Accumulation of refractory factors for pegylated interferon plus ribavirin therapy in older female patients with chronic hepatitis C

Aim: Several host and viral factors have been reported to influence the effectiveness of pegylated interferon plus ribavirin combination therapy for chronic hepatitis C. In Japan, where the age of treated patients is comparatively high, recent studies have reported poor response to treatment in older female patients, but little is known about the relationship between advanced age in women and previously reported factors. Methods: Using a database of 1167 patients chronically infected with hepatitis C virus (HCV) genotype 1b, we analyzed the amino acid sequences of the HCV core protein and interferon sensitivity determining region (ISDR) and examined the relationships among predictive factors. Results: The proportion of patients with substitutions at core 70, which is associated with poor response to pegylated interferon plus ribavirin therapy, increased with age only in female patients. A similar trend was observed for ISDR wild type (wt). We also found that core 70 wt is associated with core 91 wt (P = 5.4 × 10^?9) as well as ISDR wt (P = 0.025). HCV RNA levels were higher in patients with core and ISDR wt (P < 0.001). Furthermore, core amino acid mutations were associated with advanced fibrosis and higher inflammatory activity (P = 0.028 and 0.048, respectively) as well as higher gamma‐glutamyltranspeptidase, alanine aminotransferase and low‐density lipoprotein cholesterol levels (P < 0.001, 0.006 and 0.001, respectively). Conclusion: A combination of factors account for poor response rate in older female patients in Japan. Elucidating the relationship between amino acid substitutions and metabolic alteration is an important step in understanding the mechanism of HCV interferon resistance.     

Mutations in the core and NS5A region of hepatitis C virus genotype 1b and correlation with response to pegylated‐interferon‐alpha 2b and ribavirin combination therapy

Summary. Mutations in two regions of hepatitis C virus (HCV) have been implicated in influencing response to interferon (IFN) therapy. Substitutions in the NS5A region of HCV have been associated with response to IFN therapy, and this region has been known as the IFN sensitivity‐determining region (ISDR). The mutations in the core region of HCV have also been reported to predict IFN response. The aim of this study was to investigate whether amino acid substitutions in the core region and ISDR among patients with HCV genotype 1b affect the response to IFN therapy. A total of 213 patients who completed IFN treatment were randomly selected. All patients received pegylated‐IFN‐alpha 2b once each week, plus oral ribavirin daily for 48 weeks. Of the 213 patients, 117 (54.9%) showed early virologic response (EVR), with HCV‐negativity, at 12 weeks. Factors related to EVR on multivariate analysis were non‐Gln70 and Leu91 in the core region, and ISDR mutant‐type. One hundred and two (47.9%) showed a sustained virologic response (SVR). SVR occurred more frequently in patients without Gln70 (55.4%) than in those with Gln70 (21.3%) (P < 0.0001). SVR was achieved in 43.6% of patients with wild‐type ISDR and 62.5% of patients with mutant‐type (P = 0.0227). Of the 34 patients who simultaneously had non‐Gln70 and mutant‐type ISDR, 26 (76.5%) achieved SVR. Factors related to SVR on multivariate analysis were non‐Gln70 and ISDR mutant‐type. In conclusion, amino acid substitutions in the core region and ISDR were useful for predicting the response to IFN in patients with HCV genotype 1b.     

Effect of treatment with interferon α-2b and ribavirin in patients infected with genotype 2 hepatitis C virus

Aim:  Nearly 20% of chronic hepatitis C (CHC) patients with genotype 2 hepatitis C virus (HCV) infection are not curable, even by interferon (IFN)–ribavirin combination therapy. The aim of this study is to investigate the factors that determine the efficacy of combination therapy in patients with genotype 2 HCV infection.
Methods:  Fifty patients with CHC who underwent a treatment of 6 MU IFN α-2b with ribavirin for 24 weeks were retrospectively analyzed.
Results:  All the patients showed no serum HCV-RNA within 12 weeks after starting the therapy. Forty-one of the 50 patients (82%) achieved a sustained virological response (SVR). The age, sex, genotype (2a vs. 2b) and grade/stage of the liver by histopathology and pretreatment viral load werenot different between the sustained responders and relapsers. Univariate analysis showed that an earlier viral clearance from blood and a larger number of amino acid substitutions in the interferon sensitivity determining region (ISDR) were predictors of SVR. Multivariate analysis showed that a large number of amino acid substitutions in the ISDR was a predictor of SVR.
Conclusion:  The characterization of the amino acid sequences of ISDR may be helpful for predicting a relapse after combination therapy in patients with genotype 2 HCV infection.     

Does sequencing the PKRBD of hepatitis C virus NS5A predict therapeutic response to combination therapy in an Australian population?

Abstract Background and Aim: The presence of four or more amino acid substitutions within the interferon sensitivity determining region (ISDR) of the hepatitis C virus (HCV) genotype 1b NS5A gene determines sensitivity to interferon (IFN) monotherapy in Japanese patients. Resistance of HCV genotype 1 to IFN-alpha has been attributed to the functional inhibition of a RNA dependent protein kinase (PKR) by the HCV NS5A PKR binding domain (PKRBD), which includes the ISDR. The ability of the ISDR and PKRBD sequence to predict a response to IFN-alpha and ribavirin combination therapy was investigated in an Australian population. Methods: The sequence of the PKRBD of NS5A, including the ISDR, for the dominant quasi-species of HCV was determined in 37 genotype 1 (genotype 1a: n = 26, genotype 1b: n = 11) and 13 genotype 3a infected patients. Results: The number of PKRBD amino acid substitutions in HCV genotype 1 infected patients with a sustained virological response was significantly higher than that in patients with a non-response to treatment (P = 0.047). It was found that only 2/37 HCV genotype 1 infected patients had four or more amino acid substitutions relative to the prototype ISDR sequence (HCV-J). Importantly, a sustained virological response was not found in any of the HCV infected patients who had a prototype ISDR genotype 1 sequence (n = 5). Conclusions: There are relatively few amino acid mutations within the ISDR of this Western Australian patient population. Patients infected with a HCV genotype 1 prototype sequence should be counseled before receiving combination IFN-alpha and ribavirin therapy as they have a poor response to treatment.     

Changes in sequences of core region,interferon sensitivity-determining region and interferon and ribavirin resistance-determining region of hepatitis C virus genotype 1 during interferon-alpha and ribavirin therapy,and efficacy of retreatment

Aim: Some regions associated with sensitivity to interferon-α and ribavirin have been identified in the hepatitis C virus (HCV) genome, including amino acid 70 in the core region (core a.a. 70), a.a. 2209–2248 (interferon sensitivity-determining region, ISDR) and a.a. 2334–2379 (interferon and ribavirin resistance-determining region, IRRDR). Methods: We examined changes in the sequences of these regions in 25 patients with chronic HCV genotype 1 infection who had not had sustained virological response (SVR) to interferon-α and ribavirin for 24–48 weeks and subsequently received retreatment for 48–72 weeks. Results: At baseline, the core a.a. 70 was mutant (resistant) type in seven patients. At the start of retreatment, the core a.a. 70 had changed from sensitive to resistant type in 2 patients, and SVR was not achieved by retreatment. The ISDR variations were resistant type (0–1 mutations) in 17 patients at baseline. After 2 weeks of treatment, amino acid change was found in two patients; in one, the substitutions returned to baseline status after treatment, and in the other, the substitution persisted. At the start of retreatment, ISDR sequences had changed from resistant to sensitive type in two patients and SVR was achieved and from sensitive to resistant type in three patients and SVR was not achieved. The IRRDR variations were resistant type (<6 mutations) in 19 patients at baseline and at the start of retreatment. Conclusion: Sequences of the core region and ISDR sometimes change during anti-HCV therapy, potentially affecting the outcomes of retreatment.     

Role of hepatitis C virus substitutions and interleukin‐28B polymorphism on response to peginterferon plus ribavirin in a prospective study of response‐guided therapy

Recent studies have indicated that amino acid (aa) substitutions in the core region and NS5A interferon sensitivity‐determining region (ISDR) of hepatitis C virus (HCV) as well as genetic polymorphisms in the interleukin‐28B (IL‐28B) locus affect the outcome of interferon (IFN)‐based therapies. We aimed to investigate the role of these factors on response to peginterferon plus ribavirin in a prospective study of response‐guided therapy. The aa sequences in core region and ISDR and rs12979860 genotypes were analysed in 115 HCV‐1 patients. The treatment was 24 weeks for patients achieving a rapid virological response (RVR), 48 weeks for those with an early virological response (EVR) and early terminated in those without an EVR. A sustained virological response (SVR) was achieved in 82% of 34 RVR patients, 45% of 74 EVR patients and 0% of seven non‐EVR patients. Logistic regression analysis showed that ISDR mutation (≥2) [odds ratio(OR): 6.024], double core 70/91 mutations (OR: 0.136), and platelet counts ≥ 15 × 10⁴/μL (OR: 3.119) were independent pretreatment factors associated with SVR. Apart from rs12979860 CC genotype, low viral load and ISDR mutation (≥2) were significant factors predictive of RVR. Combination of rs12979860 genotype and baseline viral characteristics (viral load and core/ISDR mutations) could predict RVR and SVR with positive predictive value of 100% and 91%, and negative predictive value of 80% and 54%, respectively. In conclusion, pretreatment screening rs12979860 genotype and aa substitutions in the core region and ISDR could help identifying patients who are good candidates for peginterferon plus ribavirin therapy.     

丙型肝炎病毒载量与基因型和抗病毒疗效的关系研究

目的探讨丙型肝炎患者血清HCV RNA载量与基因型的关系及其对抗病毒治疗疗效的影响。方法113例慢性丙型肝炎患者接受聚乙二醇干扰素联合利巴韦林抗病毒治疗。采用实时荧光定量PCR法检测血清HCV RNA载量,应用CE1区测序遗传树比对分析法检测HCV基因型。结果 113例患者分别感染1b、2a、3a、3b和6a共5种基因亚型,其HCV RNA载量（lgcopies/ml）分别为6.6973±1.19245、6.0824±1.68603、6.8393±1.03400、6.5533±1.29577和7.1503±1.16115,经单因素方差分析无明显统计学差异（P=0.166）;治疗前高血清HCV RNA载量者（≥107copies/ml）与低HCV RNA载量者（〈107copies/ml）完成治疗后获得SVR的比例,无论在所有患者（76.4%对75.9%,P=0.950）,还是在HCV1型（66.7%对60.0%,P=0.641）或非1型感染者（82.4%对87.9%,P=0.526）中均无统计学差异。结论治疗前血清HCV RNA载量与HCV基因型无关,血清HCV RNA载量对聚乙二醇干扰素联合利巴韦林抗病毒的疗效无明显影响。     

Effect of treatment with interferon alpha-2b and ribavirin in patients infected with genotype 2 hepatitis C virus.

Aim: Nearly 20% of chronic hepatitis C (CHC) patients with genotype 2 hepatitis C virus (HCV) infection are not curable, even by interferon (IFN)-ribavirin combination therapy. The aim of this study is to investigate the factors that determine the efficacy of combination therapy in patients with genotype 2 HCV infection. Methods: Fifty patients with CHC who underwent a treatment of 6 MU IFN alpha-2b with ribavirin for 24 weeks were retrospectively analyzed. Results: All the patients showed no serum HCV-RNA within 12 weeks after starting the therapy. Forty-one of the 50 patients (82%) achieved a sustained virological response (SVR). The age, sex, genotype (2a vs. 2b) and grade/stage of the liver by histopathology and pretreatment viral load werenot different between the sustained responders and relapsers. Univariate analysis showed that an earlier viral clearance from blood and a larger number of amino acid substitutions in the interferon sensitivity determining region (ISDR) were predictors of SVR. Multivariate analysis showed that a large number of amino acid substitutions in the ISDR was a predictor of SVR. Conclusion: The characterization of the amino acid sequences of ISDR may be helpful for predicting a relapse after combination therapy in patients with genotype 2 HCV infection.     

Effect of ribavirin in genotype 1 patients with hepatitis C responding to pegylated interferon alfa-2a plus ribavirin

BACKGROUND & AIMS: Pegylated interferon alfa-ribavirin combination is the standard treatment for chronic hepatitis C, but the mechanisms by which ribavirin enhances the rate of sustained hepatitis C virus (HCV) eradication remain unknown. We aimed to investigate the role of ribavirin in HCV clearance during therapy and to evaluate the consequences of ribavirin discontinuation in patients infected with genotype 1 hepatitis C who cleared HCV RNA at week 24. METHODS: A total of 516 patients were treated with pegylated interferon alfa-2a, 180 microg/wk, plus ribavirin, 800 mg/day. Seventy percent were RNA negative at week 24. They were randomized to continue with the combination or receive pegylated interferon alone. RESULTS: Responders at week 24 who stopped ribavirin had a significantly higher rate of breakthroughs during, and relapses after, therapy (sustained virologic response, 52.8% vs 68.2%; P = .004), but their side-effect profile and quality of life tended to improve. Multiple logistic regression analysis in the pegylated interferon alfa monotherapy group allowed identification of responders at week 24 who could stop ribavirin without losing their chance of a sustained virologic response, based on baseline viral load and age. Forty-eight weeks of ribavirin may not be needed when HCV RNA is undetectable at week 2. CONCLUSIONS: We made 3 conclusions from this study. First, ribavirin primarily acts by sustaining the virologic response to pegylated interferon alfa; second, ribavirin must be administered for the full treatment duration in most genotype 1-infected patients who respond; third, baseline parameters may help identify patients who could discontinue ribavirin or reduce the dose without losing their chance of success.     

Mutations in ISDR of NS5A gene influence interferon efficacy in Chinese patients with chronic hepatitis C virus genotype 1b infection

BACKGROUND AND AIM: The interferon sensitivity determining region (ISDR) in the non-structural 5A protein (NS5A) gene of hepatitis C virus genotype 1b (HCV-1b) has been demonstrated in Japanese patients; however, contradictory data have been reported from other parts of the world, particularly from Europe and the USA. This study investigated whether mutations in the ISDR of NS5A gene influence interferon efficacy in Chinese patients with chronic HCV-1b infection. METHODS: Forty-five Chinese patients with chronic HCV infection were enrolled in a retrospective study. Of these patients, 20 with HCV-1b infection completed an interferon monotherapy course and 6-month follow-up. The pretreatment mutations in the nucleic acid sequence of NS5A 2209-2248 (ISDR) of HCV-1b were identified by sequencing RT-PCR products followed by comparison with the prototype sequence (HCV-J). Correlation with the clinical efficacy of interferon alpha therapy was then analyzed retrospectively. RESULTS: The statistical analysis indicated a significant correlation between the mutations in ISDR of HCV-1b and sustained virological response to interferon alpha treatment (P < 0.05), and an association of the mutations in ISDR with the pretreatment serum alanine aminotransferase levels (P < 0.01) in Chinese patients with chronic HCV-1b infection. CONCLUSIONS: The results support the concept that the response of HCV-1b infected patients towards interferon therapy is influenced by the mutations within the ISDR of NS5A gene.     

Predictive factors for interferon and ribavirin combination therapy in patients with chronic hepatitis C

AIM： To confirm the predictive factors for interferon （IFN）-α and ribavirin combination therapy for chronic hepatitis patients with hepatitis C virus （HCV） genotype lb. METHODS： HCV RNA from 50 patients infected with HCV genotype lb was studied by cloning and sequencing of interferon sensitivity determining region （ISDR）, PKR- eIF2α phosphorylation homology domain （PePHD）. Patients were treated with IFN-α and ribavirin for 6 mo and grouped by effectiveness of the therapy. A variety of factors were analyzed. RESULTS： Our data showed that age, HCV RNA titer, and ISDR type could be used as the predictive factors for combined IFN-α and ribavirin efficacy. Characteristically, mutations in PePHD appeared only when the combination therapy was effective. Other factors, such as sex and alanine aminotransferase （ALT） level, were not related to its efficacy. Adjusting for age and HCV RNA titer indicated that the ISDR type was the most potent predictive factor. CONCLUSION： HCV RNA ISDR type is an important factor for predicting efficacy of IFN-α and ribavirin combination therapy in Korean patients.     

An open-label randomized controlled study of pegylated interferon/ribavirin combination therapy for chronic hepatitis C with versus without fluvastatin

Summary. Pegylated interferon (PEG‐IFN)/ribavirin combination therapy is the standard‐of‐care (SOC) treatment for chronic hepatitis C patients infected with hepatitis C virus (HCV) genotype 1b and high viral load. The addition of fluvastatin to SOC treatment has been suggested to be effective for better outcome in retrospective pilot analyses. We investigated whether the combination of fluvastatin with PEG‐IFN/ribavirin could actually improve sustained viral response (SVR) in patients with HCV genotype 1b and high viral load. A randomized, open‐labeled, controlled study was conducted between July 2008 and December 2009 in 101 chronic hepatitis C patients allocated to PEG‐IFN/ribavirin combination therapy with or without fluvastatin. SVR rates were calculated in groups, stratifying host and viral factors. We also analyzed predictive factors for SVR among patients on fluvastatin with multivariate regression analysis. Rapid and early virological, and end of treatment response rates in the fluvastatin group were not significantly different from those in the non‐fluvastatin group. Notwithstanding, SVR rate was significantly higher in the fluvastatin group than in the non‐fluvastatin group (63.0%vs 41.7%, P = 0.0422). Comparison of the two groups stratifying demographic data and HCV characteristics showed significantly higher SVR rates to more than 80% in males, more than two mutations in the interferon sensitivity determining region (ISDR), and a history of relapse among the fluvastatin group than the non‐fluvastatin group. Being male and major genotype IL28B single nucleotide polymorphisms (SNPs) were independent predictive factors for SVR among patients on fluvastatin with multivariate analysis. Fluvastatin‐combined with PEG‐IFN/ribavirin therapy significantly improves SVR rates in patients with HCV genotype 1b and high viral load. Male and major genotype IL28B SNPs were independent predictors for SVR among patients on fluvastatin combination therapy.     

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.     

Selection of HCV NS5A quasispecies during IFN therapy in patients with chronic HCV

Interferon treatment of chronic hepatitis C virus infection is successful in a minority of patients. The sequence of the interferon sensitivity determining region (ISDR) of the NS5A protein may determine the outcome of therapy in patients infected with HCV genotype 1. To determine whether IFN treatment caused selection of ISDR quasispecies and whether sequences bearing the putative IFN-resistance motif (HCV-J sequence) were selected, we examined amino acid changes in the ISDR in patients with HCV of different genotypes with and without therapy. We found that the ISDR sequence was highly variable and variability was greatest in patients with HCV of genotype 1. IFN treatment was found to exert a selection pressure on ISDR quasispecies, but the putative interferon-resistant variant was not enriched in patients of any genotype. Hence factors other than the sequence of the ISDR region played a role in the IFN resistance of these patients.     

Early virologic response after peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin treatment in patients with chronic hepatitis C

Patients infected with hepatitis C virus (HCV) genotype 1 and with serum HCV RNA concentrations over 800 000 IU/mL have relatively low rates of virologic response to pegylated interferons. The 2 forms of pegylated interferon have different pharmacokinetic profiles, and pilot studies comparing them have yielded varying results. We compared the virologic response to 12 weeks of treatment with peginterferon alpha-2a plus ribavirin vs peginterferon alpha-2b plus ribavirin in 380 patients who were infected with HCV genotype 1 and had high viral loads. We observed no between-group differences in viral load reduction over time and no differences in the percentage of patients treated with peginterferon alpha-2a or peginterferon alpha-2b plus ribavirin who achieved early virologic response (EVR), defined as >/=2-log reduction in HCV RNA concentration or undetectable HCV RNA at 12 weeks (66%vs 63%). Serum levels of interferon were more frequently below the level of quantitation in patients treated with peginterferon alpha-2b plus ribavirin (58-68%) than in those treated with peginterferon alpha-2a plus ribavirin (1-2%). Patients treated with peginterferon alpha-2b plus ribavirin had higher rates of discontinuation for safety reasons (6%vs 1%). In conclusion, a substantial percentage of patients infected with HCV genotype 1 and high viral load can achieve EVR when treated with peginterferon and ribavirin. The 2 pegylated interferons showed comparable anti-HCV activity during the first 12 weeks of treatment when combined with the same doses of ribavirin (1000-1200 mg/day), but discontinuations for safety reasons were higher in the patients treated with peginterferon alpha-2b plus ribavirin.     

Hepatitis C: viral and host factors associated with non‐response to pegylated interferon plus ribavirin

Treatment for chronic hepatitis C virus (HCV) infection has evolved considerably in the last years. The standard of care (SOC) for HCV infection consists in the combination of pegylated interferon (PEG‐IFN) plus ribavirin. However, it only induces a sustained virological response (SVR) in half of genotype 1‐infected patients. Several viral and host factors have been associated with non‐response: steatosis, obesity, insulin resistance, age, male sex, ethnicity and genotypes. Many studies have demonstrated that in non‐responders, some interferon‐stimulated genes were upregulated before treatment. Those findings associated to clinical, biochemical and histological data may help detect responders before starting any treatment. This is a very important issue because the standard treatment is physically and economically demanding. The future of HCV treatment would probably consist in the addition of specifically targeted antiviral therapy for HCV such as protease and/or polymerase inhibitors to the SOC. In genotype 1 patients, very promising results have been reported when the protease inhibitor telaprevir or boceprevir is added to the SOC. It increases the SVR rates from approximately 50% (PEG‐IFN plus ribavirin) to 70% (for patients treated with a combination of PEG‐IFN plus ribavirin plus telaprevir). Different elements are associated with non‐response: (i) viral factors, (ii) host factors and (iii) molecular mechanisms induced by HCV proteins to inhibit the IFN signalling pathway. The goal of this review is to present the mechanisms of non‐response, to overcome it and to identify factors that can help to predict the response to anti‐HCV therapy.     

Chronic hepatitis C responds poorly to combination therapy in chronic hepatis B carriers

BACKGROUND: The effect of conventional interferon-based therapy of hepatitis B virus (HBV) and hepatitis C virus (HCV) dual infection is controversial. Yet, no studies have been carried out into pegylated interferon treatment for chronic HBV/HCV coinfection. We aimed to evaluate the response rate and side effects of conventional or pegylated interferon combined with ribavirin on chronic HBV/HCV coinfection therapy. METHODS: The study included 36 chronic hepatitis patients (M/F: 28/8, mean age 47+/-12 years) who were positive for HBsAg and anti-HCV. They were tested for the presence of HBV-DNA by hybridisation assay, and the samples giving negative results were retested by polymerase chain reaction (PCR). All patients were tested for HCV-RNA using PCR, and the HCV genotype was determined. RESULTS: Nineteen patients were given standard interferon either alone or in combination with ribavirin, whereas 17 were given pegylated interferon and ribavirin combination therapy. None of the patients had HBV-DNA positivity; however, all had HCV-RNA detectable by PCR. All the patients had HCV genotype 1b. The mean alanine aminotransferase and aspartate aminotransferase levels were 118+/-65 U/l and 90+/-95 U/l respectively. Five patients in each group discontinued the treatment due to side effects. Only two patients (one from each group) reached sustained virological response. CONCLUSION: Neither pegylated nor conventional interferon based regimes were effective for HBV/HCV coinfection, in which the dominant virus was HCV. Pegylated interferon and ribavirin therapy was not superior to conventional interferon based regimes in the treatment of HBV/HCV coinfection.     

In vivo interferon system assessed by 2′‐5′ oligoadenylate synthetase activity in chronic hepatitis C virus patients treated with pegylated interferon and ribavirin

Aim: 2′,5′ oligoadenylate synthetase (2‐5AS), an enzyme induced by interferon, is an accurate indicator of the antiviral effect of interferon. We measured it during pegylated interferon based therapies in patients with chronic hepatitis C virus (HCV) in order to determine the dynamics of antiviral status in vivo and the relationship between the response to exogenous interferon and the outcome of therapy. Methods: A total of 160 patients with chronic HCV were treated with pegylated interferon alfa 2a or 2b or non‐pegylated interferon, with or without ribavirin. Serum 2‐5AS activity was measured by radioimmunoassay assay kits every 2 weeks. Results: In 60 patients treated with pegylated interferon alfa 2a or 2b, 2‐5AS levels increased to 7–40 times (average 235 pmol/dL) above the pretreatment levels (30 pmol/dL), which were significantly higher than the levels during non‐pegylated interferon therapy. Ribavirin did not enhance 2‐5AS levels. 2‐5AS levels between sustained virological response (SVR) and non‐SVR, including null responders to pegylated interferon plus ribavirin therapy were not significantly different. Conclusion: 2‐5AS levels were significantly higher in patients treated with pegylated interferon than in those treated with non‐pegylated interferon, suggesting that pegylated interferon is more potent at inducing interferon response genes resulting in an improved antiviral effect. Ribavirin did not appear to be related to interferon response gene induction.