Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders

Lok, Anna S.; Gardiner, David F.; Hézode, Christophe; Lawitz, Eric; Bourlière, Marc; Everson, Gregory T.; Marcellin, Patrick; Rodrı́guez-Torres, Maribel; Pol, Stanislas; Serfaty, Lawrence; Eley, Timothy; Huang, Shenlin; Li, Jianling; Wind‐Rotolo, Megan; Yu, Fei; McPhee, Fiona; Grasela, Dennis M.; Pasquinelli, Claudio

doi:10.1016/j.jhep.2013.10.019

Cited by 131 publications

(115 citation statements)

References 24 publications

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“…This finding may explain the low rates of virologic breakthrough seen in the phase 3 clinical trials of ABT-450/r, ombitasvir, and dasabuvir with or without RBV, since similarly constructed drug regimens that did not use pharmacokinetic enhancement have been associated with high rates of virologic breakthrough (51,52). In addition, the lower dosing of ABT-450, facilitated by the boosting effect of ritonavir, may correlate with the low rates of treatment discontinuation and good tolerability seen in these large clinical trials (19)(20)(21)(22)(23).…”

Section: Resultsmentioning

confidence: 99%

In Vitro and In Vivo Antiviral Activity and Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450

Pilot‐Matias

Tripathi

Cohen

et al. 2015

Antimicrob Agents Chemother

110

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bThe development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219-and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log 10 was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11-602 is registered at ClinicalTrials.gov under registration no. NCT01074008.) H epatitis C virus (HCV) infection is a global health problem, with 160 to 180 million individuals infected worldwide (1, 2). Chronic HCV infection can lead to serious liver disease, including cirrhosis, liver failure, and hepatocellular carcinoma. There are 7 major HCV genotypes, which differ in their geographic distribution, disease progression, and response to therapy (3). In the United States, Europe, and Japan, genotype 1 is the most prevalent genotype, and globally it accounts for approximately 60% of HCV infections (4).Therapy for those infected with HCV genotype 1 improved with the approval of the NS3/4A protease inhibitors (PIs) telaprevir, boceprevir, and, more recently, simeprevir (5-10). Although the addition of a PI to pegylated interferon (pegIFN) and ribavirin (RBV) therapy significantly improved sustained virologic response (SVR) rates compared to those with pegIFN/RBV therapy alone, IFN-based therapies are associated with treatment-limiting toxicities (11). In addition, there are many patients who are ineligible for IFN-based treatment due to comorbidities such as depression (12). Early clinical trials with these PIs also demonstrated that drug resistance developed within days after initiation of treatment (13-15). The rapid selection of resistant variants is facilitated by a high rate of virus production and the infidelity of the HCV RNA polymerase (16). Thus, there is a need for effective treatme...

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Section: Resultsmentioning

confidence: 99%

In Vitro and In Vivo Antiviral Activity and Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450

Pilot‐Matias

Tripathi

Cohen

et al. 2015

Antimicrob Agents Chemother

110

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“…Eleven (11%) samples were misclassified. Given the influence of the HCV-1-subtype in the anti-HCV therapy response, an alternative classification method is warranted.T he effect of the hepatitis C virus (HCV) genotype 1 subtype on the response to treatment can be dramatic for some direct antiviral agent (DAA)-containing regimens (1)(2)(3)(4)(5)(6)(7)(8)(9). This is the case for simeprevir, a DAA recently approved for clinical use, that in combination with pegylated interferon and ribavirin (peg-IFN/ RBV) has a lower sustained virological response (SVR) rate for subtype 1a than for 1b (2).…”

mentioning

confidence: 99%

“…Similarly, daclatasvir plus peg-IFN/RBV treatment also achieves higher SVR rates among HCV1b-infected patients than among HCV-1a-infected individuals (4). For interferon-free regimens, DAA combinations such as asunaprevir plus daclatasvir may only be indicated for subtype 1b, because of high relapse rates observed among patients with subtype 1a (3,4). Because of these, accurate subtyping of HCV genotype 1-infected patients is needed for those who are candidates for DAAs.…”

mentioning

confidence: 99%

Reassessment of Genotype 1 Hepatitis C Virus Subtype Misclassification by LiPA 2.0: Implications for Direct-Acting Antiviral Treatment

et al. 2014

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The accuracy of LiPA 2.0 for hepatitis C virus 1 (HCV-1) subtype classification was analyzed. LiPA 2.0 genotype results from 101 HCV-1-infected patients were compared to genotype findings determined by direct core sequencing. Eleven (11%) samples were misclassified. Given the influence of the HCV-1-subtype in the anti-HCV therapy response, an alternative classification method is warranted.T he effect of the hepatitis C virus (HCV) genotype 1 subtype on the response to treatment can be dramatic for some direct antiviral agent (DAA)-containing regimens (1)(2)(3)(4)(5)(6)(7)(8)(9). This is the case for simeprevir, a DAA recently approved for clinical use, that in combination with pegylated interferon and ribavirin (peg-IFN/ RBV) has a lower sustained virological response (SVR) rate for subtype 1a than for 1b (2). Simeprevir plus peg-IFN/RBV treatment achieves rates of SVR similar to those for peg-IFN/RBV treatment in HCV-1a-infected patients who present the viral variation Q80K. This variation is frequent in the HCV-1a subtype, but it is not found in HCV-1b (2, 5). Similarly, daclatasvir plus peg-IFN/RBV treatment also achieves higher SVR rates among HCV1b-infected patients than among HCV-1a-infected individuals (4). For interferon-free regimens, DAA combinations such as asunaprevir plus daclatasvir may only be indicated for subtype 1b, because of high relapse rates observed among patients with subtype 1a (3, 4). Because of these, accurate subtyping of HCV genotype 1-infected patients is needed for those who are candidates for DAAs.Sequencing of specific HCV genome regions with subsequent phylogenetic analysis is considered the gold standard of HCV genotyping (10). However, it includes several complex techniques and is time consuming. For these reasons, LiPA 2.0 is currently one of the most widely used genotyping assays. However, several studies have reported HCV genotyping errors using this commercial method (11-13). Those studies were not designed to evaluate the frequency of HCV-1 subtyping misclassifications, and they included few HCV-1-infected patients. Therefore, due to the high prevalence of HCV-1 infections in western countries and the importance of correct subtyping in clinical decisions, the accuracy of this method for HCV-1 subtyping needs to be evaluated in larger samples. For these reasons, we aimed to evaluate the accuracy of LiPA 2.0 for classifying HCV-1 by subtypes.This study was performed according to the ethical guidelines of the 1975 Declaration of Helsinki, and it was approved by the ethics committee of the Hospital Universitario de Valme (Seville, Spain).The first 110 consecutive patients starting from October 2001, who received a course of peg-IFN/RBV treatment in our hospital and who were infected with HCV-1, according to the LiPA 2.0 determination, were selected. All of them were Caucasian with a median age (quartile 1 to quartile 3) of 42 years (range, 39 to 46 years). Among the patients, 82 (81%) were male, and 48 (47.5%) were infected with HIV.To determine the HCV-1 subtype, we analyzed...

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“…In HCV-monoinfected patients ASV was studied in a randomized, open-label, 24-wk-treatment study [69] where all 101 patients enrolled received DCV (60 mg) once daily and ASV as follows: 38 with genotype 1b also received ASV (200 mg) twice (DUAL A1) or once daily (DUAL A2), 36 with genotype 1a and 5 with genotype 1b also received ASV twice (QUAD B1) or once daily (QUAD B2) plus Peg-IFN/RBV and 18 patients with genotype 1a and 4 with genotype 1b also received ASV twice daily plus RBV (TRIPLE B3). An SVR12 was obtained in 78% of patients in DUAL A1, 65% in DUAL A2, 95% in QUAD B1, and 95% in QUAD B2.…”

Section: Studies On Hiv/hcv Coinfected Patientsmentioning

confidence: 99%

Treatment of chronic hepatitis C in patients with HIV/HCV coinfection

Coppola

Martini

Pisaturo

et al. 2015

WJV

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frequent causes of comorbidity and mortality in the human immunodeficiency virus (HIV) population, and liver-related mortality is now the second highest cause of death in HIV-positive patients, so HCV infection should be countered with adequate antiviral therapy. In 2011 began the era of directly acting antivirals (DAAs) and the HCV NS3/4A protease inhibitors telaprevir and boceprevir were approved to treat HCV-genotype-1 infection, each one in combination with pegylated interferon alfa (Peg-IFN) + ribavirin (RBV). The addition of the first generation DAAs, strongly improved the efficacy of antiviral therapy in patients with HCVgenotype 1, both for the HCV-monoinfected and HIV/ HCV coinfected, and the poor response to Peg-IFN + RBV in HCV/HIV coinfection was enhanced. These treatments showed higher rates of sustained virological response than Peg-IFN + RBV but reduced tolerability and adherence due to the high pill burden and the several pharmacokinetic interactions between HCV NS3/ 4A protease inhibitors and antiretroviral drugs. Then in 2013 a new wave of DAAs arrived, characterized by high efficacy, good tolerability, a low pill burden and shortened treatment duration. The second and third generation DAAs also comprised IFN-free regimens, which in small recent trials on HIV-positive patients have shown comforting preliminary results in terms of efficacy, tolerability and adherence.

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Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders

Cited by 131 publications

References 24 publications

In Vitro and In Vivo Antiviral Activity and Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450

In Vitro and In Vivo Antiviral Activity and Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450

Reassessment of Genotype 1 Hepatitis C Virus Subtype Misclassification by LiPA 2.0: Implications for Direct-Acting Antiviral Treatment

Treatment of chronic hepatitis C in patients with HIV/HCV coinfection

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