1356 Quadruple Therapy With BMS-790052, BMS-650032 and Peg-Ifn/RBV for 24 Weeks Results in 100% Svr12 in HCV Genotype 1 Null Responders

Lok, Anna S.; Gardiner, David F.; Lawitz, Eric; Martorell, Claudia; Everson, G.; Ghalib, R.; Reindollar, Robert; Rustgi, V.; McPhee, Fiona; Wind‐Rotolo, Megan; Persson, Anja Bondke; Zhu, Kuang Kuang; Dimitrova, Dessislava I.; Eley, Timothy; Guo, Tao; Grasela, Dennis M.; Pasquinelli, Claudio

doi:10.1016/s0168-8278(11)61358-5

Cited by 62 publications

(40 citation statements)

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“…Although the subtype 1b variants conferred lower-level resistance (a 5-to 28-fold shift in EC 50 ), the variants in subtype 1a conferred higher levels of resistance (233-to 5,367-fold shift in EC 50 ) (7). The reported clinical resistance pattern appears similar to that seen in vitro; patients with viral breakthrough on a dual combination of protease inhibitor asunaprevir and NS5A inhibitor daclatasvir had NS5A Q30E/R, L31M/V, and Y93C/N variants (29). The prevalence of resistant variants in the context of the NS5A inhibitors is highly dependent on subtype due to several of the positions having different baseline amino acids in each subtype (see individual subtype majority amino acid in Table 2).…”

Section: Baselinesupporting

confidence: 57%

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

Bartels

Sullivan

Zhang

et al. 2013

J Virol

135

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The prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3-to 25-fold increased 50% inhibitor concentration [IC 50 ]) to telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC 50 ) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide activesite NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.

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Section: Baselinesupporting

confidence: 57%

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

Bartels

Sullivan

Zhang

et al. 2013

J Virol

135

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“…23 However, only 2 of 9 patients with genotype 1a achieved SVR 24 with the dual DAA regimen, compared with 9 of 10 patients who received both DAAs and Peg-IFN/RBV. These differences suggest that viral genotype can influence responses to DAA regimens that do not include Peg-IFN/RBV, and outcomes can be optimized with individualized therapy that considers viral genotype, among other factors.…”

Section: Discussionmentioning

confidence: 97%

“…[20][21][22] In a 24-week study of null responders in the United States, daclatasvir and asunaprevir demonstrated potent antiviral effects, both as a dual DAA regimen and in a quadruple regimen that included Peg-IFN/RBV. 23 Overall, 36% of dual-therapy recipients achieved SVR, including both of the 2 patients with genotype 1b infection. However, patients with genotype 1a experienced frequent viral breakthrough with the dual regimen and only 2 of 9 achieved SVR, suggesting subtype-associated differences in resistance barrier and response.…”

mentioning

confidence: 93%

Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b–infected null responders

Chayama¹,

Takahashi²,

et al. 2012

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Patients with chronic hepatitis C virus (HCV) infection and previous null response to pegylated interferon (Peg-IFN) and ribavirin (RBV) have limited therapeutic options. HCV genotype 1 is the most common worldwide and the most difficult to treat; genotype 1b is the most common subtype of genotype 1 outside North America. The enhanced antiviral activity achieved by combining two direct-acting antiviral (DAA) agents may improve clinical outcomes. This open-label, phase IIa study included 10 patients with chronic HCV genotype 1b infection and previous null response (<2 log10 reduction in HCV RNA after 12 weeks) to Peg-IFN and RBV. Patients received dual DAA treatment for 24 weeks with the nonstructural protein 5A replication complex inhibitor, daclatasvir (60 mg once-daily), and the nonstructural protein 3 protease inhibitor, asunaprevir (initially 600 mg twice-daily, then subsequently reduced to 200 mg twice-daily). The primary efficacy endpoint was the proportion of patients with sustained virologic response (SVR) at 12 weeks post-treatment (SVR12). Nine patients completed 24 weeks of treatment; 1 patient discontinued treatment after 2 weeks. In the 9 patients who completed the full course of treatment, HCV RNA was undetectable at week 8 and remained undetectable through the end of treatment; all 9 patients achieved SVR12 and SVR24. HCV RNA also remained undetectable post-treatment in the patient who discontinued after 2 weeks. There was no viral breakthrough. Diarrhea and headache, generally mild, were the most common adverse events; transaminase elevations were reported in 3 patients, but did not result in discontinuation. Conclusions : Dual therapy with daclatasvir and asunaprevir, without Peg-IFN and RBV, can achieve high SVR rates in difficult-to-treat patients with HCV genotype 1b infection and previous null response to Peg-IFN and RBV.

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“…Its in vitro potency translated into anti-HCV activity in the clinic. Initial viral RNA declines with high sustained virologic response (SVR) have been achieved for both interferon-ribavirin (IFN-RBV) and IFN-RBV-free regimens in combination therapies (1,(3)(4)(5)(6)(7)(8).In a 14-day multiple-ascending-dose (MAD) monotherapy study, chronically infected patients, treated with DCV at 1, 10, 30, 60, and 100 mg QD (once daily) or 30 mg BID (twice daily) for 14 days (4 subjects per cohort), generally experienced rapid and marked viral load declines (3, 4). Although viral breakthrough (VBT) was observed for both GT-1a-and -1b-infected patients, RNA declined below the level of detection (Ͻ10 IU/ml) in several GT-1b-infected patients, and viral RNA remained detectable in the majority of GT-1a-infected patients (3, 4).…”

mentioning

confidence: 99%

Persistence of Resistant Variants in Hepatitis C Virus-Infected Patients Treated with the NS5A Replication Complex Inhibitor Daclatasvir

Wang

Sun

O’Boyle

et al. 2013

Antimicrob Agents Chemother

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Daclatasvir (DCV; BMS-790052) is a hepatitis C virus (HCV) NS5A replication complex inhibitor (RCI) with picomolar to low nanomolar potency and broad genotypic coverage in vitro. Viral RNA declines have been observed in the clinic for both alpha interferon-ribavirin (IFN-␣-RBV) and IFN-RBV-free regimens that include DCV. Follow-up specimens (up to 6 months) from selected subjects treated with DCV in 14-day monotherapy studies were analyzed for genotype and phenotype. Variants were detected by clonal sequencing in specimens from baseline and were readily detected by population sequencing following viral RNA breakthrough and posttreatment. The major amino acid substitutions generating resistance in vivo were at residues M28, Q30, L31, and Y93 for genotype 1a (GT-1a) and L31 and Y93 for GT-1b, similar to the resistance substitutions observed with the in vitro replicon system. The primary difference in the resistance patterns observed in vitro and in vivo was the increased complexity of linked variant combinations observed in clinical specimens. Changes in the percentage of individual variants were observed during follow-up; however, the overall percentage of variants in the total population persisted up to 6 months. Our results suggest that during the 14-day monotherapy, most wild-type virus was eradicated by DCV. After the end of DCV treatment, viral fitness, rather than DCV resistance, probably determines which viral variants emerge as dominant in populations. D aclatasvir (DCV; BMS-790052) is a hepatitis C virus (HCV)NS5A replication complex inhibitor (RCI) with picomolar to low nanomolar potency and broad genotypic coverage in vitro. In the replicon system, 50% (i.e., half-maximal) effective concentrations (EC 50 s) of DCV are 50 and 9 pM against genotype 1a (GT1a) and GT-1b, respectively (1, 2). Its in vitro potency translated into anti-HCV activity in the clinic. Initial viral RNA declines with high sustained virologic response (SVR) have been achieved for both interferon-ribavirin (IFN-RBV) and IFN-RBV-free regimens in combination therapies (1,(3)(4)(5)(6)(7)(8).In a 14-day multiple-ascending-dose (MAD) monotherapy study, chronically infected patients, treated with DCV at 1, 10, 30, 60, and 100 mg QD (once daily) or 30 mg BID (twice daily) for 14 days (4 subjects per cohort), generally experienced rapid and marked viral load declines (3, 4). Although viral breakthrough (VBT) was observed for both GT-1a-and -1b-infected patients, RNA declined below the level of detection (Ͻ10 IU/ml) in several GT-1b-infected patients, and viral RNA remained detectable in the majority of GT-1a-infected patients (3, 4).Genome variants of HCV NS5A that emerged in viral specimens collected during and after treatment with DCV in vivo (clinical cases) and in vitro (replicons) are similar (1, 2, 4, 9). To date, all amino acid substitutions observed in vitro that are associated with resistance to DCV and its analogs synthesized by us mapped to the N-terminal region of NS5A (1, 2, 9, 10). For GT-1b, the major resistance substitutions ...

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1356 Quadruple Therapy With BMS-790052, BMS-650032 and Peg-Ifn/RBV for 24 Weeks Results in 100% Svr12 in HCV Genotype 1 Null Responders

Cited by 62 publications

References 0 publications

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b–infected null responders

Persistence of Resistant Variants in Hepatitis C Virus-Infected Patients Treated with the NS5A Replication Complex Inhibitor Daclatasvir

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