Antiviral effects of peginterferon alpha-2b and ribavirin following 24-week monotherapy of telaprevir in Japanese hepatitis C patients

Ozeki, Itaru; Akaike, Jun; Karino, Yoshiyasu; Arakawa, Takeshi; Kuwata, Yasuaki; Ohmura, Takumi; Sato, Takahiro; Kamiya, Naohiro; Yamada, Itsunari; Chayama, Kazuaki; Kumada, Hiromitsu; Toyota, Joji

doi:10.1007/s00535-011-0411-0

Cited by 28 publications

(22 citation statements)

References 33 publications

(51 reference statements)

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“…One previous study indicated that mice infected with the resistant strain (A156F [99.9%]) developed only low-level viremia, and the virus was successfully eliminated with IFN therapy (27). In the other clinical report, telaprevir-resistant variants that emerged during 24-week telaprevir monotherapy were eliminated by the combination therapy of PEG-IFN plus ribavirin (28). Furthermore, this finding probably suggests that a small number of mutant-type viral RNAs may be incomplete or defective, since a large proportion of viral genomes are thought to be defective due to their high replication and mutation rates (29).…”

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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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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“…However, SVR was detected 24 weeks after combination therapy with PEG-IFN α-2b, ribavirin, and TVR. 4,17,30,31) Therefore, these results did not suggest SVR, but these might be steps to SVR.…”

Section: Discussionmentioning

confidence: 73%

Successful Telaprevir Treatment in Combination of Cyclosporine against Recurrence of Hepatitis C in the Japanese Liver Transplant Patients

Kikuchi

Okuda

Ueda

et al. 2014

Biological & Pharmaceutical Bulletin

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Telaprevir (TVR) is a protease inhibitor used in combination with pegylated interferon alfa-2b and ribavirin for hepatitis C, and TVR strongly inhibits CYP3A4 and CYP3A5. We reported successful TVR treatment of liver transplant patients with recurrence of hepatitis C during receiving immunosuppressive therapy. Before initiation of triple therapy, all patients switched from tacrolimus to cyclosporine, which has a lower inhibitory effect on CYP3A4 and CYP3A5 than tacrolimus. To avoid graft failure, we measured the cyclosporine blood concentrations at 0, 2, and 6 h after administration to maintain the target level (150-200 ng/ mL) within 1 week after initiation of TVR and adjusted the dose of cyclosporine. The dose of cyclosporine was decreased 0.24-0.40 fold in all patients after initiation of TVR treatment. In 3 patients, the dose of TVR was decreased two-thirds of starting dose because of adverse effects, including anorexia and skin rash. However, the HCV RNA level rapidly decreased to undetectable levels within 1 month. Furthermore, all patients completed the TVR therapy in 12 weeks and did not experience liver graft rejection. In addition, we found the rapid elimination of inhibitory effect of TVR on the disposition of cyclospirne in the all four cases and therefore, rapid increase in the dosage of cyclosporine would be required immediately after the end of TVR administration. These results suggest that frequent measurement of cyclosporine levels was important for successful TVR triple therapy and prevention of rejection.

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“…26,27 Therefore, telaprevir must be administered as part of triple therapy with peginterferon and ribavirin to Emerging treatments for chronic HCV suppress viral breakthrough. Triple therapy consequently only increases the risk of adverse effects and imposes further restrictions on an already restrictive therapy.…”

Section: Telaprevir and Antiviral Resistancementioning

confidence: 99%

Emerging treatments for chronic hepatitis C

Hayes

Chayama

2015

Journal of the Formosan Medical Association

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Advances in understanding the hepatitis C virus (HCV) life cycle and the urgent need to find complementary direct-acting antiviral (DAA) therapies has led to substantial advancements in treating chronic hepatitis C. The introduction of telaprevir and boceprevir in 2011 increased the sustained virological response (SVR) rate from approximately 50% to > 70%, but this therapy further restricted patient eligibility and is only approved for treating HCV genotype 1 infection. Interferon has long remained the backbone of HCV therapy and helps prevent viral breakthrough. However, interferon has limited effectiveness and is associated with severe adverse effects and toxicity, especially among cirrhotic patients. Moving to interferon-free therapies should greatly improve SVR rates and offer new treatments for other HCV genotypes and for ineligible patients or patients failing to respond to prior therapies. However, without the relative safety of interferon to suppress viral escape, vigilance will be required to select appropriate therapies and monitor resistance. Several DAAs are currently undergoing clinical trials and will soon undergo the approval process. Goals of future HCV clinical research will be to identify combinations of DAAs with high genetic barriers, investigate optimal treatment doses and durations, and determine the role of ribavirin in DAA therapies.

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Antiviral effects of peginterferon alpha-2b and ribavirin following 24-week monotherapy of telaprevir in Japanese hepatitis C patients

Cited by 28 publications

References 33 publications

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

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

Successful Telaprevir Treatment in Combination of Cyclosporine against Recurrence of Hepatitis C in the Japanese Liver Transplant Patients

Emerging treatments for chronic hepatitis C

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