10 Peginterferon Lambda-1a (Lambda) Compared to Peginterferon Alfa-2a (Alfa) in Treatment-Naive Patients With HCV Genotypes (G) 2 or 3: First Svr24 Results From Emerge Phase Iib

Zeuzem, Stefan; Arora, S.; Bacon, B.; Box, Terry; Charlton, Michael; Diago, M.; Dieterich, Doug; Mur, R. Esteban; Everson, G.; Fallon, Michael J.; Ferenci, Péter; Flisiak, Robert; George, Joseph; Ghalib, R.; Gitlin, Norman; Gładysz, Andrzej; Gordon, S.; Greenbloom, Susan; Hassanein, Tarek; Jacobson, Ira M.; Jeffers, Lennox J.; Kowdley, Kris V.; Läwitz, E.; Lee, S.S.; Leggett, B.; Lueth, Stefan; Nelson, Donald E.; Pockros, P.; Rodrı́guez-Torres, Maribel; Rustgi, Vinod K.; Serfaty, Lawrence; Sherman, Morris; Shiffman, M.; Solà, R.; Sulkowski, Mark S.; Vargas, Hugo E.; Vierling, John M.; Yoffe, Boris; Ishak, Laura; Fontana, David; Xu, Dao-zhen; Gray, Travis; Horga, A; Hillson, Jan; Lopez-Talavera, J.C.; Muir, Andrew J.

doi:10.1016/s0168-8278(12)60024-5

Cited by 13 publications

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“…The pegylated interferon‐λ arm had a higher SVR than the pegylated interferon‐α arm, especially in genotype 3 patients (57.1‐83.3% versus 40%). However, the numbers included were low and patients with cirrhosis were virtually excluded since only 2/118 patients had cirrhosis at baseline . Given its better safety profile, pegylated interferon‐λ holds promise in the treatment of genotype 3 patients.…”

Section: Hcv Genotype 3 and Response To Antiviral Therapymentioning

confidence: 99%

“…However, the numbers included were low and patients with cirrhosis were virtually excluded since only 2/118 patients had cirrhosis at baseline. 74 Given its better safety profile, pegylated interferon-k holds promise in the treatment of genotype 3 patients. However, further studies are needed to confirm its efficacy and safety in this population.…”

Section: Response To Host-targeting Antivirals and Pegylated Interfermentioning

confidence: 99%

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Is genotype 3 of the hepatitis C virus the new villain?

2014

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Genotype 3 of the hepatitis C virus (HCV) has been long considered an easy-to-treat infection, with higher cure rates ( 70%) than other viral genotypes with the standard combination of pegylated interferon-a and ribavirin. However, the relative insensitivity of this genotype to most protease inhibitors and the recent unexpected data on decreased effectiveness of sofosbuvir have raised questions on how to achieve universal cure, a goal that seems reasonable for other genotypes. In addition, increasing clinical and experimental data show that HCV genotype 3 may be associated not only with severe steatosis, but also with accelerated fibrosis progression rate and increased oncogenesis. Conclusion: Currently available data suggest that we should increase our efforts to understand the virology and pathogenesis of HCV genotype 3, aiming at better and more potent, genotype-targeted treatments. (HEPATOLOGY 2014;59:2403-2412 A pproximately 185 million people are infected worldwide with the hepatitis C virus (HCV). 1 HCV is a major human pathogen causing progressive liver damage, culminating in cirrhosis and hepatocellular carcinoma (HCC), and various extrahepatic complications, ranging from type 2 diabetes to cardiovascular disorders. 2 HCV has a positive singlestranded RNA genome, characterized by a high heterogeneity, leading to classification of HCV isolates in at least seven genotypes and several subtypes. 3,4 Genotype 1 is the most prevalent genotype worldwide, accounting for 60% of the global infections, with a higher proportion of subtype 1b in Europe and 1a in the USA. Genotype 2 is found in the Mediterranean region and in some parts of Africa and the Americas. Genotype 3 is highly prevalent in the European population of intravenous drug users, and in a large proportion of patients-irrespective of risk factor-in Southern Asia. Overall, it is estimated that about 10-15% of the world HCV reservoir is accounted for by genotype 3. 5 Genotype 4 is the most prevalent type in the Middle East and in sub-Saharan Africa, and has spread to a significant proportion of infected persons across Europe, especially in drug users. Genotypes 5 and 6 are rare and concentrated in isolated clusters in France, Belgium, Syria, and Southern Africa. 6 The novel genotype 7 was identified in rare patients from Canada and Belgium, possibly infected in Central Africa. 4 The identification of HCV genotypes and subtypes is of obvious epidemiological interest. In addition, genotyping is critical to select the type and duration of antiviral therapy, due to a different response to antiviral therapy. Thus, genotype 1 has been considered, until now, the most difficult to treat genotype, with sustained virological response (SVR) rates of 50% with a dual therapy based on the combination of pegylated interferon-a and ribavirin, 7-9 only recently increasing to 70% with the addition of a protease inhibitor. 10,11 Dual therapy reaches higher SVR rates in genotypes 2 and 3 ( 70-80%) and intermediate rates in patients with genotype 4. Finally, some viral gen...

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Section: Hcv Genotype 3 and Response To Antiviral Therapymentioning

confidence: 99%

Section: Response To Host-targeting Antivirals and Pegylated Interfermentioning

confidence: 99%

Is genotype 3 of the hepatitis C virus the new villain?

2014

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“…Results from the phase 2 EMERGE trial investigating lambda as a new therapeutic agent against chronic infection with HCV isolates representing GT1 to GT4 were recently reported (14). Compared with a standard form of alfa-RBV, a lambda-based regimen showed similar to slightly better SVR 24 rates in patients infected with GT2 or GT3 but, more importantly, was associated with significantly fewer IFN-related adverse events.…”

Section: Discussionmentioning

confidence: 99%

“…These observations suggest that systemic administration of IFN-1 may be associated with fewer side effects than alfa-based treatments. Indeed, proof-of-concept clinical studies with lambda indicated minimal adverse events and hematologic effects, while demonstrating promising antiviral activity in patients with chronic HCV GT2 or GT3 infection (14). Moreover, a series of genome-wide association studies (GWASs) independently reported a strong association between common host genetic polymorphisms in the region of the locus for the IL28B gene (which encodes IFN-3), spontaneous viral clearance, and a more favorable outcome to alfa-based treatments in chronic HCV subjects (15,16).…”

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confidence: 99%

Combinations of Lambda Interferon with Direct-Acting Antiviral Agents Are Highly Efficient in Suppressing Hepatitis C Virus Replication

Friborg

Levine

Chen

et al. 2013

Antimicrob Agents Chemother

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The clinical efficacy of a pegylated form of human lambda 1 interferon (IFN-1; also referred to herein as lambda) has been demonstrated in patients chronically infected with hepatitis C virus (HCV) representing genotypes 1 through 4. In these proof-ofconcept studies, lambda showed an improved safety profile compared to the pegylated form of alfa interferon (referred to herein as alfa). In the study described in this report, an assessment of the in vitro antiviral activity of type III IFNs toward different HCV replicons revealed that the unpegylated recombinant form of IFN-1 (rIFN-1) exerted the most robust effect, while rIFN-3 exhibited greater activity than rIFN-2. More importantly, cross-resistance to rIFN-1 was not observed in replicon cell lines known to have reduced susceptibility to investigational direct-acting antiviral (DAA) agents targeting the essential HCV nonstructural protein NS3, NS5A, or NS5B. When combined with either rIFN-␣, the NS3 protease inhibitor (NS3 PI) asunaprevir (ASV), the NS5A replication complex inhibitor (NS5A RCI) daclatasvir (DCV), or the NS5B polymerase site I inhibitor (NS5B I) BMS-791325, rIFN-1 displayed a mixture of additive and synergistic effects. In three-drug combination studies, inclusion of lambda with ASV and DCV also yielded additive to synergistic effects. In line with these observations, it was demonstrated that a regimen that used a combination of rIFN-1 with one or two DAAs was superior to an IFN-free regimen in clearing HCV RNA in genotype 1a cell lines representing wild-type and NS3 protease inhibitor-resistant sequences. Overall, these data support further clinical development of lambda as part of alternative combination treatments with DAAs for patients chronically infected with HCV.

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“…Thus, quadruple regimens present another paradox in that a quadruple regimen could be required for difficult-to-treat patients with cirrhosis but will carry a greater risk. There is the possibility that PEG-IFNs with fewer haematological side effects (eg, PEG-IFNλ) could be useful in this context, but this too requires proof 46 47. This fact, and perhaps the unwelcome need for quadruple PEG-IFN regimens, may mean that PEG-IFN has a long goodbye.…”

Section: What About Ifn-sparing Regimens?mentioning

confidence: 99%