In this randomized, controlled trial involving patients with chronic infection with hepatitis C virus (HCV) genotype 1, the addition of the HCV-specific protease inhibitor telaprevir to therapy with ...peginterferon and ribavirin improved the rate of sustained virologic response. Patients treated with telaprevir were more likely than those treated with peginterferon and ribavirin alone to stop treatment because of adverse events, and severe rash was the most common reason for discontinuation.
In patients with hepatitis C virus (HCV) genotype 1, the addition of the HCV-specific protease inhibitor telaprevir to therapy with peginterferon and ribavirin improved the rate of sustained virologic response. However, patients treated with telaprevir were more likely to stop treatment because of adverse events.
Worldwide, an estimated 180 million people have a chronic infection with hepatitis C virus (HCV).
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Hepatitis C is a leading cause of cirrhosis and hepatocellular carcinoma and is the leading indication for liver transplantation in the United States.
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The current treatment for HCV infection is peginterferon alfa combined with ribavirin and administered for 24 weeks (for HCV genotype 2 or 3) or 48 weeks (for HCV genotype 1, the most prevalent genotype in Europe and North America).
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The aim of HCV therapy is a sustained virologic response, defined as an undetectable serum HCV RNA level 24 weeks after cessation . . .
Summary Background Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. ...We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin. Methods In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1·5 μg/kg plus ribavirin 800–1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400–1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00423670. Findings Patients in all four boceprevir groups had higher rates of SVR than did the control group (58/107 54%, 95% CI 44–64, p=0·013 for PRB28; 58/103 56%, 44–66, p=0·005 for PR4/PRB24; 69/103 67%, 57–76, p<0·0001 for PRB48; and 77/103 75%, 65–83, p<0·0001 for PR4/PRB44; vs 39/104 38%, 28–48 for PR48 control). Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 27%), and a rate of relapse (six of 27 22%) similar to control (12/51 24%). Boceprevir-based groups had higher rates of anaemia (227/416 55% vs 35/104 34%) and dysgeusia (111/416 27% vs nine of 104 9%) than did the control group. Interpretation In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone. Funding Merck.
BackgroundCXCR3-associated chemokines CXCL9–CXCL11 promote histologic progression in chronic hepatitis C virus (HCV) infection, as indicated by elevated intrahepatic levels of messenger RNA in ...patients with advanced inflammation and fibrosis. We evaluated the potential of peripheral chemokine levels to discriminate among patients with chronic HCV infection who had different stages of fibrosis MethodsPeripheral levels of CXCR3-associated chemokines were measured by enzyme-linked immunosorbent assay of plasma samples obtained from 93 patients with chronic HCV infection. Of the subjects, 79 (85%) were white, and 68 (73%) were infected with HCV genotype 1 ResultsExpression of all 3 chemokines, when analyzed as a group, was significantly associated with intrahepatic inflammation and fibrosis. Plasma levels of CXCL10 were significantly elevated in patients with advanced fibrosis, whereas CXCL9 levels were significantly elevated in patients with advanced inflammation. By proportional odds multivariate modeling, we observed an association between fibrosis and CXCL10 (P<.002) as well as between fibrosis and inflammation (P<.001). Of the individual parameters, the CXCL10 level was most useful in identifying patients with more-severe (stage 3–4) fibrosis. Discriminatory ability was improved by the combination of CXCL10 and CXCL9 ConclusionsThe strong association between CXCR3-associated chemokines and fibrosis suggests that they may have promise as noninvasive markers of hepatic fibrosis in a predominantly white HCV genotype 1–infected population
In patients with genotype 1 chronic hepatitis C infection, telaprevir (TVR) in combination with peginterferon and ribavirin (PR) significantly increased sustained virologic response (SVR) rates ...compared with PR alone. However, genotypic changes could be observed in TVR-treated patients who did not achieve an SVR.
Population sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment.
Resistant variants were observed after treatment with a telaprevir-based regimen in 12% of treatment-naïve patients (ADVANCE; T12PR arm), 6% of prior relapsers, 24% of prior partial responders, and 51% of prior null responder patients (REALIZE, T12PR48 arms). NS3 protease variants V36M, R155K, and V36M+R155K emerged frequently in patients with genotype 1a and V36A, T54A, and A156S/T in patients with genotype 1b. Lower-level resistance to telaprevir was conferred by V36A/M, T54A/S, R155K/T, and A156S variants; and higher-level resistance to telaprevir was conferred by A156T and V36M+R155K variants. Virologic failure during telaprevir treatment was more common in patients with genotype 1a and in prior PR nonresponder patients and was associated with higher-level telaprevir-resistant variants. Relapse was usually associated with wild-type or lower-level resistant variants. After treatment, viral populations were wild-type with a median time of 10 months for genotype 1a and 3 weeks for genotype 1b patients.
A consistent, subtype-dependent resistance profile was observed in patients who did not achieve an SVR with telaprevir-based treatment. The primary role of TVR is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The complementary role of PR is to clear any remaining telaprevir-resistant variants, especially higher-level telaprevir-resistant variants. Resistant variants are detectable in most patients who fail to achieve SVR, but their levels decline over time after treatment.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination ...with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. Methods For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800 000 IU/mL vs ≥800 000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov , number NCT01329978. Results We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77–96) in cohort A, 97 patients (89%, 82–94) in cohort B, and by 135 (87%, 81–92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug—anaemia and neutropenia—were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. Interpretation Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. Funding Gilead Sciences.
Summary Background Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their ...use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1–3 HCV infection. Methods In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1–3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18–70 years, had an HCV RNA concentration of 50 000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 μg per week) and ribavirin (1000–1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov , number NCT01188772. Findings In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events—fatigue, headache, nausea, and chills—were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77–97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80–98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37–77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12. Interpretation Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1. Funding Gilead Sciences.
Chronic HBV infection is an important public health problem worldwide and in the United States. A treatment algorithm for the management of this disease, published previously by a panel of U.S. ...hepatologists, has been revised on the basis of new developments in the understanding of the disorder, the availability of more sensitive molecular diagnostic tests, and the licensure of new therapies. In addition, a better understanding of the advantages and disadvantages of new treatments has led to the development of strategies for reducing the rate of resistance associated with oral agents and optimizing treatment outcomes. This updated algorithm was based primarily on available evidence by using a systematic review of the literature. Where data were lacking, the panel relied on clinical experience and consensus expert opinion. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to low or undetectable levels. Assays can now detect serum HBV DNA at levels as low as 10 IU/mL and should be used to establish a baseline level, monitor response to antiviral therapy, and survey for the development of drug resistance. Interferon alfa-2b, lamivudine, adefovir, entecavir, peginterferon alfa-2a, telbivudine, and tenofovir are approved as initial therapy for chronic hepatitis B and have certain advantages and disadvantages. Although all of these agents can be used in selected patients, the preferred first-line treatment choices are entecavir, peginterferon alfa-2a, and tenofovir. Issues for consideration for therapy include efficacy, safety, rate of resistance, method of administration, and cost.
In this trial in patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon and ribavirin, retreatment with three new oral antiviral agents and ...ribavirin resulted in a sustained virologic response in 96% of patients.
Patients with chronic hepatitis C virus (HCV) infection are at risk for progressive liver fibrosis, cirrhosis, portal hypertension, hepatocellular carcinoma, and decompensated liver disease. HCV infection can be cured with antiviral therapy, reducing the risk of illness and death associated with end-stage liver disease.
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For more than a decade, patients with HCV genotype 1 infection have been treated with peginterferon–ribavirin dual therapy, resulting in rates of sustained virologic response of approximately 40 to 50%.
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Response rates among previously untreated patients have been shown to increase to 68 to 75% with peginterferon–ribavirin plus a protease inhibitor (telaprevir or boceprevir, . . .
In this study, once-daily treatment with oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients with genotype 1, 2, or 3 HCV infection, ...including those in whom previous therapy with telaprevir or boceprevir had failed.
Chronic infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide and is a major cause of cirrhosis and hepatocellular carcinoma.
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HCV-related morbidity and mortality are increasing; since 2007, HCV-related deaths in the United States have exceeded those from human immunodeficiency virus (HIV) infection.
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HCV is classified into six major genotypes.
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Genotypes 1, 2, and 3 are found worldwide, with subtype 1a predominating in the United States and subtype 1b predominating in Europe, Japan, and China.
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Peginterferon alfa–ribavirin treatment for chronic HCV infection is associated with a sustained virologic response (undetectable HCV RNA . . .
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