A model to predict long-term sustained response to interferon therapy in chronic hepatitis C

Interferon therapy is used widely for chronic hepatitis C but only a minority of treated patients achieve a long-lasting sustained response. We have developed, by logistic regression, a mathematical model to estimate the probability of sustained response in an individual patient with chronic hepatitis C when treated with interferon-α (IFN-α). The model, which includes age, sex, disease duration, pretreatment serum γ-glutamyl-transpeptidase, alanine aminotransferase and virus genotype, was developed from a database of 307 patients and validated in a new set of 200 patients. It performed well as goodness-of-fit ( P = 0.71 and P = 0.15 in the development and test sample, respectively) and discrimination (area under receiver operating curve = 0.79 in the development and 0.78 in the test sample, respectively). This model may provide decision support in the treatment of chronic hepatitis C with IFN-α.     

Hepatitis C virus genotypes and hepatic fibrosis regulate 24-h decline of serum hepatitis C virus RNA during interferon therapy in patients with chronic hepatitis C

BACKGROUND AND AIMS: Recently, hepatitis C virus (HCV) dynamics during interferon (IFN) therapy have been studied in detail. We examined factors that regulate the viral kinetics and the relationship between the viral kinetics and clinical effect of IFN therapy. METHODS: Eighty-eight patients with chronic hepatitis C entered this study. All patients had been treated with 3 MU of IFN-beta twice a day for the first 2-4 weeks, then IFN-alpha for the next 20-22 weeks (three injections per week). The levels of serum HCV RNA were determined by Amplicor HCV Monitor version 1.0, before and 24 h after the first injection of IFN; then the decline of HCV was calculated. Liver inflammation and fibrosis were scored as 0 (none), 1 (mild), 2 (moderate) or 3 (severe) using biopsy specimens. RESULTS: The decline of serum HCV RNA was 1.42 +/- 0.65 log copies/mL in genotype 1b and 1.83 +/- 0.72 in genotype 2a or 2b (P < 0.01). By a logistic regression model, genotype (1b, 2a or 2b) and hepatic fibrosis (0 or 1, 2 or 3) associated with 24-h decline of serum HCV RNA, independently. As the predictor of IFN therapy, the decline of serum HCV RNA and serum HCV RNA levels before IFN therapy were the independent significant factors (P < 0.001). CONCLUSIONS: The decline of serum HCV RNA during the first 24 h of IFN therapy was regulated by genotypes and hepatic fibrosis. The decline of serum HCV RNA and initial HCV load were independent factors that can be the predictor of the subsequent sustained viral response to IFN therapy.     

Predicting interferon therapy efficacy from hepatitis C virus genotype and RNA titer

We classified 53 Japanese patients with chronic hepatitis C who were treated with natural interferon- into genotypes and also tested the amounts of hepatitis C virus (HCV) RNA. The rate of the long-term complete response group, whose alanine aminotransferase levels remained within the normal range during the six months after therapy, was significantly higher (P<0.01) in the type-III patients (4/5, 80.0%) than in type-II patients (4/43, 9.3%). For these long-term complete responders, the amounts of HCV RNA was less than 10⁷ copies/ml serum in type-II patients, whereas two type-III patients with relatively high amounts of HCV RNA responded completely. These results confirm that the genotype of HCV is an important factor for predicting the response to interferon therapy. The amounts of HCV RNA can also predict its efficacy in type-II patients.This work was supported by a Grant-in-Aid from the Ministry of Education, Science and Culture, Japan, and the Research Group of Intractable Hepatitis sponsored by the Ministry of Health and Welfare of Japan.     

Factors useful in predicting the response to interferon therapy in chronic hepatitis C

To determine how various factors influence the response to interferon (IFN) therapy, we retrospectively studied 157 consecutive Japanese patients with chronic hepatitis C who received various treatment schedules of IFN. They were divided into two groups on the bases of outcome. One group was comprised of 65 patients who achieved a sustained normalization of serum alanine aminotransferase (ALT) levels for at least 6 months after treatment, while the other group was comprised of 84 patients with persistent elevation of serum ALT levels, despite treatment. Genotyping of hepatitis C virus (HCV) was done by polymerase chain reaction (PCR) with genotype specific primers, analysing the variations in nucleotide sequence within the NS 5 region of the HCV genome, namely genotypes PT, K1, K2a and K2b. We then used a multivariate analysis to determine the factors related to mode of treatment, patient characteristics and HCV genotype in relation to the response to IFN therapy. Of the 16 factors analysed, the HCV genotype (genotype K2a or K2b, P < 0.0008), treatment schedule (intermittent administration following a daily schedule, designated as combined schedule, P > 0.0014) and liver histology just before treatment (chronic persistent hepatitis or mild chronic aggressive hepatitis, P < 0.0324) were the most strongly correlated with a normalizing response to IFN therapy. These results suggest that not only are the IFN treatment schedule and patient profile significant, but the properties of the virus also influences the response. However, as the IFN treatment schedule is the only changeable factor, it should be designed to maximize the benefit of IFN therapy.     

Clearance of serum hepatitis C virus RNA after interferon therapy in relation to virus genotype

Abstract: The effect of recombinant interferon-alfa on serum HCV RNA levels in Japanese patients with chronic hepatitis C was investigated. At 24 weeks of treatment, 41 (32.5%) of 126 patients lost HCV RNA from serum, and aminotransferases were normalized in 31 (75.6%) of these 41 cases. HCV genotypes were categorized into four types (Type I, II, III, IV); the frequencies among the patients were: Type I: 0%, Type II: 70.6%, Type III: 20.6%, and Type IV: 6.3%. At the end of the 24-week treatment, HCV RNA levels were remarkably decreased in Type III patients and became undetectable in 18 (69.2%) of 26. In contrast, only 18 (20.2%) of 89 patients with Type II and two of eight with Type IV lost HCV RNA from sera. The relation between HCV genotype (Type III) and response to IFN therapy was also confirmed using a logistic regression model. HCV genotype seems to be an important factor in determining the response to IFN in patients with chronic hepatitis C.     

Relationship between serum HCV markers and response to interferon therapy in chronic hepatitis C

Hepatitis C virus is the most frequent cause of chronic non-A, non-B hepatitis, and the antibodies to structural and nonstructural proteins encoded by viral genome have been suggested to be markers of ongoing HCV infection. We studied the behavior of these antibodies during interferon therapy in 18 patients with chronic hepatitis C and also during a follow-up period of at least four years. A significant decrease of anti-HCV titer was found only in patients who had shown positive response to therapy and all of them were anti-HCV negative at the end of follow-up. Analysis by recombinant immunoblotting assay showed that only anti-c100 were affected by interferon therapy, whereas anti-c22 and anti-c33 were not modified. Using polymerase chain reaction to detect small amounts of HCV genome in serum, we could confirm that the behavior of HCV-RNA during and after interferon therapy is similar to that of anti-HCV and the loss of anti-c100 seems to be closely related to HCV-RNA disappearance from serum. Our patients with chronic hepatitis C were found to be of type 1b and 2, according to the recent score of Simmonds, and the clearance of serum HCV-RNA during treatment and its sustained negative status are closely related to genotype 2 and to long-term positive response to interferon.     

Integrity of the NS5A (amino acid 2209 to 2248) region in hepatitis C virus 1b patients non‐responsive to interferon therapy

Abstract: Background/Aims: In hepatitis C virus‐1b, it has been suggested that an amino acid stretch (aa 2209–2248) of the carboxy terminal half of the non‐structural 5A (NS5A) region participates in the response to interferon treatment. We tested the hypothesis that absence of mutations in the NS5A (aa 2209–2248) sequence is required for interferon resistance. We also investigated the importance of different HCV‐1b isolates in interferon response in France. Methods: We determined the NS5A sequences of 70 patients with chronic hepatitis C before IFN therapy and then compared them with HCV‐J prototype sequence. The isolates were determined by NS5B sequencing, the “gold standard” method for genotyping and subtyping. Pre‐therapeutic viral load was also measured. Results: No sustained virological response was observed in the patients without amino acid substitutions in the NS5A (aa 2209–2248) sequence, and in the patients with HCV‐J isolates. Viral load was significantly higher in the patients with no amino acid substitutions in the NS5A (aa 2209–2248) sequence. Conclusions: In HCV‐1b infected patients, an HCV‐J strain with no amino acid substitution in the NS5A (aa 2209–2248) region indicates a poor prognosis for response to IFN therapy. The low interferon response rate in HCV‐1b infection in Europe is probably not due to a difference between isolates.     

Viral and host factors in the prediction of response to interferon-α therapy in chronic hepatitis C after long-term follow-up

Acute infection with hepatitis C virus (HCV) develops into a chronic hepatitis in about 50–70% of patients. Treatment of these patients with interferon-α (IFN-α) results in a sustained long-term response in only 15–20% but causes numerous unwanted side-effects in a higher percentage of patients. The aim of our study was to define host or viral parameters that would allow identification of responders and non-responders to IFN-α prior to the onset of treatment. We studied a group of 87 patients suffering from chronic hepatitis C who were treated with IFN-α. After long-term follow-up, 18 patients (21%) showed a sustained response to IFN-α therapy (normalization of serum transaminases and loss of viral RNA from serum) for up to 7 years after therapy had ceased. By univariate and multivariate analyses, no host factors were found to be predictive of response to therapy. Neither the degree of inflammation or fibrosis in liver biopsy samples obtained before treatment nor immunogenetic factors (major histocompatibility complex II haplotype and tumour necrosis factor-α promoter polymorphism) were associated with response to therapy. In contrast, viral parameters showed a strong association with response to therapy. HCV genotype 3 was found significantly more frequently in responders (P = 0.034), and mean HCV RNA concentration was lower in responders (3.1 × 10⁴) than in non-responders (2.5 × 10⁵) (P = 0.01). By multivariate analysis, both HCV genotype and HCV RNA concentration were independent predictors of response to therapy. However, exact prediction of response to treatment for an individual patient was not possible on the basis of pretreatment viral RNA concentration or viral genotype. The best association with response to therapy was found to be clearance of HCV RNA from serum 3 months after the start of treatment (32 of 34 partial and sustained responders vs 0 of 53 non-responders; P = 0.001). In conclusion, determination of pretreatment viral factors, but not host factors, was significantly correlated with treatment response but did not give an accurate prediction for patients, whereas clearance of HCV RNA from serum after 3 months of therapy was predictive of response to therapy.     

Efficacy of consensus interferon in the treatment of chronic hepatitis C

BACKGROUND AND AIMS: Consensus interferon (CIFN) is a newly developed type I interferon. The aim of this study was to investigate the safety and efficacy of CIFN in the treatment of patients with chronic hepatitis C and to determine the predictors for sustained response. METHODS: Patients were randomized to receive 3 micrograms or 9 micrograms CIFN three times a week for 24 weeks, followed by 24 weeks of observation. Efficacy was assessed by normalization of serum transaminase levels and disappearance of serum hepatitis C virus (HCV)-RNA at the end of treatment and at 24 weeks after stopping treatment. Histologic response was defined as a decrease of at least two points in the Knodell necroinflammatory score at week 48 and was compared with baseline. RESULTS: There were no serious adverse effects related to CIFN therapy. Overall, 44% of patients receiving 3 micrograms and 48% of patients receiving 9 micrograms had normalization of serum transaminase levels and disappearance of HCV viremia at the end of treatment. At 24 weeks after stopping treatment, 16% of patients in receiving 9 micrograms and 12% of patients receiving 3 micrograms had sustained responses. The histologic responses in patients receiving 9 micrograms and those receiving 3 micrograms were 60% and 36%, respectively. The necroinflammatory score was significantly reduced from baseline to week 48 in both groups. In addition, bodyweight < 60 kg and pretreatment serum HCV-RNA level < 0.5 MEq/mL can serve as predictors for sustained response to CIFN treatment. CONCLUSIONS: These findings suggest that 9 micrograms CIFN is safe and effective in the treatment of patients with chronic hepatitis C.     

Biochemical response to interferon therapy correlates with interferon sensitivity-determining region in hepatitis C virus genotype 1b infection

Biochemical responders maintain normal alanine aminotransferase levels after interferon (IFN) therapy despite persistent presence of hepatitis C virus (HCV) RNA in their sera. There have been few reports on predictive factors for biochemical response. A region associated with sensitivity to IFN was identified in the nonstructural protein 5 A of genotype 1b [aa 2209–2248; IFN sensitivity-determining region (ISDR)]. The substitutions in ISDR correlate with sustained response to IFN. In this report, we assessed the association of ISDR with biochemical response. The sequences of ISDR were determined in 62 patients with HCV genotype 1b treated by IFN in two randomized controlled trials. 30 patients had wild ISDR (identical to HCV-J), 20 intermediate ISDR (1–3 amino acid substitutions compared with HCV-J), and 12 mutant ISDR (four or more amino acid substitutions). All 12 patients with mutant ISDR had a sustained response, while only one of those with wild or intermediate ISDR had a sustained response ( P  < 0.0001). In the 49 patients other than sustained responders, the patients with intermediate ISDR obtained biochemical response significantly more frequently (52.6%, 10/19) than those with wild-type ISDR (20.0%, 6/30) ( P  < 0.05). Multivariate analysis indicated the number of substitutions in ISDR as the most important predictor for biochemical response (discriminant coefficient=1.08, P  < 0.05) and sustained response (discriminant coefficient=6.13, P  < 0.0001). In phylogenetic analysis, clustering of sustained responders and biochemical responders was observed. These results demonstrate that the substitutions in ISDR are the most important predictor for biochemical response to IFN in patients infected with genotype 1b as well as for sustained response.     

Clinical significance of SEN-virus on interferon response in chronic hepatitis C patients

BACKGROUND AND AIM: A novel virus, SEN-virus (SENV), was recently discovered. It has been reported as a candidate for a non-A-E hepatitis virus. However, much is still unknown about the clinical significance of SENV. The aim of the present study was to clarify the clinical significance of SENV in patients coinfected with SENV and hepatitis C virus (HCV). METHODS: The 52 subjects had chronic hepatitis C and had undergone interferon (IFN) therapy. SEN virus DNA was investigated by using polymerase chain reaction with SENV-specific primers, which we designed to detect all strains of SENV. Additionally, SENV-D and -H were detected by consensus primers. RESULTS: Thirty-five patients were SENV-DNA positive and 22 patients were SENV-D- or -H-positive before IFN therapy. After IFN therapy, in the HCV-RNA eradication group, all cases normalized their serum alanine aminotransferase (ALT). However, in the no eradication group, the ALT no-response rate was 68.7%. In contrast, in the SENV eradication group, the ALT no-response rate was 51.9%, and in the no eradication group, it was 37.5%. Also, in the SENV-D and -H eradication group, the ALT no-response rate was 54.5%, and in the no eradication group, it was 36.4%. The changes in ALT after IFN therapy were significantly correlated with the changes in HCV RNA, but no correlation was found with the SENV DNA presence. CONCLUSIONS: Hepatocellular injury in patients with chronic hepatitis who are coinfected with HCV and SENV appears to primarily be caused by HCV, and is less attributable to SENV.     

Development of small hepatocellular carcinoma in a patient with chronic hepatitis C after 77 months of a sustained and complete response to interferon therapy

We report a case of hepatocellular carcinoma (HCC) that developed 77 months following sustained and complete response to interferon (IFN) therapy for chronic hepatitis C. A 67-year-old Japanese woman presented with a small mass in the liver that was diagnosed as HCC, 77 months after having completed IFN therapy and having shown a complete response to the therapy with sustained normalization of serum aminotransferases and eradication of serum hepatitis C virus (HCV). Hepatitis C virus RNA was also not detected in the resected tumorous and non-tumorous liver tissues by polymerase chain reaction. This suggests that all patients with chronic HCV infection should be followed closely for as long as possible for the potential development of HCC, even after a complete and sustained response to IFN treatment.     

De novo hepatitis B virus infection in hepatocellular carcinoma following eradication of hepatitis C virus by interferon therapy

Epidemiological studies have revealed that hepatocellular carcinoma (HCC) is still observed in hepatitis C virus (HCV)‐positive patients with a sustained response to interferon (IFN) treatment, although a substantial decrease in the incidence of hepatocellular carcinoma (HCC) has been achieved in those patients. Why HCC develops in patients who have a complete clearance of HCV remains unclear. Here, we provided evidence of latent hepatitis B virus (HBV) infection in an initially HCV‐positive chronic hepatitis patient who developed HCC after the complete eradication of HCV by IFN therapy. Although he was initially negative for anti‐hepatitis B surface antigen (HBsAg) or circulating HBV DNA but positive for anti‐hepatitis B core antigen (anti‐HBc) in his sera, he developed HBsAg and HBV DNA during the course of the management of a series of cancers. HBV DNA was detectable in the liver tissues before HBV reactivation and the viral sequences derived from his anti‐HBc‐positive liver showed 100% homology to that from the serum after HBsAg appearance. These findings indicates that HCV‐positive individuals who are positive for anti‐HBc in the absence of HBsAg could have latent HBV infection in their liver tissues and intrahepatic HBV infection may play a pivotal role in the development of HCC after the IFN‐mediated eradication of HCV.     

Zinc supplementation enhances the response to interferon therapy in patients with chronic hepatitis C

We evaluated the synergistic effect of zinc supplementation on the response to interferon (IFN) therapy in patients with intractable chronic hepatitis C in a pilot study using natural IFN-α with or without zinc. No clinical differences were observed between patients treated with IFN alone ( n =40) and IFN with polaprezinc (IFN + Zn, n =35). All patients were positive for HCV genotype Ib and had more than 10⁵ copies of the virus/mL serum. Ten million units of natural IFN-α was administered daily for 4 weeks followed by the same dose every other day for 20 weeks. In the IFN + Zn group, patients received an additional dose of 150 mg/day polaprezinc orally throughout the 24-week IFN course. No additional side-effects of polaprezinc were noted but four out of 40 IFN alone treatment and three out of 35 IFN + Zn group withdrew because of side-effects. Complete response (CR) was defined as negative HCV RNA in the serum on PCR and normal aminotransferase level 6 months after therapy. Incomplete response (IR) was normal liver enzyme and positive serum HCV RNA. Both of them were evaluated at the 6 months after the completion of the treatment. Patients with higher levels of serum HCV (more than 5 × 10⁵ copies/mL) had little response in both treatment groups. Patients with moderate amount of HCV (10⁵ to 4.99 × 10⁵/mL) showed high response rates in combination group (CR: 11/27, 40.7%; CR + IR 15/27, 64.3%), better than IFN alone (CR: 2/15, 18.2%; CR + IR: 2/15, 18.2%). Serum zinc levels were higher in patients with IFN + Zn group than in the IFN group. Our results indicate that zinc supplementation enhances the response to interferon therapy in patients with intractable chronic hepatitis C.