Prediction of Treatment Efficacy and Telaprevir-Resistant Variants after Triple Therapy in Patients Infected with Hepatitis C Virus Genotype 1

Akuta, Norio; Suzuki, Fumitaka; Fukushima, Taito; Kawamura, Yusuke; Sezaki, Hitomi; Suzuki, Yoshiyuki; Hosaka, Tetsuya; Kobayashi, Masahiro; Hara, Tasuku; Kobayashi, Mariko; Saitoh, Satoshi; Arase, Yasuji; Ikeda, Kenji; Kumada, Hiromitsu

doi:10.1128/jcm.01129-13

Cited by 20 publications

(24 citation statements)

References 35 publications

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“…We confirm in our study the detection of PI-resistant variants at baseline in both SVR and non-SVR patients as already reported by others using either population sequencing assays or NGS (10,15,17,23,(32)(33)(34). Nevertheless, the association between these mutations and the profile of viral load decrease in dual therapy might also be of importance (35,36).…”

Section: Discussionsupporting

confidence: 91%

Ultradeep Pyrosequencing of NS3 To Predict Response to Triple Therapy with Protease Inhibitors in Previously Treated Chronic Hepatitis C Patients

Larrat

Kulkarni

Claude³

et al. 2015

J Clin Microbiol

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Despite the gain in sustained virological responses (SVR) provided by protease inhibitors (PIs), failures still occur. The aim of this study was to determine if a baseline analysis of the NS3 region using ultradeep pyrosequencing (UDPS) can help to predict an SVR. Serum samples from 40 patients with previously nonresponding genotype 1 chronic hepatitis C who were retreated with triple therapy, including a PI, were analyzed. Baseline UDPS of the NS3 gene was performed on plasma and peripheral blood mononuclear cells (PBMC). Mutations conferring resistance to PIs were sought. The overall diversity of the quasispecies was evaluated by calculating the Shannon entropy (SE). Resistance mutations were found in plasma and PBMC but were not discriminating enough to predict an SVR. NS3 quasispecies heterogeneity was significantly lower at baseline in patients achieving an SVR than in those not achieving an SVR (SE of 26.98 ؎ 16.64 ؋ 10 ؊3 versus 44.93 ؎ 19.58 ؋ 10 ؊3 , P ‫؍‬ 0.0047). With multivariate analysis, the independent predictors of an SVR were fibrosis of stage F <2 (odds ratio [OR], 13.3; 95% confidence interval [CI], 1.25 to 141.096; P < 0.03) and SE below the median (OR, 5.4; 95% CI, 1.22 to 23.87; P < 0.03). More than the presence of minor mutations at the baseline in plasma or in PBMC, the NS3 viral heterogeneity determined by UDPS is an independent factor for an SVR in previously treated patients receiving triple therapy that includes a PI. In the treatment of patients with chronic hepatitis C of genotype 1, the addition of a protease inhibitor (PI) (boceprevir [BOC] or telaprevir [TPV]) to pegylated interferon alpha (PegIFN-␣) and ribavirin (RBV) has increased the rate of sustained virological responses (SVR) compared to that with dual therapy (PegIFN-␣/ RBV), both in naive and treatment-experienced patients (1-4). The role of the PIs is crucial, and failures of triple therapy are mainly due to mutations in the viral NS3 protease gene (5). Mutations are favored by the high rate of error of the hepatitis C virus (HCV) RNA-dependent RNA polymerase, estimated to be between 10 Ϫ3 to 10 Ϫ5 per copied base pair (6), combined with the high rate of viral replication (up to 1 ϫ 10 12 particles produced per day) (7), resulting in one mutation for every genome copied (8). Consequently, the large number of viral quasispecies generated constitutes a reservoir for the emergence of resistant strains. The early appearance (Ͻ15 days) of resistance mutations in patients treated with PIs alone strongly suggests that quasispecies harboring drug resistance mutations preexist at low frequencies (9). PIresistant mutations have been detected as the majority strain in blood of 2% to 19% of patients before treatment, according to the study and the number of mutations considered (10-15). The association between these mutations found in plasma and the failure of triple therapy is not clear. Moreover, data on other compartments such as peripheral blood mononuclear cells (PBMC) are lacking.Next-generation sequencing (NGS) technologies...

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Section: Discussionsupporting

confidence: 91%

Ultradeep Pyrosequencing of NS3 To Predict Response to Triple Therapy with Protease Inhibitors in Previously Treated Chronic Hepatitis C Patients

Larrat

Kulkarni

Claude³

et al. 2015

J Clin Microbiol

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“…However, these populations did not directly change into major populations exhibiting clinical resistance and disappeared at the reelevation of the viral titer, whereas it was likely that the population with wild-type T54T at baseline acquired clinical resistance by developing the T54A mutation. Previous reports demonstrated the possibility that a trace mixture of resistant mutations at baseline does not lead to clinical resistance (10,11). The phenomenon was further clarified by the present study with the use of phylogenetic analysis, and it was considered difficult to predict TVR resistance at baseline.…”

Section: Discussionmentioning

confidence: 64%

“…On the other hand, it was recently reported that even DAA treatment-naive HCV might naturally have a substantial number of variants resistant to PIs, and this issue has been given attention (9). However, it was also reported that such naturally resistant HCV did not always exhibit treatment resistance (10,11).…”

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confidence: 99%

“…Due to the recent development of deep sequencing techniques using next-generation sequencers (15)(16)(17)(18), detailed analysis of quasispecies has become possible. Several deep sequencing studies have been undertaken to disclose the origin of DAA-resistant variants through analyzing DAA-resistant variant populations over time (10,11,16,19,20). On the other hand, previous investigations tended to focus on hot spots for specific mutations but lacked the phylogenetic analysis that is needed to determine the origins of certain viral populations.…”

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confidence: 99%

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Deep Sequencing and Phylogenetic Analysis of Variants Resistant to Interferon-Based Protease Inhibitor Therapy in Chronic Hepatitis Induced by Genotype 1b Hepatitis C Virus

Sato

Maekawa

Komatsu

et al. 2015

J Virol

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Because of recent advances in deep sequencing technology, detailed analysis of hepatitis C virus (HCV) quasispecies and their dynamic changes in response to direct antiviral agents (DAAs) became possible, although the role of quasispecies is not fully understood. In this study, to clarify the evolution of viral quasispecies and the origin of drug-resistant mutations induced by interferon (IFN)-based protease inhibitor therapy, the nonstructural-3 (NS3) region of genotype 1b HCV in 34 chronic hepatitis patients treated with telaprevir (TVR)/pegylated interferon (PEG-IFN)/ribavirin (RBV) was subjected to a deep sequencing study coupled with phylogenetic analysis. Twenty-six patients (76.5%) achieved a sustained viral response (SVR), while 8 patients did not (non-SVR; 23.5%). When the complexity of the quasispecies was expressed as the mutation frequency or Shannon entropy value, a significant decrease in the IFNL3 (rs8099917) TT group and a marginal decrease in the SVR group were found soon (12 h) after the introduction of treatment, whereas there was no decrease in the non-SVR group and no significant decrease in mutation frequency in the IFNL3 TG/GG group. In the analysis of viral quasispecies composition in non-SVR patients, major populations greatly changed, accompanied by the appearance of resistance, and the compositions were unlikely to return to the pretreatment composition even after the end of therapy. Clinically TVR-resistant variants were observed in 5 non-SVR patients (5/8, 62.5%), all of which were suspected to have acquired resistance by mutations through phylogenetic analysis. In conclusion, results of the study have important implications for treatment response and outcome in interferon-based protease inhibitor therapy. IMPORTANCEIn the host, hepatitis C virus (HCV) consists of a variety of populations (quasispecies), and it is supposed that dynamic changes in quasispecies are closely related to pathogenesis, although this is poorly understood. In this study, recently developed deep sequencing technology was introduced, and changes in quasispecies associated with telaprevir (TVR)/pegylated interferon (PEG-IFN)/ribavirin (RBV) triple therapy and their clinical significance were investigated extensively by phylogenetic tree analysis. Through this study, the associations among treatment response, changes in viral quasispecies complexity in the early stage of treatment, changes in the quasispecies composition, and origin of TVR-resistant variant HCV were elucidated. R ecently, various novel small compounds with potent antiviral effects called direct antiviral agents (DAAs) have been developed for the treatment of chronic hepatitis C (1), and their significant antiviral activity is literally changing the world of anti-hepatitis C virus (HCV) therapy. Among these, nonstructural 3 (NS3) and NS4A protease inhibitors (PIs) were first approved for clinical use, and telaprevir (TVR) and simeprevir (SMV) became available for HCV infection in several countries, including Japan, in combination with pegy...

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“…Host genetic factors (e.g., IL28B genotype), and viral factors (e.g., amino acid substitutions in the core/NS5A region) have often been used as pretreatment predictors of poor virological response to PEG-IFN-ribavirin dual therapy (9-11, 15, 17) and telaprevir-PEG-IFN-ribavirin triple therapy (24)(25)(26). However, the pretreatment factors associated with the detection of telaprevir-resistant variants at the time of reelevation of viral load are still unknown.…”

Section: Discussionmentioning

confidence: 99%

Utility of Detection of Telaprevir-Resistant Variants for Prediction of Efficacy of Treatment of Hepatitis C Virus Genotype 1 Infection

et al. 2014

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bThe clinical usefulness of detecting telaprevir-resistant variants is unclear. Two hundred fifty-two Japanese patients infected with hepatitis C virus (HCV) genotype 1b received triple therapy with telaprevir-peginterferon (PEG-IFN)-ribavirin and were evaluated for telaprevir-resistant variants by direct sequencing at baseline and at the time of reelevation of the viral load. An analysis of the entire group indicated that 76% achieved a sustained virological response. Multivariate analysis identified a PEG-IFN dose of <1.3 g/kg of body weight, an IL28B rs8099917 genotype (genotype non-TT), detection of telaprevir-resistant variants of amino acid (aa) 54 at baseline, nonresponse to prior treatment, and a leukocyte count of <5,000/mm 3 as significant pretreatment factors for detection of telaprevir-resistant variants at the time of reelevation of the viral load. In 63 patients who showed nonresponse to prior treatment, a higher proportion of patients with no detected telaprevir-resistant variants at baseline (54%) achieved a sustained virological response than did patients with detected telaprevir-resistant variants at baseline (0%). Furthermore, 2 patients who did not have a sustained virological response from the first course of triple therapy with telaprevir received a second course of triple therapy with telaprevir. These patients achieved a sustained virological response by the second course despite the persistence of very-high-frequency variants (98.1% for V36C) or a history of the emergence of variants (0.2% for R155Q and 0.2% for A156T) by ultradeep sequencing. In conclusion, this study indicates that the presence of telaprevir-resistant variants at the time of reelevation of viral load can be predicted by a combination of host, viral, and treatment factors. The presence of resistant variants at baseline might partly affect treatment efficacy, especially in those with nonresponse to prior treatment. N ew strategies have been introduced recently for the treatment of chronic hepatitis C virus (HCV) infection based on the inhibition of protease in the nonstructural 3 (NS3)/NS4 region of the HCV polyprotein. Of the new agents currently available, telaprevir (VX-950) is used for the treatment of chronic HCV infection (1). Three studies (PROVE1, PROVE2, and a Japanese study [2][3][4]) showed that a 24-week regimen of triple therapy (telaprevir, peginterferon [PEG-IFN], and ribavirin) for 12 weeks followed by dual therapy (PEG-IFN and ribavirin) for 12 weeks (also called the T12PR24 regimen) achieved sustained virological response (SVR) (negative for HCV RNA for Ͼ24 weeks after the withdrawal of treatment) rates of 61%, 69%, and 73%, respectively, in patients infected with HCV genotype 1 (HCV-1). However, another study (PROVE3) found lower SVR rates to the T12PR24 regimen (39%) in nonresponders to previous PEG-IFN-ribavirin therapy infected with HCV-1 who did not achieve HCV RNA negativity during or at the end of the initial triple therapy course (5).Telaprevir-based therapy is reported to induce resistant varia...

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Prediction of Treatment Efficacy and Telaprevir-Resistant Variants after Triple Therapy in Patients Infected with Hepatitis C Virus Genotype 1

Cited by 20 publications

References 35 publications

Ultradeep Pyrosequencing of NS3 To Predict Response to Triple Therapy with Protease Inhibitors in Previously Treated Chronic Hepatitis C Patients

Ultradeep Pyrosequencing of NS3 To Predict Response to Triple Therapy with Protease Inhibitors in Previously Treated Chronic Hepatitis C Patients

Deep Sequencing and Phylogenetic Analysis of Variants Resistant to Interferon-Based Protease Inhibitor Therapy in Chronic Hepatitis Induced by Genotype 1b Hepatitis C Virus

Utility of Detection of Telaprevir-Resistant Variants for Prediction of Efficacy of Treatment of Hepatitis C Virus Genotype 1 Infection

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