BRIEF COMMUNICATION: Efficacy of ribavirin plus interferon α on viraemia of GB virus-C/hepatitis G virus: Comparison with interferon α alone

We investigated the efficacy of ribavirin plus interferon (IFN) α on GB virus-C (GBV-C)/hepatitis G virus (HGV) viraemia and compared it with that of interferon α alone in patients coinfected with hepatitis C virus (HCV) and GBV-C/HGV. Serum HCV and GBV-C/HGV-RNA were studied in eight patients with HCV and GBV-C/HGV coinfection, five received IFNα and three received oral ribavirin plus IFNα. Mean serum GBV-C/HGV titre at the end of therapy was significantly lower than the titre just before therapy and patients with lower pretreatment titre had a better sustained response rate. Sustained virological response of GBV-C/HGV to IFNα alone and ribavirin plus IFNα at the end of follow up was observed in one each, respectively. Thus, GBV-C/HGV in patients with HCV and GBV-C/HGV coinfection does respond to IFNα and ribavirin plus IFNα may not induce a higher sustained response.     

Interferon and ribavirin therapy does not select for resistance mutations in hepatitis C virus polymerase

Summary.  Ribavirin has a minor and transient effect on hepatitis C virus (HCV) replication and has been suggested to select a novel mutation, F415Y, in the RNA-dependent RNA polymerase of subtype 1a viruses. Twenty-nine patients with chronic hepatitis C (subtyped by INNO LiPA as 1a, 17; 1b, 11; 1a/1b, 1) who were nonresponders to interferon-based therapies were identified retrospectively and screened at Baseline, week 24 of treatment, and 24 weeks post-treatment. Selection of resistance mutations, including at amino acid position 415 of the polymerase, was investigated. Using clonal sequencing and pyrosequencing of the NS5B gene, we screened for the F415Y resistance mutation among patients who received combination therapy with ribavirin and interferon α. Of the 15 subtype 1a patients treated with interferon plus ribavirin, only one had the F415Y change at week 24, and an F/Y mixture was still present 24 weeks after therapy. Four additional patients in this group had the F415Y change 24 weeks post-therapy. The NS5B genes were sequenced in order to identify amino acid changes associated with ribavirin therapy, but no evidence was found that ribavirin selects for particular amino acids in the RNA-dependent RNA polymerase. Ribavirin, a weak inhibitor of HCV replication, does not select for resistance mutations in the sequence of the HCV RNA polymerase.     

Interferon plus ribavirin in patients with hepatitis C virus positive mixed cryoglobulinemia resistant to interferon

OBJECTIVE: Only a small fraction of patients with hepatitis C virus (HCV) positive mixed cryoglobulinemia achieve longterm recovery after interferon (IFN) therapy; we evaluated the effectiveness and safety of combination therapy (interferon plus ribavirin) in nonresponders or those who relapsed after one or more courses of IFN. METHODS: Twenty-seven patients with HCV positive mixed cryoglobulinemia were studied. All were treated with IFN-a2b (3 MU 3 times weekly) for one year, plus daily oral ribavirin 1000 or 1200 mg. RESULTS: Five patients (18.5%) obtained complete recovery from viral infection and from all signs and symptoms of disease. During treatment, most patients (85%) improved clinically. All 5 responders were "relapsers" to the first treatment(s). CONCLUSION: Combination therapy of IFN plus ribavirin could be useful for patients with mixed cryoglobulinemia resistant to IFN as monotherapy.     

Customizing treatment to patient populations

Combination treatment with pegylated interferon plus ribavirin is the most effective therapy for patients with chronic hepatitis C virus (HCV); however, responses are less than optimal in some subpopulations of patients. Emerging insights are suggesting that viral kinetics can be used to predict response. The rapidity of response has been shown to be a more important predictor of sustained virologic response than the duration of therapy. In patients with HCV genotype 2 or 3, shorter durations of treatment might be sufficient in rapid responders and could minimize the risk of toxic effects. Weight-based dosing of ribavirin has emerged as another important consideration. This strategy seems to be most important for difficult-to-treat patients with HCV genotype 1 or advanced fibrosis, and for African-Americans, and is possibly important for patients who have genotype 3 and a high viral load. Re-treatment of nonresponders with interferon-based therapy has been associated with low rates of sustained virologic response. Consensus interferon might offer a new option for patients who do not achieve an early treatment response to standard or pegylated interferon plus ribavirin.     

Impairment of metabolic function in chronic hepatitis C is related to factors associated with resistance to therapy

OBJECTIVE: Liver disease causes a loss of hepatic function, and remission is associated with improved functional hepatic mass. The object of the present study was to investigate whether liver metabolic function assessed by antipyrine clearance is related to other disease characteristics influencing response to therapy in chronic hepatitis C. METHODS: Patients (n = 96) received three different treatment regimens: one group received interferon alfa-2b for 48 wk; in a second group with maintained positive hepatitis C virus (HCV) RNA after 12 wk, interferon was combined for 36 wk with oral ribavirin; and patients who were relapsers or nonresponders to a previous therapy with interferon alone received interferon alfa-2b plus ribavirin for 48 wk. RESULTS: Twenty-five patients (26%) showed sustained normalization of ALT levels and negative HCV RNA 6 months after therapy. The response was more likely to be sustained in patients with a genotype other than 1 (52.0% vs 15.5% in patients with genotype 1, p < 0.001), and the percentage of sustained responders was higher among patients who demonstrated negativity of HCV RNA at the end of 4 wk of treatment (64% vs 13% without negativity, p < 0.001). Sustained response was associated with significantly lower baseline serum ferritin (-46%, p < 0.01) and duration of infection (-33%, p < 0.01). Baseline antipyrine clearance was higher in sustained responders than in nonresponders (+19%, p < 0.05) and lower in genotype 1 patients than in those with a genotype other than 1 (-24%, p < 0.05). Antipyrine clearance increased by 12% at the end of the 48-wk course of treatment among sustained responders (+34% vs nonresponders, p < 0.001) and still remained elevated at the end of the follow-up (+35% vs nonresponders, p < 0.001). CONCLUSION: In summary, the present study shows that liver oxidative metabolism is related to antiviral response rates and suggests that much of the effect is explained by viral genotype.     

Early ribavirin pharmacokinetics, HCV RNA and alanine aminotransferase kinetics in HIV/HCV co-infected patients during treatment with pegylated interferon and ribavirin

BACKGROUND/AIMS: We evaluated whether early ribavirin pharmacokinetics differ comparing hepatitis C/human immunodeficiency virus coinfected sustained virological responders and nonresponders. METHODS: Twenty-four treatment-naive coinfected patients received pegylated-interferon alfa-2b (12 kDa) (1.5 microg/kg) once weekly plus daily ribavirin (13.6 mg/kg/d) for up to 48 weeks. Serum HCV RNA, serum alanine aminotransferase, and plasma ribavirin levels were measured frequently during the first 16 days of therapy and monthly thereafter. RESULTS: Six patients were sustained responders. During the first 4 weeks of treatment, median plasma ribavirin levels and area under the ribavirin curve were significantly lower (p<0.0001 and p<0.01, respectively) in sustained responders compared with nonresponders. Compared to ribavirin levels at weeks 2 and 4, ribavirin levels in sustained responders continued to increase significantly until week 8 (p<0.02). At week 4, hemoglobin declines were significantly (p=0.002) greater in sustained responders than nonresponders. At week 1, serum HCV RNA levels and changes in alanine aminotransferase levels relative to baseline could identify likely responders better than plasma ribavirin levels. CONCLUSIONS: We conjecture that intracellular ribavirin accumulation may be enhanced early in treatment in coinfected sustained responders, although this hypothesis should be investigated further. At week 1, serum HCV RNA and changes in alanine aminotransferase levels relative to baseline might identify likely responders.     

Genetic and biochemical diversity in the HCV NS5B RNA polymerase in the context of interferon α plus ribavirin therapy

Summary. The hepatitis C virus (HCV) RNA polymerase (RdRp) may be a target of the drug ribavirin, and it is an object of drug development. Independent isolates of any HCV subtype differ genetically by approximately 10%, but the effects of this variation on enzymatic activity and drug sensitivity are poorly understood. We proposed that nucleotide use profiles (G/U ratio) among subtype 1b RdRps may reflect their use of ribavirin. Here, we characterized how subtype 1b genetic variation affects RNA polymerase activity and evaluated the G/U ratio as a surrogate for ribavirin use during pegylated interferon α and ribavirin therapy. Genetic and biochemical variation in the RdRp was compared between responders who would be largely sensitive to ribavirin and relapsers who would be mostly resistant. There were no consistent genetic differences between responder and relapser RdRps. RNA polymerization, RNA binding and primer usage varied widely among the RdRps, but these parameters did not differ significantly between the response groups. The G/U ratio among a set of subtype 1a RdRps increased rather than decreased following failed therapy, as would be expected if it reflected ribavirin use. Finally, RdRp activity was significantly associated with ALT levels. These data indicate that (i) current genetic approaches cannot predict RNA polymerase behaviour, (ii) the G/U ratio is not a surrogate for ribavirin use, (iii) RdRp activity may contribute to liver disease by modulating viral mRNA and antigen levels, and (iv) drug candidates should be tested against multiple patient‐derived enzymes to ensure widespread efficacy even within a viral subtype.     

Peginterferon alpha-2a (40 KD) plus ribavirin for the treatment of chronic hepatitis C in Japanese patients

Background: The efficacy and safety of peginterferon alpha‐2a (40 KD) (peg‐IFNα‐2a) plus ribavirin has not been reported for Japanese patients with chronic hepatitis C. The aim of this study was to evaluate this combination in treatment‐naïve patients and in non‐responders or relapsers to interferon monotherapy. Methods: Overall, 201 treatment‐naïve patients with hepatitis C virus (HCV) genotype‐1b were randomly assigned to 180 µg peg‐IFNα‐2a once‐weekly plus ribavirin 600–1000 mg/day or peg‐IFNα‐2a plus placebo for 48 weeks. Additionally, peg‐IFNα‐2a plus ribavirin was administered for 48 weeks to 100 non‐responders or relapsers (85% genotype‐1) to previous interferon monotherapy. Results: A sustained virological response (SVR) was attained among significantly more treatment‐naïve patients receiving combination therapy than monotherapy (61% vs 26%, P < 0.001). For patients with high baseline HCV RNA, the SVR rate was 59% with peg‐IFNα‐2a plus ribavirin versus 24% with peg‐IFNα‐2a monotherapy. Among non‐responders or relapsers to previous interferon monotherapy, 54% attained an SVR. Adverse events were generally mild, and discontinuations rates due to adverse events or laboratory abnormalities were low. Conclusion: In Japanese patients, peg‐IFNα‐2a plus ribavirin provided significant improvement in SVR rates compared with peg‐IFNα‐2a alone in treatment‐naïve patients, and was effective as re‐treatment for non‐responders or relapsers to previous treatment with interferon monotherapy.     

Triple antiviral therapy in HCV positive patients who failed prior combination therapy

INTRODUCTIONWhile advances in the treatment of HCV chronic hepatitis have markedly improved outcomes for treatment-na?ve patients, a large number of patients still fail to eradicate HCV infection[1-4], and improving the re-treatment success rates of these…     

Association of host pharmacodynamic effects with virologic response to pegylated interferon alfa-2a/ribavirin in chronic hepatitis C

Patients receiving therapy for chronic hepatitis C virus (HCV) infection frequently experience cytopenias and weight loss. We retrospectively assessed the pharmacodynamic effects of pegylated interferon (PEG-IFN) alfa-2a and ribavirin by evaluating the relationship between changes in hematologic parameters, body weight, and virologic response. Patients with HCV genotypes 1, 4, 5, or 6 receiving 24 or 48 weeks of PEG-IFN alfa-2a and ribavirin therapy were pooled from four phase 3/4 trials. Maximum decreases in hemoglobin level, neutrophil count, platelet count, and weight during therapy were assessed according to virologic response category (sustained virologic response [SVR], relapse, breakthrough, and nonresponder) and race/ethnicity. Of 1,778 patients analyzed, more than half were male, non-Hispanic Caucasian, and infected with HCV genotype 1; had a baseline HCV RNA >800,000; and had alanine aminotransferase levels ≤3 × the upper limit of normal. Virologic responders (SVR, relapse, and breakthrough) experienced greater maximum decreases from baseline in hemoglobin level, neutrophil count, platelet count, and weight compared with nonresponders; however, no clear trend was observed between SVR, relapse, and breakthrough. After adjusting for drug exposure and treatment duration, only decreases in neutrophil count remained associated with virologic response. Significantly greater declines in neutrophil (P < 0.0001) and platelet (P < 0.005) count were observed at weeks 4, 12, and 24 of therapy in virologic responders compared with nonresponders. This difference between responders and nonresponders was also observed among racial/ethnic groups, although statistical significance was not consistent across all groups. Conclusion: This post hoc analysis of HCV patients treated with PEG-IFN alfa-2a and ribavirin shows that maximum decreases from baseline in hematologic parameters and weight loss were associated with virologic response. However, after adjusting for drug exposure and accounting for duration of therapy, only neutropenia was independently associated with virologic response.     

A randomized trial of induction doses of interferon alone or in combination with ribavirin or ribavirin plus amantadine for treatment of nonresponder patients with chronic hepatitis C

Background Efficacy and safety of interferon induction therapy alone or in combination with ribavirin or ribavirin plus amantadine were evaluated in chronic hepatitis C patients who were nonresponders to primary antiviral treatment. Methods The study was designed to have 225 HCV nonresponder patients, but at an interim analysis the response rate difference between groups was lower than expected and the enrollment was stopped when 75 patients had been randomized to receive interferon-α2a (group A, n = 26), interferon-α2a plus 15 mg/kg per day of ribavirin (group B, n = 24), or interferon-α2a plus ribavirin plus 200 mg/day of amantadine hydrochloride (group C, n = 25). Treatment duration was 48 weeks. The dose of interferon was 6 MU/day for 4 weeks followed by 3 MU/day for the remaining 44 weeks. Results On intention-to-treat, the sustained virological response at 24 weeks of follow-up was 11.5% in group A, 12.5% in group B, and 12% in group C. Therapy was discontinued because of adverse effects in three patients in group A (11.5%), three in group B (12.5%), and two in group C (8%). Conclusions Nonresponders with chronic hepatitis C may achieve a sustained virological response rate of approximately 12% if retreated with interferon induction treatment followed by administration of a daily dose. The addition of ribavirin or amantadine did not seem to improve the response rates.     

Long-term follow-up study of sustained biochemical responders with interferon therapy

A proportion of chronic hepatitis C patients who were treated with interferon have a sustained normalization of transaminase levels after interferon therapy without hepatitis C virus (HCV)-RNA clearance. We determined their clinical characteristics and long-term outcome in relation to progression to liver cirrhosis (LC) and the development of hepatocellular carcinoma (HCC). A total of 250 patients with chronic hepatitis C who were treated with interferon were studied for 8 to 11 years' posttherapy. Sixty-seven patients (27%) were complete responders with clearance of HCV RNA. Twenty-six (10%) were biochemical responders who had sustained normal alanine transaminase (ALT) levels without viral clearance. The remaining patients were short-term responders (n = 70) and nonresponders (n = 87). Biochemical responders were older, had higher levels of pretreatment HCV RNA in serum than complete responders, and had less advanced liver histology than nonresponders. Histologic grading scores decreased significantly at the end of therapy, while the staging scores did not change significantly. The annual incidence of cirrhosis was 0% in biochemical and complete responders, which was significantly lower than nonresponders and the controls (P = .0001). The annual incidence of HCC was 0.37% in complete responders and 0.50% in biochemical responders, which was significantly lower than nonresponders (P = .0001 for both). Our findings suggest that biochemical responders had high pretreatment viral levels with less advanced liver histology, and their long-term outcome appeared to be good irrespective of the persistence of the virus.     

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.     

Effect of antiviral treatment in patients with chronic HCV infection and t(14;18) translocation

Hepatitis C virus (HCV) may be associated with the mixed cryoglobulinemia syndrome and other B-cell lymphoproliferative disorders (LPDs). The t(14;18) translocation may play a pathogenetic role. Limited data are available regarding the effects of antiviral therapy on rearranged B-cell clones. We evaluated the effects of interferon and ribavirin on serum, B-lymphocyte HCV RNA, and t(14; 18) in 30 HCV+, t(14;18)+ patients without either mixed cryoglobulinemia syndrome or other LPDs. The t(14;18) translocation was analyzed by both bcl-2/JH polymerase chain reaction and bcl-2/JH junction sequencing in peripheral blood mononuclear cells in all patients. Fifteen untreated patients with comparable characteristics served as controls. Throughout the study, the presence or absence of both t(14;18) and HCV RNA sequences were, in most cases, associated in the same cell samples. At the end of treatment, t(14;18) was no longer detected in 15 patients (50%) with complete or partial virologic response, whereas it was persistently detected in nonresponders (P <.05), as well as in 14 of 15 control patients. In 4 responder patients, t(14;18) and HCV RNA sequences were no longer detected in blood cells after treatment, but were again detected after viral relapse; the same B-cell clones were involved in the pretreatment and posttreatment periods. In conclusion, this study suggests that antiviral therapy may induce regression of t(14;18)-bearing B-cell clones in HCV+ patients and that this phenomenon may be related, at least in part, to the antiviral effect of therapy. This in turn suggests that antiviral treatment may help prevent or treat HCV-related LPDs.     

Antiviral activity of telaprevir and boceprevir for the treatment of hepatitis C virus infection in treatment-experienced patients

Around 50% of hepatitis C virus (HCV)-positive patients infected with genotype 1 are nonresponders to the combination of pegylated interferon (pegIFN) and ribavirin, including relapsers, and partial and null responders and, as such, are exposed to the risk of progression to cirrhosis and its complications, resulting in HCV-related morbidity and mortality. Repeat treatment using the same combination in such patients results in <5% viral eradication and there are no therapeutic prospects for patients who fail, as maintenance therapy has not proved efficacious. The triple association of direct-acting antivirals specific of HCV, and especially the first-generation protease inhibitors boceprevir and telaprevir, increases this percentage to around 65%, with variations according to the previous response to therapy of patients (85% of relapsers, 50% of partial responders and 30% of null responders). These encouraging results extend the therapeutic indications and costs of therapy during virological follow-up, and influence the rules of discontinuation. Information on the management of these new molecules also allows a larger number of patients to be cured and reduces the occurrence of viral resistance. Thus, the aim of the present review is to summarize the efficacy of the triple association of pegIFN, ribavirin and telaprevir or boceprevir in treatment-experienced patients who failed to respond to dual pegIFN and ribavirin therapy.     

Analysis of sequence configurations of the ISDR,PKR-binding domain,and V3 region as predictors of response to induction interferon-alpha and ribavirin therapy in chronic hepatitis C infection

Interferon (IFN) and ribavirin combination therapy for chronic hepatitis C virus (HCV) infection yields a sustained response rate of only 40%. Previous studies have linked IFN responsiveness to viral sequence variation in parts of the E2 and NS5A genes, but this remains controversial. We studied pretreatment sera from 28 subjects (23 with HCV genotype 1a) who received high-dose IFN induction followed by IFN–ribavirin combination therapy. Serum HCV sequences were amplified and compared from 14 responders with undetectable HCV RNA 24 weeks after therapy and 11 nonresponders (excluding three who dropped out of the study). Analysis included the E2 PKR eIF-2 phosphorylation homology domain (PePHD, codons 659–670), where the sequence was well conserved, and codons 2001–2420 of NS5A. In NS5A, the proposed PKR binding domain (codons 2209–2274), containing the putative IFN sensitivity determining region (ISDR, codons 2209–2248), showed too little variation among subjects to differentiate responders and nonresponders. NS5A codons 2356–2385 (which includes the V3 region) exhibited more variation. Here, six of 12 genotype 1a responders showed four or more amino acid changes from the prototype HCV-1 sequence, as compared with one of eight nonresponders, but this fell short of statistical significance (P = 0.16). NS5A sequences from posttreatment sera were examined in six nonresponders to look for selection of treatment-resistant viral subpopulations, but no consistent change was detected. In conclusion, our results indicate that the sequences of the ISDR, the PKR-binding domain, and the PePHD are unlikely to have predictive value for IFN treatment success in those infected with HCV genotype 1a. However, the finding of greater variability among treatment responders in the carboxy end of NS5A suggests that the V3 region merits further investigation.     

Changes in serum hepatitis C virus RNA in interferon nonresponders retreated with interferon plus ribavirin: a preliminary report.

Ribavirin, a nucleoside analogue, inhibits replication of RNA and DNA viruses and may control hepatitis C virus (HCV) infection through modulation of anti-inflammatory and antiviral actions. Ribavirin monotherapy has no effect on serum HCV RNA levels. In combination with interferon, this agent appears to enhance the efficacy of interferon. The aim of this study was to monitor serum HCV RNA levels early during therapy with interferon and ribavirin compared with that previously seen in the same patients during interferon monotherapy. Five patients who previously showed no response to therapy with interferon alfa 3 MU three times weekly for 6 months were retreated with the identical dose of interferon alfa 2b in combination with oral ribavirin 1,000 mg/day. Serum HCV RNA levels were monitored at baseline, week 4, week 8, and week 12 of therapy by a quantitative multicycle polymerase chain reaction assay. In the first 8 to 12 weeks, serum HCV RNA levels showed a greater decrease in all patients when retreated with combination therapy compared with interferon alone. Mean (+/- SEM) serum HCV RNA levels for interferon therapy alone were 3.3 +/- 0.95, 1.2 +/- 0.95, 1.6 +/- 1.2, and 2.3 +/- 1.2 x 10(6) copies/ml at week 0, 4, 8, and 12, respectively. This was compared with 3.3 +/- 0.83, 0.3 +/- 0.2, 0.03 +/- 0.02, and 0.15 +/- 0.14 x 10(6), respectively, for the interferon and ribavirin group (p < 0.07 at week 8). Two of five patients had undetectable serum HCV RNA during combination therapy. Combination therapy with interferon and ribavirin in prior interferon nonresponders reduces serum HCV RNA levels compared with interferon alone. This may suggest some additional antiviral effect of ribavirin when given with interferon.     

Accelerated decline in lung function and impaired reversibility with salbutamol in asthmatic patients with chronic hepatitis C virus infection: a 6-year follow-up study

PURPOSE: Chronic hepatitis C virus (HCV) infection may have adverse effects on pulmonary function in patients with chronic obstructive pulmonary disease. This prospective study was designed to determine whether chronic HCV infection affects decline in lung function and airway responses to salbutamol in asthmatic patients. METHODS: Interferon alpha (6 MIU three times a week for 6 months) was given to 55 HCV-positive asthmatic patients, 18 of whom had a virologic response to interferon. Pre- and postbronchodilator forced expiratory volume in 1 second (FEV(1)) and reversibility with salbutamol or oxitropium at years 1, 3, and 6 after interferon therapy were examined. RESULTS: We found a significant decrease in pre- and postbronchodilator FEV(1) from year 1 to years 3 and 6 only in interferon nonresponders. Reversibility with salbutamol at years 3 and 6 was significantly lower in interferon nonresponders than in HCV-negative patients (P <0.0001) and interferon responders (P <0.0001). Moreover, there was a steep decline in reversibility with salbutamol during the follow-up period only in interferon nonresponders. In contrast, reversibility with oxitropium at years 3 and 6 was significantly higher in interferon nonresponders than in HCV-negative patients and interferon responders, and there was a steep increase in reversibility with oxitropium only in interferon nonresponders. In addition, declines in the diffusing capacity of the lung for carbon monoxide during follow-up were significantly greater in interferon nonresponders than in HCV-negative patients and interferon responders. CONCLUSION: Chronic HCV infection is associated with an accelerated decline in lung function and impaired reversibility with salbutamol among asthmatic patients who do not respond to interferon therapy.     

Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection

BACKGROUND & AIMS: Pegylated interferon (IFN)-alpha plus ribavirin is the most effective treatment of chronic hepatitis C but has unpleasant side effects and high costs. A large proportion of patients do not respond to therapy for reasons that are unclear. We used gene expression profiling to investigate the molecular basis for treatment failure. METHODS: Expression profiling was performed on percutaneous needle liver biopsy specimens taken before therapy. Gene expression levels were compared among 15 nonresponder, 16 responder, and 20 normal liver biopsy specimens. Differential gene expression was confirmed using real-time polymerase chain reaction. RESULTS: We identified 18 genes whose expression differed significantly between all responders and all nonresponders (P < .005). Many of these 18 genes are IFN sensitive and 2 (ISG15/USP18) are linked in a novel IFN-regulatory pathway, suggesting a possible rationale for treatment resistance. Using a number of independent classifier analyses, an 8-gene subset accurately predicted treatment response for 30 of 31 patients. The classifier analyses were applicable to patients with genotype 1 infection and were not correlated with viral load, disease activity, or fibrosis. CONCLUSIONS: Hepatic gene expression profiling identified consistent differences in patients who subsequently fail treatment with pegylated IFN-alpha plus ribavirin: up-regulation of a specific set of IFN-responsive genes predicts nonresponse to exogenous therapy. These data may be of use in predicting clinical responses to treatment.