Interferon responsiveness in patients infected with hepatitis C virus 1b differs depending on viral subtype

BACKGROUND: Genotype 1b of hepatitis C virus (HCV) comprises mainly three subtypes, each named for its geographic prevalence (worldwide, W; Japan, J; and not in Japan, NJ). AIM: To characterise the newly identified subtypes of genotype 1b and to review factors associated with response to interferon (IFN) for each subtype. PATIENTS: Chronic hepatitis patients (80 men and 41 women; mean age 48.5 years, range 20.7--69.3) with HCV genotype 1b (W type, n=41; J type, n=38) or genotype 2a (n=42) were treated according to the same IFN protocol. Forty four patients (36.4%) negative for serum HCV RNA six months after cessation of treatment were considered complete responders. METHODS: Factors associated with complete response were investigated. RESULTS: Genotype 2a patients had lower viral loads (odds ratio 0.11 (95% confidence intervals (CI) 0.049--0.256)) and a better IFN response (odds ratio 0.25 (95% CI 0.117--0.552)) than genotype 1b patients whereas W type and J type patients had similar viral loads and responses to IFN. IFN response in W type patients was associated with female sex (odds ratio 0.23 (95% CI 0.055--0.983)) and low viral load (odds ratio 84.00 (95% CI 14.04--502.6)) whereas response in J type patients was related to transfusion history (odds ratio 7.20 (95% CI 1.443--35.91)), low viral load (odds ratio 117.0 (95% CI 17.82--768.3)), and genetic mutation in the interferon sensitivity determining region of the virus (odds ratio 0.08 (95% CI 0.013--0.553)). Multivariate analysis found low viral load (odds ratio 64.19 (95% CI 14.66--281.06)) to be the only significant independent factor associated with IFN response. CONCLUSIONS: Factors associated with IFN responsiveness in HCV infection differ with viral subtype.     

Hepatitis C virus subtype 3b infection in a hospital in Japan: Epidemiological study

To elucidate the epidemiology of infection with hepatitis C virus (HCV) subtype 3b (a rare subtype thought to have originated in Southeast Asia) in Japan, we examined the genotypic subtype in 1397 patients with HCV-related chronic liver diseases. Of 1330 patients with identified HCV RNA genotypes, 960 had subtype 1b, 243 had subtype 2a, 97 had subtype 2b, 14 (1.1%) had subtype 3b, and 16 had other types of HCV or mixed subtypes. The age, gender, and severity of liver disease in patients with HCV subtype 3b did not differ from these features in patients with other subtypes. Eleven of the 14 patients with the 3b subtype had once worked at Company A in Tokyo, Japan. Multivariate logistic analysis showed that working history at that company was independently associated with the incidence of the subtype; the risk ratio was 207.2 (P<0.0001). All 11 patients from Company A had received medical services, between 1953 and 1981, at Clinic C, which undertook medical care of the company staff. All 11 patients had received repeated intramuscular or intravenous injections for treatment of various diseases or for preventive vaccination for contagious diseases. The rare HCV subtype 3b, appeared to have been transmitted among the employees of a company through the performance of certain medical practices.     

Molecular epidemiologic analysis of hepatitis C virus infection in injecting drug users with acute hepatitis C in Japan

BACKGROUND AND AIM: The aim of this study was to examine whether particular hepatitis C virus (HCV) subtypes are spreading among injecting drug users (IDUs) in Yamaguchi prefecture, on the south-western tip of the island of Honshu in Japan, as found in European countries. METHODS: We prospectively enrolled acute hepatitis C patients from January 2001 to March 2003. E2 gene sequences of HCV isolates from IDUs with acute hepatitis C were phylogenetically compared to those from 30 chronic hepatitis C patients with the same HCV subtypes who had or did not have a history of intravenous drug use. RESULTS: Nine of 11 patients (82%) with acute hepatitis C were IDUs. The HCV subtypes were 2a in four and 2b in five, which contrasted with the high prevalence of subtype 1b in patients with chronic liver diseases in Japan. IDUs with acute hepatitis C (22.0 +/- 2.4 years old) were significantly younger than those with chronic hepatitis C (49.5 +/- 9.5 years old) for subtype 2a (P = 0.0005), but not for subtype 2b (25.6 +/- 5.4 vs 28.1 +/- 2.4 years old). Some HCV isolates of subtype 2b from IDUs with acute hepatitis C were phylogenetically related to those from IDUs with chronic hepatitis C. By contrast, there was no phylogenetic segregation of HCV in IDUs with subtype 2a. HCV isolates from non-IDUs were genetically divergent from each other and those from IDUs, irrespective of the HCV subtype. CONCLUSION: Hepatitis C virus of the non-1b subtype, particularly subtype 2b, seemed to be transmitted between IDUs very recently in Yamaguchi prefecture, Japan.     

Relationship between hepatocellular carcinoma and subtypes of hepatitis C virus: A nationwide analysis

Although hepatitis C virus (HCV) has now been classified into several subtypes, the clinical significance of HCV subtypes is not well known. Typing of HCV is now routinely performed in Japan. In the present study, HCV subtypes in hepatocellular carcinoma (HCC) patients were analysed from nationwide data collected in Japan using a standard questionnaire. Answers to the questionnaire concerning HCV subtypes in patients with chronic hepatitis (CH), liver cirrhosis (LC) and HCC were obtained from 14 hospitals. The prevalence of the 1b-related subtype, which includes the mixed subtype of 1b and 2a or 2b, in patients with LC and HCC in each hospital was higher than in patients with CH, with few exceptions. However, the differences were not statistically significant because of the small number of patients in each hospital. In summarized data from all 14 hospitals, the 1b-related subtype was found in 1370 of 1922 patients with CH (71.2%). In 356 LC and 426 HCC patients, the prevalence of the 1b-related subtype was 79.8 and 80.5%, respectively. The prevalence of the 1b-related subtype in patients with LC and HCC was significantly higher than in patients with CH. There was no significant difference between the prevalence of the 1b-related subtype in patients with HCC and LC. These results indicate that the oncogenic activity of subtype 1b, although not yet clearly characterized, may be stronger than subtypes 2a and 2b.     

Effects of combination therapy with interferon and ofloxacin on chronic type C hepatitis: A pilot study

Interferon is effective in only a limited number of patients with the 1b type of hepatitis C virus (HCV), indicating that a combination therapy with other antiviral drugs may be essential to obtain better results. In the present pilot study, the effects of a combination therapy with interferon (IFN) and an antibacterial drug, ofloxacin, were analysed. Ten patients with chronic type C hepatitis received the combination therapy (combination group). Six million units of natural IFN-α were administered daily for 3 weeks and then three times a week for 21 weeks. The combination therapy was initiated at the beginning of the eighth week of IFN treatment and 600 mg ofloxacin per day was administered for 12 weeks. As a control, changes in HCV-RNA were also analysed in patients who were treated with only IFN for the same period (IFN-alone group). In the combination group, serum transaminase levels and the titres of HCV decreased significantly with ofloxacin administration. Such changes were not observed in the IFN-alone group. The incidence of HCV-negativity at the end of ofloxacin administration of the combination group was significantly higher than in the IFN-alone group. The complete response rate was twice as high in the combination group as in the IFN-alone group. In two patients who did not respond well to the IFN-alone treatment, ofloxacin administration was commenced after the 24th week. Serum transaminase levels were normalized and HCV-RNA became negative in these two patients after the administration of ofloxacin. These results suggest that combination therapy with IFN and ofloxacin may be an effective treatment for chronic type C hepatitis.     

Interferon‐α/β for treatment of chronic hepatitis C infection in the era of direct‐acting antiviral agents

Type I interferons (IFN‐α/β), with or without ribavirin, have been the only agents that can eradicate the hepatitis C virus (HCV). An IFN‐free regimen combining oral direct‐acting antiviral agents (DAA) will be approved soon for genotype 1 patients. Here, we discuss the role of IFN‐α/β in the forthcoming “era of DAA” with consideration of limitations and concerns about IFN‐free therapies. First, the therapeutic efficacy of first‐generation DAA varies among the different subtypes. While the rate of sustained virological response (SVR) is 60–90% among patients with genotype 1b, the rate often falls short of 50% in patients with genotype 1a. IFN and ribavirin can still be indicated for patients with genotype 1a as a platform for combination with DAA. Second, there is concern about the emergence of drug‐resistance resulting from inappropriate use of DAA. The clinical significance of pre‐existing resistant variants has not been elucidated. Drug resistance may affect the efficacy of next‐generation treatments. An IFN and ribavirin backbone in combination with DAA is an effective measure to prevent the emergence of drug resistance and/or to suppress pre‐existing resistant viruses. Third, it remains unknown whether the incidence of hepatocellular carcinoma (HCC) will be reduced in patients who achieve SVR with IFN‐free regimens. In contrast, there are many reports in Japan demonstrating the preventive effects of IFN on the development of HCC. When patients do not achieve SVR with first‐generation DAA, low‐dose IFN maintenance therapy is a treatment option until the next‐generation therapy with pan‐genotypic potency and high genetic barrier become available.     

Differences in background characteristics of patients with chronic hepatitis C who achieved sustained virologic response with interferon‐free versus interferon‐based therapy and the risk of developing hepatocellular carcinoma after eradication of hepatitis C virus in Japan

We compared the background characteristics of patients with chronic hepatitis C who achieved eradication of hepatitis C virus (HCV), that is sustained virologic response (SVR), with interferon (IFN)‐based versus IFN‐free antiviral therapy in Japan. In addition, we used a previously reported risk assessment model to compare the incidence of hepatocellular carcinoma (HCC) after SVR by treatment type. Pretreatment characteristics of 1533 patients who achieved SVR with IFN‐based therapy and 1086 patients with IFN‐free therapy from five institutions across Japan were compared. The risk of HCC after SVR was assessed based on pretreatment characteristics, and the incidence of HCC after SVR was estimated in both groups. Age and serum alpha‐fetoprotein levels were higher, platelet count was lower, and liver fibrosis was more advanced in patients who achieved SVR with IFN‐free therapy compared with IFN‐based therapy. The incidence of HCC after SVR in the IFN‐free group was estimated to be more than twofold higher than in the IFN‐based therapy group (7.29% vs. 3.09%, and 6.23% vs. 3.01% when excluding patients who have underwent curative treatment for HCC). There are large differences in pretreatment characteristics between patients who achieved SVR with IFN‐based and IFN‐free therapies in Japan, which are associated with differential risk of HCC after SVR. These differences can influence the incidence of HCC after SVR and should be taken into consideration when comparing IFN‐based and IFN‐free therapies in terms of hepatocarcinogenesis suppression with HCV eradication.     

Triple therapy of initial high-dose interferon with ribavirin and amantadine for patients with chronic hepatitis C

Aims: We previously reported the potential effect of combination therapy of an initial high‐dose interferon (IFN) and amantadine on the eradication of HCV‐RNA in patients with chronic hepatitis C. The additive effects of amantadine on interferon and ribavirin combination therapy remain controversial. In this study we investigated the efficacy of initial high‐dose IFN with ribavirin and amantadine on the virological response in patients with chronic hepatitis C with a high viral load of genotype 1b. Methods: Twenty‐two patients with high viral loads of genotype 1b hepatitis C virus were enrolled in this pilot study. Patients were administered IFN‐beta for four weeks and then IFN‐alpha2b for 22 weeks with daily oral administration of ribavirin and amantadine. Results: A sustained virological response (SVR) was shown in 31.8% (seven of 22 patients). With the naïve patients, the SVR rate was 21.4% (three of 14 patients). In patients who could not eradicate HCV‐RNA by previous IFN monotherapy, the SVR rate was 50% (four of eight patients). Conclusion: Triple therapy with an initial high dose of IFN with ribavirin and amantadine may be effective, especially for chronic hepatitis C IFN‐retreatment patients with a high viral load of genotype 1b.     

Association between HCV amino acid substitutions and outcome of peginterferon and ribavirin combination therapy in HCV genotype 1b and high viral load

Background and Aim: We prospectively compared the sensitivity to interferon (IFN) and the efficacy of antiviral combination therapy with peginterferon (PEG‐IFN) and ribavirin for chronic hepatitis C virus (HCV) genotype 1b infection according to the amino acid sequences of the HCV core, E1, and NS5A regions reported to be associated with the outcome of antiviral therapy. Methods: A total of 107 patients with HCV genotype 1b were investigated. All patients received combination therapy with PEG‐IFN alpha‐2b and ribavirin. Amino acids 70 and 91 (core), 139 (E1), and 2209–2248 (NS5A) of HCV were analyzed by direct nucleotide sequencing. Results: The reduction in HCV RNA concentration at 24 h after a single administration of conventional IFN‐alpha and after the start of combination therapy was significantly less marked, and rates of complete early virologic response, end‐of‐treatment response, and sustained virologic response (SVR) were significantly lower (all P < 0.0001) in patients with glutamine at amino acid 70 (n = 29) than in those with arginine at that position (n = 70). We found no differences associated with the other amino acid positions. Amino acid 70 was an independent factor for the responses to the therapy in multivariate analysis. Conclusion: The identity of amino acid 70 of the HCV core region affected the sensitivity to IFN; patients with glutamine at amino acid 70 of HCV showed resistance to IFN. Consequently, it strongly affected the outcome of combination therapy with PEG‐IFN and ribavirin in Japanese patients with HCV genotype 1b.     

High incidence of type 1 diabetes mellitus during or shortly after treatment with pegylated interferon α for chronic hepatitis C virus infection

Background: Development of diabetes mellitus (DM) during or shortly after treatment with interferon α (IFN‐α) in patients with chronic hepatitis C virus (HCV) infection has been reported sporadically. We prospectively screened for DM during and after IFN‐α therapy for chronic HCV infection. Methods: Blood glucose levels of patients with chronic HCV infection were routinely assessed at all outpatient visits during and after treatment with pegylated‐IFN‐α (Peg‐IFN‐α) and ribavirin (Riba). Results: Between December 2002 and October 2005, 189 non‐diabetic patients were treated with Peg‐IFN‐α/Riba, of whom five developed type 1 DM (2.6%), three type 2 DM (1.6%) and one an indeterminate type of DM. Classical symptoms of DM were present in three patients who developed DM shortly after cessation of Peg‐IFN‐α/Riba. In the other patients, symptoms of DM were either indistinguishable from side effects caused by Peg‐IFN‐α/Riba or absent. Conclusion: Our study showed a high incidence of type 1 DM during Peg‐IFN‐α/Riba therapy for chronic HCV infection. Symptoms of DM may be absent or mistaken for Peg‐IFN‐α/Riba‐associated side effects. To diagnose DM without delay, we propose routine assessment of blood glucose at all outpatient visits during and after Peg‐IFN‐α/Riba treatment in chronic HCV patients.     

Evaluation of twice-daily administration of interferon-beta for chronic hepatitis C

To improve the efficacy of interferon (IFN) in the treatment of chronic hepatitis C, administration of IFN-beta twice per day was evaluated. Thirty-eight patients with chronic hepatitis C (26 males and 12 females, aged 25-67 years) were included. Patients were treated with a new protocol that included twice-daily treatment with IFN-beta. Three million units (MU) of IFN-beta was administered twice daily every day for 4 weeks followed by 10 MU of IFN-alpha2b, every day for 2 weeks and then three times a week for 18 weeks (total IFN-beta, 148 MU; IFN-alpha2b, 680 MU). Complete responders (CR) were defined by alanine aminotransferase levels that normalized within 6 months after completion of IFN therapy and remained normal for more than 6 months, and by serum hepatitis C virus (HCV) RNA levels that became negative as determined using the Amplicor assay. Twenty-one of 38 (55.3%) patients were CR. Nine of 21 (42.9%) patients with HCV serotype 1 were responders compared with nine of 12 (75.0%) patients with HCV serotype 2. In patients with an HCV titre greater than 1 million equivalents ml-1 (1 MEq ml-1), nine of 24 (37.5%) responded, and in patients with HCV titres less than 1 MEq ml-1, 12 of 14 (85.7%) responded. In patients with HCV serotype 1 and greater than 1 MEq ml-1 HCV RNA, four of 15 (26.7%) responded to IFN. Two-thirds (66.7%) of the patients who became negative for HCV RNA after 2 weeks of therapy responded, while 72.7% of those with positive HCV RNA after 2 weeks of therapy were non-responders. Proteinuria was frequently observed as an adverse effect of twice-daily administration of IFN-beta. The combination of twice-daily administration of IFN-beta for 4 weeks followed by IFN-alpha showed a high response rate in patients with chronic hepatitis C, but in patients with both serotype 1 and a high titre of HCV RNA, response rates were still low. Thus, the HCV RNA titre 2 weeks after starting therapy with IFN was useful for predicting the eventual response to IFN.     

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.     

Fluctuation patterns of HCV-RNA serum level in patients with chronic hepatitis C

The serum level of hepatitis C virus (HCV)-RNA is clinically important as a predictor of the response to interferon (IFN) therapy in patients with chronic hepatitis C. If serum HCV-RNA levels fluctuate during follow-up, and IFN therapy is begun at the time of a low HCV-RNA level, the IFN therapy may be more effective. We evaluated the fluctuation of HCV-RNA serum levels for 2 years in 212 patients with chronic hepatitis C, untreated with IFN who had HCV genotype 1b and an HCV-RNA level of 10 Meq/ml or more at first consultation. The HCV-RNA level was measured monthly for 2 years with an HCV branched DNA probe assay (b DNA probe assay). We classified HCV-RNA patterns into three types by the ratio of maximum HCV-RNA level (a) to minimum HCV-RNA level (b). In pattern 1 (constant type, 151 patients; 71.2%) the a/b ratio was 1–5. In pattern 2 (slight fluctuation type, 46 patients; 21.7%) the a/b ratio was 5–10. In pattern 3 (severe fluctuation type, 15 patients; 7.1%), the a/b ratio was 10 or more. Next, we evaluated the factors associated with the three patterns. Acute exacerbation of chronic hepatitis was regarded as an increase in serum alanine aminotransferase (ALT) level to more than 250 IU/l. The incidence of acute exacerbation for a 2-year follow-up was 13.9% (21/151) in pattern 1, 19.6% (9/46) in pattern 2, and 53.3% (8/15) in pattern 3. Multivariate analysis showed that acute exacerbation was the most important factor in the manifestation pattern 3. In conclusion, we found that: (1) about 70% of patients had a constant HCV-RNA levels for 2 years. (2) A few patients had severe fluctuation of serum HCV-RNA level after acute exacerbation of chronic hepatitis. Received: July 23, 1999 / Accepted: September 24, 1999     

Efficacy of interferon-alpha treatment in Japanese children with chronic hepatitis C

BACKGROUND: We investigated the efficacy of natural interferon (IFN)-alpha treatment in 34 Japanese children with chronic hepatitis C. METHODS: Thirty-four children completed 6 months of therapy with natural IFN-alpha and were followed for 12 months or longer. We examined the serum hepatitis C virus (HCV) RNA titer and liver histology before, during, and after IFN treatment. RESULTS: At 6 months after the cessation of IFN-alpha treatment, 16 patients (47%) had normal serum alanine aminotransferase concentration and no detectable serum HCV RNA. There were no major side-effects, excluding some influenza-like symptoms during the IFN-alpha treatment. Most genotype 2a patients had a complete response (80%). Moreover, patients who had a low HCV RNA titer (<102 copies/mL) after 1 month of IFN-alpha treatment became complete responders at 6 months after the cessation of treatment. Histological improvement was observed in almost all patients after IFN-alpha treatment. CONCLUSION: Interferon-alpha treatment is safe and effective for children with chronic hepatitis C and has no serious side-effects. A HCV RNA concentration of <102 copies/mL after 1 month of IFN-alpha treatment and genotype 2a may be useful predictors of long-term IFN efficacy.     

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.     

Hepatitis C virus infection and genotypes in Japanese hemophiliacs

Abstract: Liver function and antibodies to hepatitis C virus and to human immunodeficiency virus-1 were examined in 195 Japanese patients with hemophilia. One hundred and seventy-three were positive for antibody to HCV and 61 for antibody to human immunodeficiency virus-1. In 63 patients, we examined HCV genotypes according to the double polymerase chain reaction method. Forty cases (63%) were infected with hepatitis C virus with a single genotype, including type 1a in five, type 1b in 21, type 2a in seven and type 2b in seven; 16 (25%) were infected with double genotypes, including types 1a+1b in 14, types 1b+2a in one and types 1b+2b in one; and four (6%) were infected with triple genotypes, including types 1a+1b+2a in two and types 1a+1b+2b in two. Genotype could not be determined in three patients by this method. In the 191 non-hemophiliac patients with chronic hepatitis C, HCV genotyping was as follows: type 1a in 0, type 1b in 121, type 2a in 40 and type 2b in 10 of 171 cases (89.5%) with single infection and types 1b+2a in five and types 2a+2b in one of six (5.5%) with double infection. In the remaining 14 patients, genotype could not be determined. Frequent transfusion of domestic and/or imported coagulation factor concentrates probably caused the high incidence of HCV infection with rare or mixed genotypes in Japanese hemophiliacs.     

Clinical features of patients with chronic liver disease associated with hepatitis C virus genotype 1a/I in Okinawa, Japan

The clinical characteristics of chronic hepatitis C virus (HCV) carriers with HCV genotype 1a/I infection were investigated and compared with those of chronic HCV carriers infected with 1b/II, 2a/III, 2b/IV and the mixed type of infection. We found that 16 of 408 (3.9%) carriers had HCV genotype 1a infection, comprising four of 67 (6.0%) blood donors, 11 of 263 (4.2%) patients with chronic hepatitis and one of 39 (2.6%) patients with liver cirrhosis. Three of 408 subjects had a mixed infection of genotypes 1a/I and 1b/II. All carriers with genotype 1a (including those with the mixed infection) were of Japanese origin and all, except one who was born in Brazil, were born in Okinawa Prefecture. Nine of 14 patients infected with genotype 1a for whom medical records were obtained had a history suggestive of infection through blood exposure; six had had blood transfusions, one had tattoos, one is a nurse and one had a history of drug addiction. There were no haemophiliacs or other multitransfused patients in the genotype 1a group. Of 10 patients infected with genotype 1a who received interferon (IFN) therapy, four (40%) showed a complete response. Although the small number of patients infected with genotype 1a in the present study precluded statistical analysis of the response to IFN, the response in patients with genotype 1a was better than the response in those infected with genotype 1b and poorer than the response in those patients infected with genotype 2a/III or 2b/IV.     

Clinical efficacy of intramuscular human interferon-βvs interferon-α2b for the treatment of chronic hepatitis C

Summary. We have conducted a randomized study to compare the efficacy and tolerance of human interferon (IFN) β vs recombinant IFN-α2b in patients with chronic active hepatitis C. Forty patients were included: 21 received IFN-α (group A) and 19 IFN-β (group B). IFN was administered intramuscularly at a dose of 6 MU three times a week (tiw) for 2 months (induction phase), followed by 3 MU tiw for 4 months. Clinical, epidemiological and pathological features were similar in the two groups. Normal alanine aminotransferase (ALT) values at the end of treatment was regarded as a response to therapy and the response rate was 57% (12/21) in group A and 5.2% (1/19) in group B ( P < 0.01). Both types of IFN induced a significant decrease in mean ALT values by the end of the induction phase ( P < 0.01). When the dose was reduced to 3 MU, a marked, but not significant increase in ALT, was seen in group B, whereas no increase was seen in group A. IFN-β was better tolerated and haematological adverse effects (platelet and leucocyte decrease) were less pronounced with IFN-β. Hence, human IFN-β was less effective than IFN-α in treating chronic hepatitis C virus (HCV). Doses of IFN-β of 3 MU intramuscular (IM) tiw were clearly insufficient and it remains to be established whether higher doses of intramuscularly IFN-β can be useful.     

Durability of Sustained Virologic Response in Chronic Hepatitis C

Background/Aims

The aim of this study is to investigate the rate of sustained virologic response (SVR) in chronic hepatitis C patients receiving antiviral treatment.

Methods

The files of patients with chronic hepatitis C treated with interferon±ribavirin between 1995 and 2009 were reviewed retrospectively. Six months after the end of treatment, patients with negative hepatitis C virus (HCV)-RNA (<50 IU/mL, as determined by the polymerase chain reaction method) were enrolled in the study.

Results

The mean age of 196 patients (89 males) was 46.13±11.10 years (range, 17 to 73 years). In biopsies, the mean stage was 1.50±0.94; histological activity index was 7.18±2.43. In total, 139 patients received pegylated interferon (IFN)+ribavirin, 21 patients received classical IFN+ribavirin, and 36 patients received IFN alone. The HCV genotypes of 138 patients were checked: 77.5% were genotype 1b, and 22.5% were other genotypes. After achievement of SVR, the median follow-up period was 33.5 months (range, 6 to 112 months), and in this period relapse was only detected in two patients (1.02%) at 18 and 48 months after treatment.

Conclusions

In total, 98.9% of patients with SVR in chronic hepatitis C demonstrated truly durable responses over the long-term follow-up period of 3 years; relapsed patients had intermittent or low-grade viremia.     

Splenectomy and antiviral treatment for thrombocytopenic patients with chronic hepatitis C virus infection

Summary. Thrombocytopenic patients with chronic hepatitis C virus (HCV) infection are poor candidates for antiviral treatment with interferon (IFN), but no standard treatment for thrombocytopenia has yet been established. We evaluated the safety of splenectomy and its efficacy for the initiation and continuation of antiviral therapy. From March 2003 to April 2006, 10 patients (mean age 62.5 years) with HCV‐related cirrhosis, low platelet count (≦106 000/mm³) and splenomegaly (spleen size ≧10 cm) underwent splenectomy. Platelet counts significantly increased at 4–8 weeks after splenectomy [pre: 64 200 ± 6900/mm³vs post 209 000 ± 40 600/mm³ (P = 0.004)]. No severe operative complications were observed. All patients subsequently received antiviral therapy. Of the eight patients who were infected with HCV genotype 1 and had a high viral load (≧100 KIU/mL), four received combination therapy with pegylated IFNα‐2b plus ribavirin, and the other four received standard IFNα‐2b plus ribavirin. One patient infected with HCV genotype 2 and another with HCV genotype 1 and a low viral load (<100 KIU/mL) were treated with pegylated IFNα‐2a. Six patients achieved sustained virologic response (SVR). Among four patients who failed to achieve SVR, one was given retreatment with pegylated IFN plus ribavirin, and the other three received low‐dose long‐term IFN therapy. Although this study was small, the treatment results were similar to those for patients without thrombocytopenia and suggested that splenectomy would not reduce the antiviral efficacy of IFNα‐based treatment.