1421 High Sustained Virologic Response Rate in Treatment-Naive HCV Genotype 1a and 1b Patients Treated for 12 Weeks With an Interferon-Free All-Oral Quad Regimen: Interim Results

Sulkowski, Mark S.; Rodrı́guez-Torres, Maribel; Läwitz, E.; Shiffman, M.; Pol, S.; Herring, Robert; McHutchison, John G.; Pang, Phil; Brainard, D.; Wyles, D.; Habersetzer, F.

doi:10.1016/s0168-8278(12)61432-9

Cited by 33 publications

(29 citation statements)

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“…25 Similar results were observed with other interferon-free regimens, indicating that genotype 1a may be more difficult to treat than genotype 1b. 26,27 The observation that the IL28B polymorphism (rs12879860) affected the rate of a sustained virologic response 12 weeks after the completion of therapy suggests that innate immunity may still be important in interferon-free regimens. However, the effect of the IL28B genotype is unclear in other interferon-free regimens.…”

Section: Discussionmentioning

confidence: 99%

“…The (23) 19 (24) 17 (22) 17 (22) 10 (22) Jaundice § 23 (28) 16 (20) 12 (16) 14 (18) 2 (4) Pruritus 14 (17) 21 (26) 29 (38) 21 (27) 13 (28) Rash ¶ 18 (22) 12 (15) 25 (32) 17 (22) 9 (20) Photosensitivity reaction‖ 22 (27) 22 (28) 19 (25) 23 (29) 15 (33) Dry skin 11 (14) 10 (12) 11 (14) 17 (22) 6 (13) Asthenia** 18 (22) 18 (22) 9 (12) 12 (15) 7 (15) Fatigue 16 (20) 13 (16) 13 (17) 18 (23) 5 (11) Moderate adverse event † † 27 (33) 32 (40) 34 (44) 28 (36) 18 (39) Nausea ‡ 2 (2) 10 (12) 5 (6) 6 (8) 2 (4) Vomiting 4 (5) 10 (12) 3 (4) 3 (4) 2 (4) Asthenia** 6 (7) 10 (12) 15 (19) …”

Section: The New Englandunclassified

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Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Zeuzem¹,

Soriano²,

Asselah³

et al. 2013

N Engl J Med

211

173

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BACKGROUND: Interferon-free regimens would be a major advance in the treatment of patients with chronic hepatitis C virus (HCV) infection. METHODS: In this phase 2b, randomized, openlabel trial of faldaprevir (a protease inhibitor) and deleobuvir (a nonnucleoside polymerase inhibitor), we randomly assigned 362 previously untreated patients with HCV genotype 1 infection to one of five groups: faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, plus ribavirin, for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); or faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). The primary end point was a sustained virologic response 12 weeks after the completion of therapy. RESULTS: The primary end point was met in 59% of patients in the TID16W group, 59% of patients in the TID28W group, 52% of patients in the TID40W group, 69% of patients in the BID28W group, and 39% of patients in the TID28W-NR group. The sustained virologic response 12 weeks after the completion of therapy did not differ significantly according to treatment duration or dosage among ribavirin-containing regimens. This response was significantly higher with TID28W than with TID28W-NR (P=0.03). Rates of a sustained virologic response 12 weeks after the completion of therapy were 56 to 85% among patients with genotype 1b infection versus 11 to 47% among patients with genotype 1a infection and 58 to 84% among patients with IL28B CC versus 33 to 64% with non-CC genotypes. Rash, photosensitivity, nausea, vomiting, and diarrhea were the most common adverse events. CONCLUSIONS: The rate of a sustained virologic response 12 weeks after the completion of therapy was 52 to 69% among patients who received interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin. (Funded by Boehringer Ingelheim; SOUND-C2 ClinicalTrials.gov number, NCT01132313.).

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Section: Discussionmentioning

confidence: 99%

Section: The New Englandunclassified

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Zeuzem¹,

Soriano²,

Asselah³

et al. 2013

N Engl J Med

211

173

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“…This regimen was well tolerated and its antiviral efficacy is closely related to the dose of DAAs and IL28B genotypes. It was also reported that lower SVR rates in genotype 1a than genotype 1b was achieved [9]. Alisporivir (ALV) is an oral cyclophilin inhibitor that has potent anti-HCV activity, so alisporivir plus ribavirin without interferon treatment is predicted to achieve high SVR in patients with HCV genotype 2 and 3.…”

Section: Future Directions Of Hcv Treatment: Is Ifn-free Treatment Pomentioning

confidence: 99%

Is Interferon-Free Treatment for HCV Possible?

Li¹

2014

J Antivir Antiretrovir

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EditorialHepatitis C virus (HCV) was first discovered in the 1970s as the pathogen to cause non-A non-B hepatitis and HCV infection is the leading cause for liver transplantation and is associated with increased risk of liver fibrosis, cirrhosis and hepatocellular carcinoma [1]. With more than 185 million people having been infected with HCV worldwide, HCV infection remains a huge medical burden in most countries. Due to the limited efficacy and extensive side-effects of the standard combination therapy with pegylated interferon alpha (IFNα) and ribavirin, development of novel antivirals is urgently needed. Much progress has been made in the understanding of the HCV life cycle, including cell surface receptors that mediate virus entry, detailed mechanisms of HCV RNA replication, viral particle assembly and egress. In the meantime, HCV replicon system that allows efficient RNA replication without viral particle production and in vitro cell culture system (HCVcc) were successfully developed [2]. Coupled with the known crystal structures of HCV NS3/4A protease and RNAdependent RNA polymerase (RdRp), these new advances make the development of new direct-acting antivirals (DAAs) for HCV possible [3]. Current Standard of Care (SOC) for the Treatment of HCVAlthough there are numerous DAAs being developed in the preclinical and clinical stages, the current standard of care (SOC) for the treatment of chronic hepatitis C in most developing countries is the combination therapy with pegylated interferon alpha (PEG-IFNα) and ribavirin (RBV) [4]. With this combined treatment, sustained virological response (SVR) is achieved in 40-54% of patients infected with HCV genotype 1 and in 65-82% of patients infected with HCV genotypes 2 and 3 [5]. The efficacy of this IFN-based therapy is influenced by both viral and host factors, such as HCV RNA level at baseline, HCV genotypes, degree of liver fibrosis, and the host polymorphisms of the IL28B gene. Combination therapy with PEG-IFNα and RBV has a relatively low SVR in patients infected with HCV genotype 1 and is poorly tolerated with serious side-effects such as neutropenia, anemia, thrombocytopenia in some patients [6]. As interferon is expensive and daily injection is inconvenient, new therapy without IFN is urgently needed. Development and clinical use of DAAsBetter understanding of the virus life-cycle, especially the solution of HCV protease and polymerase structures makes the development of direct-acting antivirals (DAAs) possible. The earliest two DAAs that were approved in Europe and the United States in 2011were inhibitors of NS3/4A protease: telaprevir and boceprevir. This leads to a new therapy for HCV genotype I-triple therapy (telaprevir or boceprevir in combination with pegIFN and RBV). It has been shown that this triple therapy is more effective than pegIFN and RBV combination regimen with a significant increase of SVR to 75% of patients chronically infected with HCV genotype1 [7]. Different groups of people respond to triple therapy very differently. This therapy fai...

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“…In association with PR, ABT-267 shows promising on-treatment results [Sullivan et al 2012]. GS-5885 (ledipasvir) has been studied either in triple regimen with PR or in quadruple regimen with PI and PR or in an IFN-free regimen with PI, NNI and ribavirin [Marcellin et al 2013;Sulkowski et al 2012d;Thompson et al 2013]. Patients treated with ledipasvir and PR for 24 or 48 weeks according to RVR reach a SVR rate of 60% in naïve GT-1 patients [Marcellin et al 2013].…”

Section: Treatment Of Gt-1 Patients Beyond Boceprevir or Telaprevirmentioning

confidence: 99%

An update on the treatment of genotype-1 chronic hepatitis C infection: lessons from recent clinical trials

Wendt

Bourlière

2013

Therapeutic Advances in Infection

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The launch of first-generation protease inhibitors (PIs) was a major step forward in hepatitis C virus (HCV) treatment. However, this major advance is, up to now, restricted to genotype-1 (GT-1) patients. However, the ongoing development of new direct-acting antiviral agents (DAAs) allows new hope for the future. The development of second-wave and second-generation PIs yields higher antiviral potency through plurigenotypic activity, more convenient daily administration, fewer side effects and, for the second-generation PIs, potential activity against resistance-associated variants. NS5B inhibitors (NS5B.I) include nucleoside/nucleotide inhibitors (NIs) and nonnucleotide inhibitors (NNIs). NIs have high efficacy across all genotypes. Sofosbuvir has highly potent antiviral activity across all genotypes in association with pegylated interferon (IFN) and ribavirin (PR), thus allowing shortened treatment duration. NS5A inhibitors (NS5A.I) have highly potent antiviral activity. It has recently been shown for the first time that NS5A.I in combination with PI can cure GT-1b null-responder patients in an IFN-free regimen. In addition, several studies demonstrate that IFN-free regimens with DAA combinations are able to cure a large number of either naïve or treatment-experienced GT-1 patients. Moreover, a quadruple regimen with PR is able to cure almost all GT-1 null-responders. The development of pan-genotypic DAAs (NIs or NS5A.I) allows new combinations with or without PR that increase the rate of sustained virological response (SVR) for all patients, even for those with cirrhosis and independently of the genotype. Therefore, the near future of HCV treatment looks promising. The purpose of this article is to provide an overview of the clinical results recently reported for HCV treatment in GT-1 patients.

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1421 High Sustained Virologic Response Rate in Treatment-Naive HCV Genotype 1a and 1b Patients Treated for 12 Weeks With an Interferon-Free All-Oral Quad Regimen: Interim Results

Cited by 33 publications

References 0 publications

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Is Interferon-Free Treatment for HCV Possible?

An update on the treatment of genotype-1 chronic hepatitis C infection: lessons from recent clinical trials

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