32.9%) had sustained normalization ALT (≤25 K.U) after the termination of IFN treatment. The HCV-RNA negative rate at 6 months after IFN therapy in patients with sustained normalization of ALT was 87.5% (21/24).     

Adequate timing of ribavirin reduction in patients with hemolysis during combination therapy of interferon and ribavirin for chronic hepatitis C

Background Hemolytic anemia is one of the major adverse events of the combination therapy of interferon and ribavirin. Because of ribavirin-related hemolytic anemia, dose reduction is a common event in this therapy. In this clinical retrospective cohort study we have examined the suitable timing of ribavirin reduction in patients with hemolysis during combination therapy.Methods Thirty-seven of 160 patients who had HCV-genotype 1b, had high virus load, and received 24-week combination therapy developed anemia with hemoglobin level <10g/dl or anemia-related signs during therapy. After that, these 37 patients were reduced one tablet of ribavirin (200mg) per day. After reduction of ribavirin, 27 of 37 patients could continue combination therapy for a total of 24 weeks (group A). However, 10 of 37 patients with reduction of ribavirin could not continue combination therapy because their <8.5g/dl hemoglobin values decreased to or anemia-related severe side effects occurred (group B). We assessed the final efficacy and safety after reduction of ribavirin in groups A and B.Results A sustained virological response (SVR) was 29.6% (8/27) in group A and 10% (1/10) in group B, respectively. A 34.4% (12/27) of SVR + biological response in group A was higher than 10% (1/10) in group B (P = 0.051), with slight significance. With respect to hemoglobin level at the time of ribavirin reduction, a rate of continuation of therapy in patients with 10g/dl hemoglobin was higher than that in patients with <10g/dl (P = 0.036).Conclusions Reduction of ribavirin at hemoglobin level 10g/dl is suitable in terms of efficacy and side effects.     

干扰素治疗慢性丙型肝炎的持续应答与复发相关因素的研究

目的 探讨丙型肝炎病毒（HCV）基因型、RNA含量与肝组织炎症活动的相关性，慢性丙型肝炎患者经干扰素治疗后复发的相关因素。方法 对慢性丙型肝炎患者的血清进行丙氨酸氨基转移酶（ALT）检测，采用Cobas Amplicor Monnitour Test．version 2．0试剂进行HCVRNA定量和Simmonds酶切分型方法进行HCV基因分型检测。对聚乙二醇化干扰素α-2a（PEG—IFN α-2a）与干扰素α-2a治疗24周结束时，取得病毒学应答的慢性丙型肝炎患者进行24周随访观察，对临床特征、病毒学特征、治疗药物等因素与复发的相关性进行分析。结果 208例丙型肝炎患者基础HCVRNA含量与ALT水平无相关性（r=0．093，P〉0．05），HCV基因1型与非基因1型之间ALT的水平差异无统计学意义，HCV基因型与RNA含量无相关性；在治疗结束取得病毒学应答的119例患者中，随访24周持续应答者61例（51．3％），复发58例（48．7％）。患者的性别、年龄、HCV感染途径、既往干扰素治疗史、天冬氨酸氨基转移酶／ALT比值、血小板计数和血清基础HCV载量等因素均与复发率无显著相关性。基因1型患者复发率（54．5％）显著高于非1型（32．1％）（x^2=4．265，P=0．039）。PEG-IFNα-2a组复发率（47．0％）低于IFNα-2a组（52．8％），但差异无统计学意义。结论 病毒基因型与慢性丙型肝炎干扰素治疗后的病毒复发显著相关。     

Long-term retreatment in chronic hepatitis C patients who were non-responders to an initial course of interferon-α2b

Nineteen patients with chronic hepatitis C who were virological non-responders (seven responder/relapse and 12 no response) to an initial 24-week course of interferon-α2b (IFN-α2b) at a dose of 3million units (MU) thrice weekly were retreated for an additional 48 weeks at the same dosing schedule and followed-up for another 24 weeks post-therapy. At the end of follow-up (week 72), six (32%) of the 19 patients were hepatitis C virus (HCV) RNA negative and were virological complete responders to retreatment. The viral genotypes in these six patients included two each with 1b and 3a, one with 2b, and another with 2a/2b; five of the six virological responder patients had cirrhosis. Significant predictors for successful retreatment included lower baseline HCV RNA concentrations prior to the first course of therapy, 2 log₁₀ reductions in serum HCV RNA during the initial treatment and classification into the virological ‘responder/relapse’ category after the first course of IFN (P < 0.01 for all observations). When the above factors were used to construct a predictive model to determine response to retreatment, it was found that the absence of a 2 log₁₀ drop in HCV RNA concentrations during the first course of IFN therapy was the most reliable indicator of non-response to retreatment (likelihood ratio = 10, P = 0.0014). In addition, the presence of HCV RNA at week 12 of retreatment was 100% predictive of virological non-response to the 48-week course of therapy. Our findings indicate that an additional 48-week course of IFN-α2b therapy at 3 MU thrice weekly will achieve a virological complete response in 60% of patients who had a 2 log₁₀ drop in HCV RNA during their first course of treatment, and measurement of week-12 HCV RNA during retreatment to identify non-responders is beneficial to patients as well as being cost-effective. Thus, a second course of IFN remains a viable option in a subgroup of non-responder patients, regardless of genotype or the presence of compensated cirrhosis.     

Risk factors for relapse in chronic hepatitis C patients who have achieved end of treatment response

Background and Aim: Some patients with chronic hepatitis C experience virologic relapse even after achieving an end of treatment response. Prolonged therapy can be effective for helping such high‐risk patients to avoid relapse. We aimed to identify factors predictive of virologic relapse in chronic hepatitis C patients who have achieved end of treatment response. Methods: We analyzed data from 242 chronic hepatitis C patients who achieved end of treatment response with peginterferon plus ribavirin therapy from 2003 to 2007. Results: Virologic relapse was identified in 32 patients (13.2%). We considered age, sex, body mass index, presence of diabetes, hemoglobin, platelet, alanine aminotransferase, stage of fibrosis, baseline hepatitis C virus RNA level, rapid virologic response, and adherence to drugs. For genotype 1 patients, older age (≥ 50 years) and higher baseline RNA level (≥ 2000 000 IU/mL) were significantly correlated with occurrence of relapse. For genotypes 2 and 3, lower adherence to peginterferon (< 80%) was an independent risk factor for relapse. Conclusions: In chronic hepatitis C patients who had achieved end of treatment response, risk factors for relapse were older age and higher baseline hepatitis C virus RNA level in genotype 1, and lower adherence to peginterferon in genotypes 2 and 3, which may be valuable to individualize duration of therapy.     

Tailoring interferon dose and monitoring viral load in hepatitis C virus genotype 1b infected patients: a pilot study

BACKGROUND AND AIMS: Complete [biochemical and virological) primary response remains the first goal of any antiviral therapy and its early assessment could be particularly useful in the management of the high viral load, genotype 1b infected patients, who have the worst chance of response. We evaluated whether tailoring interferon dose according to pre-treatment viral load and early monitoring of quantitative HCV-RNA could either improve or predict the results of recombinant alpha-2a interferon treatment in these patients. PATIENTS: Fifty-three consecutive genotype 1b HCV-infected patients, stratified in two groups by viral load (cut off 6 MEq/ml), received randomly 6 or 9 MU of recombinant alpha-2a interferon thrice weekly for 6 months, followed by 6 MU for another 6 months. METHODS: HCV-RNA was measured [b-DNA] assay) two months apart prior to therapy, at baseline, after 2 weeks of therapy and monthly thereafter. RESULTS: In the high viraemic group, complete primary response was observed in 80% of patients treated with high dose recombinant alpha 2a interferon and only in 14.3% of low dose treated patients [p<0.03]. In low viraemic patients, complete primary response was 53. 8% in low dose patients and 80% (8 out of 10) in the high dose group. Sustained response was 60% in high viraemic patients treated with high dose and absent in those treated with low dose [p<0.05]. One log viral load decrease at 2 or 4 weeks showed 0.87 and 0.80 positive predictive values, 0.95 and 1.0 negative predictive values with 96% and 100% sensitivities and 83% and 70% specificities. CONCLUSIONS: 6 MU recombinant alpha-2a interferon thrice weekly schedules were completely ineffective in the large majority (85.7%) of patients with viral load above 6 million HCV-RNA copies/ml and the treatment failure could be predicted by lack of one log viral load decrease after 2-4 weeks of treatment.     

Prediction of relapse or sustained response in biochemical responders by serum hepatitis C virus RNA monitoring during interferon therapy

Normalization of serum aminotransferase levels is achieved in ≈ 50% of chronic hepatitis C patients treated with interferon (IFN); however, in about one-half of these patients the hepatitis relapses after therapy. In this study we investigated the efficacy of serum hepatitis C virus (HCV) RNA monitoring during IFN therapy to predict the outcome of a biochemical end-of-treatment (ETR) response. Eighty patients with chronic hepatitis C received leucocyte (natural) IFN-α (13 patients) or recombinant IFN-α2a (67 patients). Antiviral therapy was given for 12 months to 43 (53.7%) responders and this group was analysed further. During follow-up, 15 relapsed and 28 showed a sustained response (median follow-up 50 months, range 39–67 months). Viraemia was monitored at baseline, and at months 1, 3, 6, 9 and 12 of treatment, by nested polymerase chain reaction (PCR) (sensitivity 10–100 copies ml^–1). A combination of positive nested PCR and HCV RNA values at the 3rd and 6th months of treatment was 100% predictive of relapse (sensitivity, 66.6%; specificity, 100%). A combination of negative nested PCR and HCV RNA values at the 1st and 3rd months of treatment was 100% predictive of sustained response (sensitivity, 39.3%; specificity, 100%). In conclusion, serum HCV RNA monitoring is an appropriate and reliable tool for predicting early outcome of the biochemical ETR response after IFN discontinuation. This could be useful in the modulation of therapeutic management of chronic hepatitis C.