Meta-analysis Shows Extended Therapy Improves Response of Patients With Chronic Hepatitis C Virus Genotype 1 Infection

Article · October 2010with15 Reads
DOI: 10.1016/j.cgh.2010.06.019 · Source: PubMed
Clinical trials provided conflicting results about whether extended duration of treatment with pegylated interferon-alfa (pegIFN-alfa) and ribavirin (more than 48 weeks) improves rates of sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) genotype 1 and slow virologic response. We performed a meta-analysis to determine the overall impact of extended treatment, compared with standard treatment, on virologic response rates in these patients. We performed a literature search to identify randomized controlled trials (RCTs) that included monoinfected, treatment-naive patients infected with HCV genotype 1; data were compared between slow responding patients treated with pegIFN-alfa-2a/b plus ribavirin for 48 weeks and those that received extended treatment (as much as 72 weeks). End points included SVR rates, end-of-treatment (EOT) response and relapse rates; they were calculated according to the DerSimonian-Laird estimate. Six RCTs assessed the benefits of extended treatment with pegIFN-alfa-2a/b and ribavirin in treatment-naive patients with HCV genotype 1 that were slow responders (n = 669). The extended treatment significantly improved SVR rates in slow responders, compared with the standard of care (14.7% increase in overall SVR; 95% confidence interval, 4%-25.5%; P = .0072). Rates of viral relapse were significantly reduced by extended treatment, but EOT response rates were similar. The frequency of voluntary treatment discontinuation, but not of serious adverse events, was significantly increased by extended therapy. Extending the duration of treatment with pegIFN-alfa-2a/b and ribavirin in patients with HCV genotype 1 and a slow response to therapy improves the rate of SVR.
    • Pegylated interferon-alpha (Peg-IFN-a) plus Ribavirin has been the most effective therapy for chronic hepatitis C [23], until the emergence of new directly acting antiviral agents (DAA) like Boceprevir and Telaprevir. Several host and viral factors influence the treatment outcome [24,25] and approximately 50% of patients with HCV genotype 1 achieve a sustained viral response (SVR) [26]. Recently, single nucleotide polymorphisms (SNPs) in the IFNL3 gene (Also known as IL28B) that influence the responsiveness of treatment of HCV infection and the clearance of HCV have been identified [27,28].
    [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to analyse the distribution of KIR haplotypes and the KIR2DL2/3 alleles in chronic HCV-infected patients in order to establish the influence on the response to pegylated interferon plus ribavirin classical treatment. The alleles study of previously associated KIR2DL2/3 showed that KIR2DL2*001 was more frequent in non-SVR (NSVR) (42.2% vs. 27.5%, p<0.05) and KIR2DL3*001 was associated with sustained viral response (SVR) (41.6% vs. 61.2%, p<0.005). The KIR2DL3*001-HLA-C1 association was also significant (24.5% vs. 45.7%, p<0.001). From the frequencies of KIR obtained, 35 genotypes were assigned on the basis of previous studies. The centromeric A/A genotype was more frequent in SVR (44.1% vs. 34.5%, p<0.005) and the centromeric B/B genotype was found to be significantly more frequent in NSVR (20.9% vs. 11.2%, p<0.001). The logic regression model showed the importance of KIR genes in predicting the response to combined treatment, since the positive predictive value (PPV) was improved (from 55.9% to 75.3%) when the analysis of KIR was included in addition to the IFNL3 rs12979860 polymorphism. The study of KIR receptors may be a powerful tool for predicting the combined treatment response in patients with chronic HCV infection in association with the determination of IFNL3 polymorphism.
    Full-text · Article · Jun 2014
    • It is chiefly effective against HCV genotype 2 or 3 [7]. The treatment duration for genotype 2 and 3 is six months, while for genotype 1 and 4 it may extend up to 12 months [8]. There are also side effects associated with therapy, which include pancytopenia, flu-like symptoms, depression, pain in the body, and elevated temperature.
    [Show abstract] [Hide abstract] ABSTRACT: Hepatitis C virus (HCV) infection is the most important problem across the world. It causes acute and chronic liver infection. Different approaches are in use to inhibit HCV infection, including small organic compounds, siRNA, shRNA and peptide inhibitors. This review article summarizes the current and future therapies for HCV infection. PubMed and Google Scholar were searched for articles published in English to give an insight into the current inhibitors against this life-threatening virus. HCV NS3/4A protease inhibitors and nucleoside/nucleotide inhibitors of NS5B polymerase are presently in the most progressive stage of clinical development, but they are linked with the development of resistance and viral breakthrough. Boceprevir and telaprevir are the two most important protease inhibitors that have been approved recently for the treatment of HCV infection. These two drugs are now the part of standard-of-care treatment (SOC). There are also many other drugs in phase III of clinical development. When exploring the various host-cell-targeting compounds, the most hopeful results have been demonstrated by cyclophilin inhibitors. The current SOC treatment of HCV infection is Peg-interferon, riba-virin and protease inhibitors (boceprevir or telaprevir). The future treatment of this life-threatening disease must involve combinations of therapies hitting multiple targets of HCV and host factors. It is strongly expected that the near future, treatment of HCV infection will be a combination of direct-acting agents (DAA) without the involvement of interferon to eliminate its side effects.
    Full-text · Article · May 2014 · Antiviral therapy
    • (2) Patients infected with HCV genotype 1 (and possibly also those infected with genotype 4) and who achieve an EVR without an RVR should be treated for 48 weeks [61,[63][64][65][66][67][68]. (3) Patients with HCV genotype 1 and a delayed virological response (DVR) can be treated for 72 weeks, provided that their HCV RNA is undetectable at week 24.
    Full-text · Article · Feb 2014
    • Based on these findings, we propose the use of “response-guided therapy”, in which a treatment regimen is modified according to viral kinetics. For the treatment of genotype 1 chronic hepatitis C, proposed treatment strategies include shortening of treatment period in patients with RVR and extension of treatment period in patients with a delayed response to the initial treatment as judged at week 12 [9–17]. For the treatment of genotype 1 high virus titer chronic hepatitis C, shortening of the treatment period may not be recommended even if RVR is achieved because of a possible reduction in the SVR rate, whereas extension of the treatment period to 72 weeks has been reported to increase the SVR rate in patients showing a delayed response to the initial treatment [12, 14–18].
    [Show abstract] [Hide abstract] ABSTRACT: Background We conducted a multicenter randomized clinical trial to determine the optimal treatment strategy against chronic hepatitis C virus (HCV) with genotype 1b and a high viral load (G1b/high). Methods The study subjects included 153 patients with G1b/high. Patients were initially treated with PEG-IFNα-2a alone and then randomly assigned to receive different treatment regimens. Ribavirin (RBV) was administered to all patients with HCV RNA at week 4. Patients negative for HCV RNA at week 4 were randomly assigned to receive PEG-IFNα-2a (group A) or PEG-IFNα-2a/RBV (group B). Patients who showed HCV RNA at week 4 but were negative at week 12 were randomly assigned to receive weekly PEG-IFNα-2a (group C) or biweekly therapy (group D). Patients who showed HCV RNA at week 12 but were negative at week 24 were randomly assigned to receive PEG-IFNα-2a/RBV (group E) or PEG-IFNα-2a/RBV/fluvastatin (group F). Results Overall, the rate of sustained virological response (SVR) was 46 % (70/153). The total SVR rate in the group (A, D, and F) of response-guided therapy was significantly higher than that in the group (B, C, and E) of conventional therapy [70 % (38/54) versus 52 % (32/61), p = 0.049]. Although IL28-B polymorphism and Core 70 mutation were significantly associated with efficacy, patients with rapid virological response (RVR) and complete early virological response (cEVR) achieved high SVR rates regardless of their status of IL-28B polymorphism and Core 70 mutation. Conclusion In addition to knowing the IL-28B polymorphism and Core 70 mutation status, understanding the likelihood of virological response during treatment is critical in determining the appropriate treatment strategy.
    Full-text · Article · Mar 2013
    • Previous studies have demonstrated that baseline viral load, viral core gene substitutions and early viral kinetics are independent predictors of SVR [15,33]. HCV-1 patients with an RVR and low baseline viral load could receive a shorter duration of therapy without compromising the SVR rates, whereas those with slow responses to therapy should receive an extended duration of therapy [6,7,16,34]. The recent genome-wide association studies (GWAS) showed that favourable IL28B SNP genotypes (rs8099917 TT or rs12979860 CC) are highly associated with SVR in HCV-1 patients with 48 weeks of therapy.
    [Show abstract] [Hide abstract] ABSTRACT: Pegylated interferon and ribavirin for 72 weeks improve sustained virological response (SVR) in HCV genotype 1 (HCV-1) slow viral responders. Whether interleukin 28B (IL28B) single nucleotide polymorphism (SNP) genotypes and on-treatment viral responses can identify non-rapid virological response (RVR) patients who benefit from 48 or 72 weeks of therapy remains unclear. Treatment-naive HCV-1 patients who failed to achieve RVR were randomly assigned to receive 48 (n=168) or 72 (n=167) weeks of therapy. Baseline factors and on-treatment virological responses at weeks 8 and 12 were evaluated for SVR in 289 compliant patients who received ≥80% of drug dosages and treatment duration, and had end of follow-up viral response. The stratified SVR rates for independent factors were compared by treatment duration. Treatment duration, IL28B rs8099917 genotypes, cirrhosis, week-8 viral response (undetectable HCV RNA at treatment week 8) and complete early virological response (cEVR) predicted SVR. In week-8 viral response patients, the SVR rates of 72-week and 48-week treatment were similar (75-88%), regardless of IL28B SNP genotypes or cirrhosis. In non-week-8 viral response patients who achieved cEVR, the SVR rate of 72-week treatment was higher than that of 48-week treatment for non-cirrhotic patients, regardless of IL28B SNP genotypes (91-100% versus 13-44%; P=0.001). Although IL28B SNP genotypes predict SVR, they play a minor role when on-treatment viral responses are taken into consideration. On-treatment viral responses at weeks 8 and 12 are the key determinants to decide the optimal treatment duration in HCV-1 patients without RVR.
    Full-text · Article · Aug 2012
    • Pegylated interferon-alpha (Peg- IFN-a) plus ribavirin constitutes the most effective therapy for chronic hepatitis C [3], but several host and viral factors influence the treatment outcome [4,5]. Approximately 50% of patients with HCV genotype 1 achieve a sustained viral response [6]. Recently, single nucleotide polymorphisms (SNP) in the IL28B gene which influence the HCV infection treatment responsiveness and the HCV clearance have been identified [7,8] .
    [Show abstract] [Hide abstract] ABSTRACT: The advent of new chronic hepatitis C virus (HCV) therapies requires characterization of patients in order to predict adequate treatment. A good candidate marker is Programmed Cell Death-1 (PD-1) which is involved in progression of HCV infection. The aim of this study was to analyse the effect of several single nucleotide polymorphisms of PD-1 gene and several previously associated factors (IL28B and KIR receptors) on treatment responses. 407 HCV chronic infected patients treated with PEG-IFN-α and ribavirin were recruited and classified according to their response to treatment. They were genotyped for PD-1 and IL28B polymorphisms, killer immunoglobulin-like receptors (KIR) and HLA genes. A multivariate logistic regression analysis and a Chi-squared Automatic Interaction Detector (CHAID) prediction model of response included these and other clinical parameters. Our results showed that PD-1.3/A allele was significantly associated with sustained virological response (SVR) in a multivariate logistic regression analysis (p<0.01, OR=2.57). Additionally, IL28B C/C genotype was the most significant predictor of an SVR to treatment in all HCV genotypes (74.5%). In IL28B C/C patients, the presence of PD-1.3/A allele increased the probability of an SVR to 93.3%. Moreover, when this analysis was made only with patients infected by HCV-1, the predictive value of IL28B C/C genotype with PD-1.3/A allele was 90%. PD-1.3/A allele is associated with SVR to treatment and notably increases the predictive value of IL28B C/C genotype. Both markers in conjunction could be a useful tool, more relevant than HCV genotype in some cases, in clinical practice.
    Full-text · Article · Feb 2012
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February 2009 · Liver international: official journal of the International Association for the Study of the Liver · Impact Factor: 4.85
Most infections with hepatitis C virus (HCV) fail to resolve spontaneously and progress to chronic hepatitis C. Genotype 1 HCV accounts for most hepatitis C infections in North America, Western Europe, and Japan. Patients infected with HCV genotype 1 are the most resistant to treatment, which results in poor treatment outcomes. Although sustained virologic response (SVR) rates have... [Show full abstract]
January 2011 · Pharmazie in unserer Zeit
Zahlreiche direkt antiviral wirksame Medikamente befinden sich derzeit in präklinischer und klinischer Entwicklung zur Behandlung der chronischen Hepatitis C. Obwohl wegen des hohen Risikos der viralen Resistenzentwicklung eine Monotherapie mit diesen Substanzen nicht möglich sein wird, belegen große Phase-II-Studien dass mit den Protease-Inhibitoren Telaprevir (PROVE-1- und PROVE-2-Studie)... [Show full abstract]
March 2010 · Journal of Hepatology · Impact Factor: 11.34
Assessing hepatitis C virus (HCV)-RNA levels is integral to response-guided therapy. Rules for early discontinuation and determination of treatment duration were mainly established with HCV-RNA assays with a detection limit of 50IU/ml (COBAS Amplicor HCV [CA]). The currently used real-time PCR-based COBAS Ampliprep/COBAS-TaqMan HCV (CAP-CTM) test has a detection limit of approximately 10IU/ml.... [Show full abstract]
November 2010 · European journal of gastroenterology & hepatology · Impact Factor: 2.25
Chronic hepatitis C alters the host's lipid metabolism and hepatitis C virus (HCV) eradication may be followed by an increase of serum cholesterol to adverse levels. We therefore aimed to determine the impact of chronic hepatitis C and its treatment on circulating lipids in a large European cohort of HCV genotype 1 patients. The serum lipid profile of 575 HCV genotype 1-infected patients was... [Show full abstract]
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