narlaprevir and Hepatitis-C--Chronic

Evaluate efficacy and safety of a combination of direct - acting antivirals narlaprevir/ritonavir with daclatasvir in patients with viral hepatitis C.. The study enrolled adult patients with HCV genotype 1b infection without demonstrated NS5A resistance - associated substitutions Y93C/H/N/S and/or L31F/M/V/I. Patients were treated with narlaprevir 200 mg QD, ritonavir 100 mg QD and daclatasvir 60 mg QD. Treatment duration was 12 weeks. Proportion of patients achieving sustained virological response 12 weeks after treatment (SVR12) was the primary efficacy endpoint.. In total, 105 (75.0%) patients were treatment with the study combination. Patients' age varied from 21 to 69 years, the mean age being 43.2±10.9 years. There were slightly more women (55.2%), and 69 patients (65.7%) had comorbidities. SVR 12 was 89.5% (95% CI 82.0-94.7%). In 10 of 11 patients with treatment failures NS5A resistance - associated substitutions in residues 31 and/or 93 were found, as well as less clinically relevant substitutions L28M, P58S, R30Q, Q62K. Adverse events (AEs) were found in less than one half of patients (45 patients, or 42.9% in the safety population). Almost all recorded AEs were mild to moderate.. Efficacy of treatment with a combination of narlaprevir/ritonavir and daclatasvir in treatment - naïve patients with HCV genotype 1b was close to 90%. This combination was found to be safe and well - tolerated.. Цель исследования. Изучение эффективности и безопасности комбинации препаратов прямого противовирусного действия нарлапревир/ритонавир и даклатасвир у пациентов с хроническим гепатитом C. Материалы и методы. В исследование включали взрослых пациентов с инфекцией, вызванной вирусом гепатита С генотипа 1b, у которых не выявлялись аминокислотные замены в NS5A-белке, связанные с лекарственной устойчивостью: Y93C/H/N/S и/или L31F/M/V/I. Пациенты получали нарлапревир 200 мг один раз в сутки, ритонавир 100 мг один раз в сутки и даклатасвир 60 мг один раз в сутки. Длительность терапии составила 12 нед. Основной показатель эффективности соответствовал доле пациентов, достигших устойчивого вирусологического ответа через 12 нед после лечения (УВО12). Результаты и обсуждение. Всего 105 (75,0%) пациентов получили лечение исследуемой комбинацией препаратов. Возраст больных варьировал от 21 года до 69 лет, составляя в среднем 43,2±10,9 года. Незначительно преобладали лица женского пола (55,2%), 69 (65,7%) пациентов имели сопутствующие заболевания. УВО12 составил 89,5% (95% ДИ 82,0-94,7%). У 10 из 11 пациентов с неудачей терапии выявлялись аминокислотные замены, связанные с лекарственной устойчивостью в аминокислотных позициях 31 и/или 93 белка NS5A и менее значимые с клинической точки зрения замены L28M, P58S, R30Q, Q62K. Нежелательные явления отмечены менее чем у половины пациентов (45 пациентов, или 42,9% популяции оценки безопасности). Почти все зарегистрированные нежелательные явления были легкой или умеренной степени тяжести. Заключение. Эффективность режима терапии комбинацией нарлапревира в сочетании с ритонавиром и даклатасвиром у ранее не получавших лечения пациентов с хроническим вирусным гепатитом C генотипа 1b составила практически 90%. Лечение данной комбинацией характеризовалось хорошими переносимостью и безопасностью.

Topics: Adult; Antiviral Agents; Carbamates; Cyclopropanes; Dipeptides; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Leucine; Middle Aged; Proline; Pyrrolidines; Ritonavir; Russia; Sulfones; Treatment Outcome; Urea; Valine

Achievement of a sustained virologic response (SVR) after peginterferon (PEG-IFN) and ribavirin (RBV) treatment is considered to be a marker for the cure of chronic hepatitis C virus (HCV) infection. Long-term follow-up of patients with SVR after treatment with a direct acting antiviral has not yet been described. We used a randomized placebo-controlled, double-blind, two-period phase 1b trial that was conducted in 40 HCV genotype 1 (treatment-naïve and treatment-experienced)-infected patients. Nineteen patients achieved SVR after treatment with the HCV protease inhibitor narlaprevir followed by PEG-IFN/RBV. In these patients, HCV-RNA tests were scheduled at 3, 6, 12 and 24 months after end of treatment. Patients were followed for a median of 27 months (range 15-32) after end of treatment with a median number of follow-up visits of 4 (range 3-8). All patients remained HCV-RNA negative over time. SVR achieved following narlaprevir and PEG-IFN/RBV-therapy was durable up to 32 months after the end of treatment.

Topics: Adult; Aged; Antiviral Agents; Cyclopropanes; Dipeptides; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Leucine; Male; Middle Aged; Placebos; Polyethylene Glycols; Proline; Recombinant Proteins; Ribavirin; RNA, Viral; Sulfones; Treatment Outcome; Urea; Viral Load

Narlaprevir, a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, has demonstrated robust antiviral activity in a placebo-controlled phase 1 study. To study evolutionary dynamics of resistant variants, the NS3 protease sequence was clonally analysed in thirty-two HCV genotype 1-infected patients following treatment with narlaprevir. Narlaprevir monotherapy was administered for one week (period 1) followed by narlaprevir/pegylated interferon-alpha-2b combination therapy with or without ritonavir (period 2) during two weeks, interrupted by a washout period of one month. Thereafter, all patients initiated pegylated interferon-alpha-2b/ribavirin combination therapy. Longitudinal clonal analysis was performed in those patients with NS3 mutations. After narlaprevir re-exposure, resistance-associated mutations at position V36, T54, R155 and A156 were detected in five patients in >95% of the clones. Narlaprevir retreatment resulted in a 2.58 and 5.06 log10 IU/mL viral load decline in patients with and without mutations, respectively (P=<0.01). After treatment, resistant variants were replaced with wild-type virus within 2-24 weeks in three patients. However, the R155K mutation was still observed 3.1 years after narlaprevir dosing in two patients in 5% and 45% of the viral population. Resistant variants could be detected early during treatment with narlaprevir. A slower viral load decline was observed in those patients with resistance-associated mutations detectable by direct population sequencing. These mutations disappeared within six months following treatment with the exception of R155K mutation, which persisted in two patients.

Topics: Adult; Antiviral Agents; Cyclopropanes; Dipeptides; Drug Therapy, Combination; Evolution, Molecular; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Leucine; Longitudinal Studies; Male; Middle Aged; Polyethylene Glycols; Proline; Protease Inhibitors; Recombinant Proteins; Ribavirin; Sequence Analysis, DNA; Sulfones; Urea; Viral Load; Viral Nonstructural Proteins

Narlaprevir (SCH 900518) is a potent inhibitor of the hepatitis C virus (HCV) nonstructural protein 3 serine protease that is primarily metabolized by the cytochrome P450-3A4 system. In order to explore the use of ritonavir-based pharmacokinetic enhancement of an HCV protease inhibitor, this study investigated the safety, tolerability, pharmacokinetics, and antiviral activity of narlaprevir (with or without ritonavir) administered as monotherapy and as combination therapy with pegylated interferon-α-2b (PEG-IFN-α-2b) to HCV genotype 1-infected patients. This was a randomized, placebo-controlled, two-period, blinded study in 40 HCV genotype 1-infected patients (naïve and treatment-experienced). In period 1, narlaprevir was administered for 7 days as 800 mg three times daily without ritonavir or 400 mg twice daily with 200 mg ritonavir twice daily. In period 2, after a 4-week washout, the same dose and regimen of narlaprevir was administered in combination with PEG-IFN-α-2b for 14 days. Upon completion of period 2, all patients initiated PEG-IFN-α-2b and ribavirin treatment. A rapid and persistent decline in plasma HCV-RNA was observed in both treatment-experienced and treatment-naïve patients during period 1, with a mean viral load decline of at least 4 log₁₀ in all treatment groups. A high percentage of both treatment-experienced (50%) and treatment-naïve (≥ 60%) patients had undetectable HCV-RNA (< 25 IU/mL) after period 2. Standard of care resulted in sustained virological response (SVR) rates of 38% and 81% in treatment-experienced and treatment-naïve patients, respectively. Narlaprevir (with or without ritonavir) alone or in combination with PEG-IFN-α-2b was safe and well tolerated.. Narlaprevir administration resulted in a robust HCV-RNA decline and high SVR rates when followed by standard of care in both treatment-experienced and treatment-naïve HCV genotype 1-infected patients.

Topics: Adult; Aged; Antiviral Agents; Cyclopropanes; Dipeptides; Drug Administration Schedule; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Inpatients; Interferon alpha-2; Interferon-alpha; Leucine; Male; Middle Aged; Outpatients; Polyethylene Glycols; Proline; Recombinant Proteins; Recurrence; Ritonavir; RNA, Viral; Sulfones; Urea; Young Adult

Our aim was to give a comparative assessment of the effectiveness of using narlaprevir in combination with pegylated interferon-alpha-2a (Peg-IFN-alpha-2a) and interferon-free mode in patients with chronic hepatitis C (CHC).. The prospective cohort study included 187 patients infected with genotype 1b of hepatitis C virus. Of these, 107 (the 1st group of patients) received narlaprevir 200 mg once a day, ritonavir 100 mg once a day, Peg-IFN-alpha-2a 180 mkg subcutaneously once a week and ribavirin at a dose depending on body weight (10001200 mg per day) for 12 weeks, and then the standart "dual" therapy (Peg-IFN-alpha-2a + ribavirin) was continued until 24 weeks. Patients of the 2nd group (n=80) received antiviral therapy in an interferon-free mode. They received narlaprevir 200 mg once daily, ritonavir 100 mg once daily, and daclatasvir 60 mg once daily for 12 weeks.. With the use of an interferon-containing treatment regimen, a sustained virological response was achieved in 92.4% of previousle untreated patients with CH and in 66.7% patients with "unsuccessful" experience of the previous course of treatment. In 5.6% of cases, there was an early termination of treatment due to the development of adverse events. 80 (100%) patients completed the course of treatment with narlaprevir in the interferon-free mode. Sustained virological response was reached by 75 (90%) patients.. Real clinical practice indicates that the use of narlaprevir in the non-interferon mode is not inferior in efficiency to the interferon-containing treatment regimen and demonstrates a more favorable safety profile.. Цель. Дать сравнительную оценку эффективности применения нарлапревира в комбинации с пегилированным интерфероном-a2а (Пег-ИФН-a2а) и в безинтерфероновом режиме у больных хроническим гепатитом С (ХГС). Материалы и методы. В проспективное когортное исследование включены 187 пациентов, инфицированных вирусом гепатита C генотипа 1b. Из них 107 человек (группа 1) получали нарлапревир по 200 мг 1 раз в сутки, ритонавир по 100 мг 1 раз в сутки, Пег-ИФН-a2а 180 мкг подкожно 1 раз в неделю и рибавирин в дозе, зависящей от массы тела (10001200 мг/сут) на протяжении 12 нед, после чего была продолжена стандартная двойная терапия (Пег-ИФН-a2а-a2а+рибавирин) до 24 нед. Больным группы 2 (n=80) противовирусную терапию проводили в безинтерфероновом режиме. Они получали нарлапревир в дозе 200 мг 1 раз в сутки, ритонавир 100 мг 1 раз в сутки и даклатасвир 60 мг 1 раз в сутки в течение 12 нед. Результаты. При применении интерферонсодержащей схемы лечения устойчивый вирусологический ответ достигнут у 92,4% ранее не леченных больных ХГС и у 66,7% пациентов с неудачным опытом предыдущего курса лечения. В 5,6% случаев имело место досрочное прекращение терапии ввиду развития нежелательных реакций. Курс лечения нарлапревиром в безинтерфероновом режиме завершили 80 (100%) пациентов. Устойчивый вирусологический ответ зарегистрирован у 75 (90%) человек. Заключение. Реальная клиническая практика свидетельствует о том, что применение нарлапревира в безинтерфероновом режиме не уступает по эффективности интерферонсодержащей схеме лечения и демонстрирует более благоприятный профиль безопасности.

Topics: Antiviral Agents; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Ribavirin; Ritonavir; Treatment Outcome