Decrease In Hepatitis C Virus RNA Levels Research Articles

First Week HCV RNA Level Under the Pegylated Interferon and Ribavirin Treatment Predicts Sustained Virological Response

This study was planned to investigate whether the decrease in the hepatitis C virus (HCV) RNA levels at the first week of combined pegylated interferon and ribavirin treatment of naive genotype 1 patients with HCV was predicting sustained virologic response (SVR). Fifty-two patients were enrolled into the study. HCV RNA levels were measured at the baseline, first, fourth, and 12th weeks of treatment. Thirty-four patients achieved SVR, which basal, first week, and fourth week HCV RNA levels were log 5.57, log 3.65, and log 1.92, respectively. Eighteen patients could not achieve SVR, which basal, first week, and fourth week HCV RNA levels were log 6.22, log 5.45, and log 3.84, respectively (P < 0.05). Patients were distributed in 2 groups according to the amount of decrease in HCV RNA levels at the first week as less or more than 1.5 log. There were 20 patients with ≥1.5 log decrease in the HCV RNA levels at the first week. They were named as patients with very rapid virologic response (VRVR). All patients (100%) with VRVR were achieved SVR. In only 14 (44%) of the 32 patients without VRVR, SVR was achieved. In 16 (84%) of the 19 patients with rapid virologic response and 33 (79%) of the 42 patients with early virologic response, SVR was achieved. A ≥1.5 log decrease (VRVR) in HCV RNA levels of patients with HCV at the first week of combined pegylated interferon and ribavirin treatment predicts SVR very strongly.

Insight into the recognition, binding, and reactivity of catalytic metallodrugs targeting stem loop IIb of hepatitis C IRES RNA.

The complex Cu-GGHYrFK-amide (1-Cu) was previously reported as a novel metallotherapeutic that catalytically inactivates stem loop IIb (SLIIb) of the hepatitis C virus (HCV) internal ribosomal entry site (IRES) RNA and demonstrates significant antiviral activity in a cellular HCV replicon assay. Herein we describe additional studies focused on understanding the cleavage mechanism as well as the relationship of catalyst configuration to structural recognition and site-selective cleavage of the structured RNA motif. These are advanced by use of a combination of MALDI-TOF mass spectrometry, melting temperature determinations, and computational analysis to develop a structural model for binding and reactivity toward SLIIb of the IRES RNA. In addition, the binding, reactivity, and structural chemistry of the all-D-amino acid form of this metallopeptide, complex 2-Cu, are reported and compared with those of complex 1-Cu. In vitro RNA binding and cleavage assays for complex 2-Cu show a KD value of 76 ± 3 nM, and Michaelis-Menten parameters of kcat =0.14 ± 0.01 min(-1) and KM =7.9 ± 1.2 μM, with a turnover number exceeding 40. In a luciferase-based cellular replicon assay Cu-GGhyrfk-amide shows activity similar to that of the 1-Cu parent peptide, with an IC50 value of 1.9 ± 0.4 μM and cytotoxicity exceeding 100 μM. RT-PCR experiments confirm a significant decrease in HCV RNA levels in replicon assays for up to nine days when treated with complex 1-Cu in three-day dosing increments. This study shows the influence that the α-carbon stereocenter has for this new class of compounds, while detailed mass spectrometry and computational analyses provide new insight into the mechanisms of recognition, binding, and reactivity.

Human La Protein Interaction with GCAC near the Initiator AUG Enhances Hepatitis C Virus RNA Replication by Promoting Linkage between 5′ and 3′ Untranslated Regions

Human La protein has been implicated in facilitating the internal initiation of translation as well as replication of hepatitis C virus (HCV) RNA. Previously, we demonstrated that La interacts with the HCV internal ribosome entry site (IRES) around the GCAC motif near the initiator AUG within stem-loop IV by its RNA recognition motif (RRM) (residues 112 to 184) and influences HCV translation. In this study, we have deciphered the role of this interaction in HCV replication in a hepatocellular carcinoma cell culture system. We incorporated mutation of the GCAC motif in an HCV monocistronic subgenomic replicon and a pJFH1 construct which altered the binding of La and checked HCV RNA replication by reverse transcriptase PCR (RT-PCR). The mutation drastically affected HCV replication. Furthermore, to address whether the decrease in replication is a consequence of translation inhibition or not, we incorporated the same mutation into a bicistronic replicon and observed a substantial decrease in HCV RNA levels. Interestingly, La overexpression rescued this inhibition of replication. More importantly, we observed that the mutation reduced the association between La and NS5B. The effect of the GCAC mutation on the translation-to-replication switch, which is regulated by the interplay between NS3 and La, was further investigated. Additionally, our analyses of point mutations in the GCAC motif revealed distinct roles of each nucleotide in HCV replication and translation. Finally, we showed that a specific interaction of the GCAC motif with human La protein is crucial for linking 5' and 3' ends of the HCV genome. Taken together, our results demonstrate the mechanism of regulation of HCV replication by interaction of the cis-acting element GCAC within the HCV IRES with human La protein.

Novel anilinocoumarin derivatives as agents against hepatitis C virus by the induction of IFN-mediated antiviral responses

The hepatitis C virus (HCV) is the main cause of progressive liver disease, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Novel anilinocoumarins were synthesized, and their efficacy against HCV replication was evaluated. We demonstrated that 3-(3',4',5'-trimethoxyanilin-1'-yl)methylaminocoumarin (6) exhibited strong anti-HCV activity at protein and RNA levels at non-toxic concentrations, with an EC(50) value of 12 ± 0.3 μM and a selective index (SI) value of 10. Combined treatment of compound 6 and interferon-α (IFN) or telaprevir induced a significant decrease in HCV RNA levels, respectively. We also found that the anti-HCV replication effect of compound 6 was due to the induction of IFN-mediated antiviral responses. This is the first report demonstrating that coumarins inhibit viral replication through an IFN-mediated anti-viral response. Collectively, compound 6 possessed potent activities against HCV replication and could be a new lead compound with higher selectivity and less toxicity.

Nanoparticle-based artificial RNA silencing machinery for antiviral therapy

RNA interference is a fundamental gene regulatory mechanism that is mediated by the RNA-induced silencing complex (RISC). Here we report that an artificial nanoparticle complex can effectively mimic the function of the cellular RISC machinery for inducing target RNA cleavage. Our results show that a specifically designed nanozyme for the treatment of hepatitis C virus (HCV) can actively cleave HCV RNA in a sequence specific manner. This nanozyme is less susceptible to degradation by proteinase activity, can be effectively taken up by cultured human hepatoma cells, is nontoxic to the cultured cells and a xenotransplantation mouse model under the conditions studied, and does not trigger detectable cellular interferon response, but shows potent antiviral activity against HCV in cultured cells and in the mouse model. We have observed a more than 99% decrease in HCV RNA levels in mice treated with the nanozyme. These results show that this nanozyme approach has the potential to become a useful tool for functional genomics, as well as for combating protein-expression-related diseases such as viral infections and cancers.

Antiviral Activity of Danoprevir (ITMN-191/RG7227) in Combination With Pegylated Interferon α-2a and Ribavirin in Patients With Hepatitis C

Current therapy options for patients with chronic hepatitis C virus (HCV) infection genotype 1 are effective in <50%. Danoprevir (ITMN-191/RG7227) is a potent, selective, and orally active inhibitor of the HCV NS3/4A serine protease. The safety and antiviral efficacy of danoprevir was examined over 14 days in combination with pegylated interferon α-2a (180 μg once weekly) and ribavirin (1000-1200 mg/day) in a double-blind, placebo-controlled, phase 1b, multiple ascending dose study consisting of 6 dose cohorts (400 mg, 600 mg, and 900 mg twice daily and 100 mg, 200 mg, and 300 mg 3 times daily). Danoprevir in combination with pegylated interferon α-2a and ribavirin was safe and generally well tolerated. The median change in HCV RNA level from baseline to the end of treatment with danoprevir at 400 mg, 600 mg, and 900 mg twice daily was -4.7 log(10) IU/mL, -5.4 log(10) IU/mL, and -5.3 log(10) IU/mL, respectively, and at 100 mg, 200 mg, and 300 mg 3 times daily was -5.5 log(10) IU/mL, -5.7 log(10) IU/mL, and -5.6 log(10) IU/mL, respectively. Placebo administered in combination with standard of care resulted in median decrease in HCV RNA level of -2.6 log(10) IU/mL (with twice daily regimen) and -2.0 log(10) IU/mL (with 3 times daily regimen). Our study showed substantial antiviral efficacy of danoprevir in combination with pegylated interferon α-2a and ribavirin. Exploration of the safety and antiviral efficacy of danoprevir in longer clinical studies is warranted.

A Step Forward in Therapy for Hepatitis C

The therapy of hepatitis C began almost 25 years ago with a small trial of recombinant human interferon alfa.1 The rationale for using interferon was its broad antiviral effects and the suspicion that it might be active against the still-undiscovered agent of non-A, non-B hepatitis. Indeed, interferon had striking effects, lowering serum aminotransferase levels and, in a proportion of patients, inducing a lasting improvement in serum enzyme levels. Not until the discovery of the hepatitis C virus (HCV) were the effects of interferon understood; treatment resulted in a decrease in HCV RNA levels, which led to a sustained absence of . . .

Racial Differences in Response to Interferon‐Based Antiviral Therapy for Hepatitis C Virus Infection: A Hardwiring Issue?

Chronic hepatitis C virus (HCV) infection is a major public health burden in the United States and worldwide. Between 2% and 3% of the world’s population has chronic HCV infection, although significant geographic variation results in a prevalence of chronic HCV of 10% in certain countries. As a result, complications of chronic HCV infection (mostly end-stage liver disease and hepatocellular carcinoma) comprise the leading indications for liver transplantation worldwide. Phylogenetic analysis has led to the description of 6 major viral genotypes, numbered 1 through 6, that differ from each other by 30% at the nucleotide level over the viral genome. The major genotypes can, in turn, be divided into subtypes (e.g., 1a or 1b) that differ by 20%. Interferon (IFN)– based regimens have been the mainstay of HCV treatment for nearly 2 decades [1, 2]. Patients with genotype 1 infection experience substantially lower rates of sustained virologic response (SVR), defined as an undetectable serum HCV RNA level 24 weeks after the end of treatment, compared with patients with HCV genotype 2 or 3 infection. With best current therapy consisting of peginterferon and ribavirin, genotype 1 infection is associated with a 45%–55% rate of SVR, whereas genotype 2 or 3 infection is associated with a 75%– 80% rate of SVR. This observation underscores the importance of viral factors in determining the response to IFN-based therapy. It has also become apparent that host factors influence the response to antiviral therapy. Several independent studies have shown that African Americans experience consistently lower rates of SVR to IFNbased regimens, compared with white persons [3– 6]. In the Study of Viral Resistance to Antiviral Therapy of Hepatitis C (Virahep-C), a multicenter trial comparing the rates of response to peginterferon and ribavirin among 205 white and 196 African American patients with chronic genotype 1 infection, only 28% of African American patients attained SVR, compared with 52% of white patients [5]. The association between African American race and decreased IFN responsiveness remained significant even after adjustment for baseline HCV RNA level, sex, age, weight, stage of hepatic fibrosis, or amount of peginterferon or ribavirin taken. Intriguingly, this study also showed that only 10% of African American patients had an undetectable HCV RNA level after 4 weeks of therapy, compared with 22% of white patients, demonstrating that at least some of the difference in IFN responsiveness between African American and white patients could be explained by differences in early viral kinetics. The article by Hoofnagle et al. [5] in this issue of the Journal extends this observation by analyzing HCV early viral kinetics in response to peginterferon and ribavirin in 301 patients (of whom 154 were African American and 187 were white) from the Virahep-C study population. Three kinetic measurements were assessed: the first-phase response, defined in this study as the decrease in HCV RNA levels between baseline and 24 or 48 h after the first dose of peginterferon, whichever was greater; the second-phase response, defined as the maximum weekly decrease in HCV RNA levels between days 7 and 28 or days 14 and 28, whichever was greater; and the total decrease from baseline to week 28. All 3 responses were predictive of SVR, although the 28-day decrease was most predictive by receiver operating curve analysis. The most striking finding of the study was that the ultimate antiviral efficacy of a 48-week course of IFN-based therapy for chronic HCV infection was, to a significant degree, determined by the viral kinetics only 24 – 48 Received 4 November 2008; accepted 4 November 2008; electronically published 24 March 2009. Potential conflicts of interest: none reported. Financial support: none reported. Reprints or correspondence: Dr. Raymond T. Chung, Gastrointestinal Unit, Massachusetts General Hospital, WRN 1007, 55 Fruit St., Boston, MA 02114 (rtchung@partners.org). The Journal of Infectious Diseases 2009; 199:1101–3 © 2009 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2009/19908-0001$15.00 DOI: 10.1086/597385 E D I T O R I A L C O M M E N T A R Y

Early Changes in Hepatitis C Virus (HCV) Levels in Response to Peginterferon and Ribavirin Treatment in Patients with Chronic HCV Genotype 1 Infection

Early changes in hepatitis C virus (HCV) RNA levels were assessed in a large cohort of African American and white patients with chronic hepatitis C due to HCV genotype 1 who underwent therapy with peginterferon alfa-2a and ribavirin in the Study of Viral Resistance to Antiviral Therapy of Hepatitis C (Virahep-C). Analyses were restricted to 341 patients who completed the first 28 days of therapy without dose modification. HCV RNA levels decreased in virtually all patients, but the amount of the change varied markedly. The overall 28-day decrease in HCV RNA levels was at least as predictive of a sustained virological response as the first- or second-phase viral kinetics responses. Factors associated with a smaller decrease in the HCV RNA level between baseline and day 28 included African American race, higher initial HCV RNA level, more severe hepatic fibrosis, and higher body weight. African American patients with similar 28-day decreases in viral levels as white patients were still less likely to achieve a sustained virological response. These results suggest that racial differences in the response to antiviral therapy are due to greater unresponsiveness to intracellular actions of interferon in African American individuals and that standard doses of peginterferon and ribavirin may be suboptimal for patients with higher body weights. Trial registration. ClinicalTrials.gov identifier: NCT00038974 .

Peginterferon Alfa-2a and Ribavirin for 24 Weeks in Hepatitis C Type 1 and 4 Patients With Rapid Virological Response

This analysis reports the rate of sustained virological response (SVR) in patients infected with hepatitis C virus (HCV) genotype 1 or 4 who were assigned to 24 weeks of treatment with pegylated interferon (peginterferon) alfa-2a 180 mug/wk plus ribavirin 1000/1200 mg/day after achieving a rapid virological response (RVR; HCV RNA level <50 IU/mL) at week 4 in a prospective trial investigating response-guided therapy. Non-RVR patients with an early virological response were randomized to 48 or 72 weeks of therapy (this is a still-ongoing trial). A total of 150 of 516 patients (29%) had an RVR, 143 of whom completed 24 weeks of treatment. Younger patients, leaner patients, and those with an HCV RNA level </=400,000 IU/mL and HCV genotype 4 infection were more likely to achieve an RVR; however, among patients with an RVR, no baseline factor predicted SVR. The SVR rate was 80.4% (115/143; 95% confidence interval [CI], 72.9-86.6) in patients who completed 24 weeks of treatment. The SVR rate was 86.7% (26/30; 95% CI, 69.3%-96.2%) in patients infected with genotype 4 and 78.8% in those infected with genotype 1 (89/113; 95% CI, 70.1%-85.9%; intent to treat: 89/120; 74.2%; 65.4-81.7%). Treatment was well tolerated. This prospective study confirms that a 24-week regimen of peginterferon alfa-2a plus ribavirin 1000/1200 mg/day is appropriate in genotype 1 and 4 patients with a low baseline HCV RNA level who achieve an RVR by week 4 of therapy.

Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop

The current recommended therapy for chronic hepatitis C is the combination of peginterferon and ribavirin, which results in a sustained clearance of hepatitis C virus (HCV) in at least half of patients. However, the mechanisms by which interferon alpha (IFN-α) and ribavirin act against HCV are not well defined. The importance of understanding the biological pathways, cellular effects, and antiviral activities of these agents is underscored by clinical observations that nonresponders frequently have little or no decrease in HCV RNA levels during treatment, suggesting intrinsic resistance to IFN-α. Cell culture and animal models of HCV have shown that the infection itself may block IFN-α induction and action. Still other findings suggest that individual innate and adaptive immune responses, host genetic factors, viral genetic diversity, and clinical comorbidities account for part of nonresponse to therapy. To provide an overview of the current knowledge of the mechanisms of action of IFN-α and ribavirin against HCV and offer guidance for future research, the American Association for the Study of Liver Diseases held a single topic conference entitled “Interferon and Ribavirin in Hepatitis C Virus Infection: Mechanisms of Response and Non-Response” on March 1-3, 2007. This article summarizes that conference.

Changes in Gene Expression during Pegylated Interferon and Ribavirin Therapy of Chronic Hepatitis C Virus Distinguish Responders from Nonresponders to Antiviral Therapy

Treating chronic hepatitis C virus (HCV) infection using pegylated alpha interferon and ribavirin leads to sustained clearance of virus and clinical improvement in approximately 50% of patients. Response rates are lower among patients with genotype 1 than with genotypes 2 and 3 and among African-American (AA) patients compared to Caucasian (CA) patients. Using DNA microarrays, gene expression was assessed for a group of 33 African-American and 36 Caucasian American patients with chronic HCV genotype 1 infection during the first 28 days of treatment. Results were examined with respect to treatment responses and to race. Patients showed a response to treatment at the gene expression level in RNA isolated from peripheral blood mononuclear cells irrespective of degree of decrease in HCV RNA levels. However, gene expression responses were relatively blunted in patients with poor viral response (<1.5 log(10)-IU/ml decrease at 28 days) compared to those in patients with a marked (>3.5 log(10)-IU/ml decrease) or intermediate (1.5 to 3.5 log(10)-IU/ml decrease) response. The number of genes that were up- or down-regulated by pegylated interferon and ribavirin treatment was fewer in patients with a poor response than in those with an intermediate or marked viral response. However AA patients had a stronger interferon response than CA patients in general. The induced levels of known interferon-stimulated genes such as the 2'5'-oligoadenylate synthetase, MX1, IRF-7, and toll-like receptor TLR-7 genes was lower in poor-response patients than in marked- or intermediate-response patients. Thus, the relative lack of viral response to interferon therapy of hepatitis C virus infection is associated with blunted interferon cell signaling. No specific regulatory gene could be identified as responsible for this global blunting or the racial differences.

Hepatitis C immune globulin to prevent HCV recurrence after liver transplantation: Chasing windmills?

Hepatitis C immune globulin to prevent HCV recurrence after liver transplantation: Chasing windmills?

Hepatitis C virus RNA kinetics during the initial 12 weeks treatment with pegylated interferon‐alpha 2a and ribavirin according to virological response

To optimize treatment of chronic hepatitis C early identification of patients who will not achieve a sustained virological response (SVR) is desirable. We investigated hepatitis C virus (HCV) RNA kinetics at day 1 (in 15 patients; genotypes 1 and non-1, 9 and 6 respectively) at weeks 1, 4 and 12 (in 53 patients; genotypes 1 and non-1, 19 and 34, respectively) during treatment with pegylated interferon alpha-2a and ribavirin. Patients with SVR had a significantly more pronounced mean log10 decline from baseline in HCV RNA levels at weeks 1 and 4 compared with patients who failed to achieve SVR (1.99 vs 0.85 at week 1, P = 0.0003 and 2.89 vs 1.72 at week 4, P = 0.0159), whereas no difference was noted after day 1. For patients with a 2-log10 decrease in HCV RNA levels at day 7, the positive predictive value (PPV) for a SVR was 92%, whereas week 12 was the best time point for predicting a later nonresponse [negative predictive value (NPV) 92%] in patients failing to achieve a 2-log10 drop. For patients with genotype non-1 and a 2-log10 decrease in HCV RNA levels the PPV for a SVR was 89% week 1, and 79% weeks 4 and 12. The corresponding NPV for patients with genotype non-1 were 43, 40 and 100% respectively. During treatment with pegylated interferon alpha-2a plus ribavirin the HCV RNA decline at week 1 was an accurate predictor of SVR in patients who had achieved a 2-log10 drop in HCV RNA levels, whereas the lack of such decline week 12 was an accurate marker of a nonresponse.

Overexpression of a DEAD box/RNA helicase protein, rck/p54, in human hepatocytes from patients with hepatitis C virus-related chronic hepatitis and its implication in hepatocellular carcinogenesis.

Hepatitis C virus (HCV) infection is the most common cause of chronic hepatitis, which frequently progresses to hepatocellular carcinoma. The pathogenesis of its persistent infection and tumour progression has not been fully characterized yet. The RCK gene was previously cloned at the breakpoint of the t(11;14)(q23;q32) chromosome translocation observed in human B-cell lymphoma cell line RC-K8. The RCK protein, rck/p54, which is a 54-kDa cytoplasmic protein belonging to the DEAD box/RNA helicase family, is considered to facilitate the translation of mRNA(s) of genes for cell proliferation and malignant transformation not only in B-cell lymphomas having the t(11;14) translocation but also in other solid tumours. The aim of this work was to examine the involvement of rck/p54 in carcinogenesis of hepatocellular carcinoma from HCV-related chronic hepatitis. We examined the expression of rck/p54 in 29 cases of HCV-related chronic hepatitis and eight cases of hepatocellular carcinoma by immunohistochemistry and Western blot analysis. Twenty-six of 29 cases with HCV-related chronic hepatitis and all cases with hepatocellular carcinoma tested overexpressed rck/p54 protein. The expression of rck/p54 was lowered by treatment with IFN-alpha in two cases who showed the decrease in HCV RNA levels. These findings suggest that rck/p54 protein is possibly involved in the replication of HCV genomes in hepatocytes and in tumourigenesis of hepatocellular carcinomas.

Clinical trial results of peginterferons in combination with ribavirin.

Of the large number of patients chronically infected with hepatitis C virus (HCV), only about one third have progressive liver disease, and will eventually develop cirrhosis and hepatocellular carcinoma. These are the patients for whom effective antiviral treatment is most needed. Therapy is currently recommended for patients with chronic hepatitis C who have abnormal alanine aminotransferase (ALT) levels, detectable hepatitis C virus ribonucleic acid (HCV RNA) in the blood, and significant necroinflammatory changes and/or fibrosis on liver biopsy. The current gold standard in terms of treatment efficacy is the combination of peginterferon (PEG-IFN) and ribavirin. The overall sustained virological response rate (SVR) with these regimens is 54 to 61% following 48 weeks of therapy. Patients with genotype 1 infection have a 42 to 51% likelihood of response to 48 weeks of therapy. Those with genotypes 2 or 3 infection will respond to 24 weeks of therapy in 78 to 82% of cases. These SVR rates are 5 to 10 percentage points higher in all patient groups than in those obtained with standard doses of interferon (IFN) and ribavirin. Retreatment of nonresponders to standard IFN monotherapy using PEG-IFN and ribavirin has achieved SVR rates of 34 to 40%. Retreatment of patients who relapsed after IFN monotherapy has resulted in an SVR rate of about 60%. A SVR after retreatment of relapsers and nonresponders with PEG-IFN and ribavirin is more likely in patients previously treated with IFN monotherapy, those with HCV genotypes 2 or 3, patients with low viral load (<2 million copies/mL), and individuals who had a significant decrease in HCV RNA levels during the initial treatment. The potential benefits of long-term anti-HCV suppressive therapy in nonresponders are currently under investigation.

Retreatment of patients with chronic hepatitis C

Significant advances have been made in the treatment of chronic hepatitis C virus (HCV) infection during the past 5 years. As a consequence, there is continuing enthusiasm for retreating patients who did not achieve sustained virological response (SVR) with previous therapy. Retreatment of non-responders to standard interferon monotherapy using interferon and ribavirin has yielded SVR rates of 12% to 15%. Retreatment with peginterferon and ribavirin has been more effective; achieving SVR rates of 34% to 40%. Retreatment of patients who relapsed after interferon monotherapy using standard interferon and ribavirin yielded SVR rates of 47%, whereas retreatment with peginterferon and ribavirin resulted in an SVR rate of about 60%. The major factors associated with a higher likelihood of an SVR after retreatment include previous relapse, previous treatment with interferon monotherapy, HCV genotypes 2 or 3, lower serum levels of HCV RNA, and having a significant decrease in HCV RNA levels during the initial course of therapy. These results help to focus retreatment with peginterferon and ribavirin on subsets of patients who are most likely to benefit. (Hepatology 2002;36:S128-S134).

Retreatment of patients with chronic hepatitis C.

Significant advances have been made in the treatment of chronic hepatitis C virus (HCV) infection during the past 5 years. As a consequence, there is continuing enthusiasm for retreating patients who did not achieve sustained virological response (SVR) with previous therapy. Retreatment of non-responders to standard interferon monotherapy using interferon and ribavirin has yielded SVR rates of 12% to 15%. Retreatment with peginterferon and ribavirin has been more effective; achieving SVR rates of 34% to 40%. Retreatment of patients who relapsed after interferon monotherapy using standard interferon and ribavirin yielded SVR rates of 47%, whereas retreatment with peginterferon and ribavirin resulted in an SVR rate of about 60%. The major factors associated with a higher likelihood of an SVR after retreatment include previous relapse, previous treatment with interferon monotherapy, HCV genotypes 2 or 3, lower serum levels of HCV RNA, and having a significant decrease in HCV RNA levels during the initial course of therapy. These results help to focus retreatment with peginterferon and ribavirin on subsets of patients who are most likely to benefit.

The rapid first phase decline in hepatitis C viremia is lower in previous nonresponders compared to treatment naive patients

Despite advances in antiviral therapy for hepatitis C Virus (HCV), a large proportion of patients fails to respond to treatment. Initiation of interferon therapy is associated with a rapid first phase decline in viremia that occurs over 24 to 48 hours and seems to reflect inhibition of viral production or release from infected cells. We compared the blocking effectiveness of consensus interferon aifacon-1 (CIFN) in previous nonresponders (NR) to that observed in naive patients. Methods: Twenty virological NR with genotype 1 infection and no cirrhosis were evaluated. Ten received a single 15 mcg dose of IFN and ten ware given a 30 mug dose. Blood samples were collected at time O, 4, 8, 24, 48, 72, 96, and 168 hours after interferon administration. Data from previously untreated patients with genotype 1 infestion who received 9 mcg (n = 12) or 15 mg (n = 13) of CIFN provided a basis for comparison (Neumann at al. Hepatology 2000;32:372A). HCV RNA levels were measured by quantitative PCR (NGI). Viral dynamics were evaluated after CIFN dosing using models described by Neumann at al. (Science 1998;282:103). Results: The effectiveness of CIFN in inhibiting HCV production or release is shown in the table. 15 mcg of CIFN was significantly less effective in blocking HCV production in NR compared to either 15 mcg (p=O.O01) or 9 mcg (p=O.03) in halves. The 30 mcg dose provided less blocking effectiveness in NR than 15 mcg in naive patients (p=O.03), and a similar effect to 9 mcg in naives. NR who had greater than a 50% decrease in HCV RNA level from baseline at the end of previous treatment had a larger reduction in viral load at 24 hours compared to those who had not achieved that level of response with prior therapy (p = 0.05). Conclusions: The blocking effectiveness of CIFN was significantly lower in previous NR compared to naive patients at similar doses, suggesting that response to further treatment in NR is limited by intrinsic HCV resistance. However, the resistance was partially overcome with higher CIFN doses.

C5b-9 and Interleukin-6 in Chronic Hepatitis C: Surrogate Markers Predicting Short-term Response to Interferon Alpha-2b

Background: Available data and our observations suggest that elevated levels of interleukin (IL)-6 and -10 and some complement parameters may be associated with a poor response to IFN alpha. We evaluated how baseline levels of C5b-9, IL-6, and IL-10 influence the outcome of IFN alpha treatment. Methods: Fifty-one patients with established chronic hepatitis C were enrolled and treated with IFN alpha-2b. Before and after a 12-week-IFN-treatment (3 MU or 5 MU tiw) serum levels of IL-6, IL-10, C5b-9 and RNA of hepatitis C virus (HCV) were assessed. Sera of 46 sex- and age-matched, healthy blood donors served as control. Results: While two-thirds of patients was considered 'responder', 14 patients had no significant decrease either in HCV RNA or in ALT levels. In the responder's group lower baseline levels of IL-6 and C5b-9 were found than those in the `non-responder' group. As a result of IFN therapy HCV RNA and C5b-9 levels significantly decreased. While the serum concentration of IL-6 increased during the follow-up period, regarding IL-10, no change was observed. In patients with 'low' baseline levels of C5b-9 (<2053 ng/ml) IFN alpha resulted in a significantly (P = 0.0005) higher decrease in HCV RNA level. Regarding `low' IL-6 values (<1.47 pg/ml) similar but somewhat less significant (P = 0.0039) difference was found if the change of HCV RNA was investigated. The odds ratio of patients with low IL-6 and/or C5b-9 to responding to IFN alpha treatment was almost 10 times (CI: 9.1 (1.8-50.9)) higher as compared with patients without 'low' levels of these parameters. Conclusion: Our data suggest that serum level(s) of IL-6 and/or C5b-9 taken prior to the initiation of IFN treatment may serve as surrogate marker(s) in evaluating patients with chronic hepatitis C whether to get IFN alpha in monotherapy or to consider having combination therapy in the form of IFN alpha-ribavirin.