HCV Protease Inhibitors Research Articles

Interactions of ketoamide inhibitors on HCV NS3/4A protease target: molecular docking studies

HCV infection in more than 200 million individuals worldwide is a principal health problem. Prior to the development of HCV protease inhibitor combination therapy, HCV infected patients were treated with pegylated interferon-α and ribavirin. The adverse side effects associated with this type of treatment may lead to the discontinuation of treatment in certain number of patients. Currently, the inhibitors of NS3/4A Protease were found promising candidates for the treatment of HCV infection. There are several inhibitors of HCV NS3/4A protease that are passing through clinical improvement showing good potency against HCV infections in a number of patients. To further recognize binding interactions and activity trend, the molecular docking studies were performed on a number of HCV NS3/4A protease ketoamide inhibitors via MOE docking protocol. The docking analysis resulted in the detection of important ligand interactions with respect to binding site of target protein and produced good correlation coefficient (r2 = 0.690) between docking score and biological activities. These molecular docking results should, in our view, contribute for further optimization of ketoamide derivatives as NS3/4A protease inhibitors.

Romiplostim For Thrombocytopenia in Patients with Hepatitis C (HCV)-Associated Liver Disease: Preliminary Report Of An Ongoing Clinical Trial

BackgroundThrombocytopenia (Tp) is frequently observed in individuals with advanced cirrhotic liver disease. Patients with HCV may develop Tp even in the absence of significant liver disease. Decreased thrombopoietin production may also contribute to the Tp. The current management of HCV infection includes the use of the Peg-interferon α (IFN) and ribavirin (RIB), which can induce a sustained viral remission in 40 to 50% of treated patients. However, Peg-INF is a known inhibitor of megakaryocyte growth and maturation and can result in treatment related Tp. Therefore, patients presenting with platelet counts <70,000/mcl are frequently excluded from treatment or often fail treatment due to the development of critically low platelet counts. With this understanding, we initiated a clinical trial of the thrombopoietin receptor agonist, romiplostim, in HCV cirrhotic patients with Tp to determine if platelet count can be increased to >100,000/mcl to allow for HCV treatment with Peg-INF/RIB. MethodsThis is a two phase clinical trial of HCV infected patients with Child-Pugh class A liver disease. All patients were required to have platelet counts <70,000/µl and have liver biopsy confirmed early cirrhosis. Phase I is a double-blind placebo controlled trial of romiplostim given up to 8 weeks to raise platelets to >100,000/mcl before initiating Peg-INF treatment. There are separate 1 to 1 randomizations for patients with platelets 70 to 50,000/µl and patients with platelets<50,000/mcl. Initial treatment dose is 1 µg/kg with weekly progressive increases in dose. For patients who failed to obtain platelet counts >100,000/µl by week 8, blind is terminated and placebo patients can enter the romiplostim arm. Phase II is a dose escalation study of romiplostim during Peg-INF/Rib treatment up to week 24 of HCV treatment. If patients are viral load negative by week 24, romiplostim treatment is held to see if the patients can sustain a safe platelet count with continued HCV therapy. If not, romiplostim is continued until completion of HCV treatment. A protocol amendment allowed the addition of HCV protease inhibitors for genotype 1a patients. ResultsAt the time of this report 21 patients (7F/14M; mean age 54.9 yrs, range 28-72yrs) have been enrolled in this trial; 13 with platelets 70 to 50,000/µl (Mean 62,000/µl; range 55 to 70,000µl) and 8 with platelet counts<50,000/µl (Mean 35,000/µl; range 25-46,000/µl). 17 patients have completed Phase I; 2 patients are ongoing, 1 patient withdrew at wk 5 with no platelet response (Blind remains) and one patient was withdrawn at wk 2 when review of the pre-randomization ultrasound found evidence of an old partial portal thrombosis. Five patients failed to obtain a platelet count of >100,000/ul by wk 8; all on placebo and were rolled over to romiplostim. The mean romiplostim dose for patients completing Phase I with platelets 70 to 50,000/µl was 2.2 mcg/kg and 3.1 mcg/kg for patients with platelets of<50,000/µl. During the 8 wk course of romiplostim there were no SAEs and no change in HCV viral load. Eleven patients have successfully completed Phase II with 24 wks of HCV treatment; with 4 patients on HCV treatment at wks 21, 20, 13 and 9. One patient was withdrawn at wk 14 due to intractable pancytopenia. 7/11 (64%) were HCV viral load negative at wk 24 and continued to completion of their HCV treatment. The mean romiplostim dose for the 11 patients completing Phase II with HCV treatment was 7µg/kg (3 to 10µg/kg). Three major SAEs occurred during Phase II. A 61 y.o. female developed pancytopenia at wk 14 unresponsive to growth factor support with a hypocellular bone marrow. She had a slow recovery of counts over several months. A 63 y.o. female developed portal vein thrombosis at wk 22 of HCV therapy. Her platelet count was 92,000/µl. She was treated with LMW heparin, continued HCV treatment with romiplostim off study and was viral load negative at wk 44 of treatment. A 50 y.o. female had a sudden death at home at wk 20 of HCV therapy. She has a platelet count of 32,000/µl on a clinic visit the day before her death and her romiplostim dose was 10µg/kg. No autopsy was performed. ConclusionIn this interim analysis of ongoing clinical trial, romiplostim appears well tolerated and effective in increasing platelet counts in HCV cirrhotic patients and can maintain a safe platelet count in the majority of patients during HCV antiviral therapy with Peg-INF/RIB.This study was funded by a grant from AMGEN. Disclosures:Liebman:Amgen: Research Funding. Off Label Use: A clinical trial of romiplostim to treat hepatitis C-related thrombocytopenia performed under an FDA IND.

Managing HIV/hepatitis C co-infection in the era of direct acting antivirals

Morbidity and mortality from co-morbid hepatitis C (HCV) infection in HIV co-infected patients are increasing; hence, the management of hepatitis co-infection in HIV is now one of the most important clinical challenges. Therefore, the development of direct acting antivirals (DAAs) for treatment of HCV has been eagerly awaited to hopefully improve HCV treatment outcome in co-infected individuals. Indeed, the availability of the first HCV protease inhibitors (PI) boceprevir and telaprevir for HCV genotype 1 patients has changed the gold standard of treating hepatitis C allowing for substantially improved HCV cure rates under triple HCV-PI/pegylated interferon/ribavirin therapy. Moreover, numerous other new DAAs are currently being studied in co-infected patient populations, also exploring shorter treatment durations and interferon-free treatment approaches promising much easier and better tolerated treatment regimens in the near future. Nevertheless, numerous challenges remain, including choice of patients to treat, potential for drug-drug interactions and overlapping toxicities between HIV and HCV therapy. The dramatically improved rates of HCV cure under new triple therapy, however, warrant evaluation of these new treatment options for all co-infected patients.

Safety and Efficacy of Interferon-free Regimens of ABT-450/r, ABT-267, ABT-333 ± Ribavirin in Patients with Chronic HCV GTI Infection: Results from the Aviator Study

Purpose: To assess safety and efficacy of regimens of ABT-450/r (HCV protease inhibitor dosed with ritonavir 100 mg, identified as a lead compound by AbbVie and Enanta) with ABT-267 (NS5A inhibitor) and/or ABT-333 (non-nucleoside NS5B inhibitor) +/- ribavirin (RBV). Overall ITT SVR12 rate for 12-week treatment with three DAAs+RBV was 98.7% (78/79) in treatment-naïve patients, and 93.3% (42/45) in null responders. Methods: Non-cirrhotic, GT1 treatment-naïve patients and prior peginterferon/RBV null responders received ABT-450/r (100/100-200/100mg QD) with 1-2 other DAAs (ABT-267 25mg QD, ABT-333 400mg BID) ± RBV for 8, 12, or 24 weeks. We present safety and SVR24 data for patients in 12 and 24-week treatment arms of three DAAs+RBV. Results: Among 247 subjects treated in the 12- and 24-week 3-DAA+RBV arms, 81.0% had IL28B non-CC genotype, 66.0% had GT1a infection, 54.8% were male, and 10.5% were Black, with mean age of 51 years. Baseline HCV RNA was 6.6 log10 IU/mL, and 37.4% had ≥F2 fibrosis. SVR24 rates were comparable in the 12 and 24-week arms (96.2% and 90.0% in treatment naïve and 93.3% and 95.3% in prior null responders, respectively). SVR24 rates (combined 12 and 24-week arms) were comparable in patients with IL28B CC vs. non-CC, GT1a vs. GT1b, baseline HCV RNA <7 log10 vs. ≥7 log10 IU/mL, and F0-F1 vs. ≥F2 fibrosis (Figure). Among these 247 subjects, four patients (1.6%) discontinued due to study drugrelated AEs. Four patients (1.6%) experienced SAEs; one (arthralgia) was possibly study drug-related. The moderate-to-severe study drug-related AEs with >10% incidence in any arm were asthenia and fatigue. Six subjects (2.8%) and one subject (0.6%) experienced G3-4 laboratory abnormalities in total bilirubin and ALT, respectively; all resolved with continued dosing.FigureConclusion: Comparable responses were seen with 12 and 24 weeks of treatment, supporting selection of a 12-week duration of therapy in these populations. Consistently high SVR rates were achieved in naïve and prior null responder patients with a 3-DAA+RBV regimen, across HCV subtype, IL28B genotype, baseline HCV-RNA, or severity of fibrosis. Disclosure - Kris V. Kowdley: Grant/Research Support: AbbVie, Boehringer Ingelheim, BMS, Gilead/Pharmasset, Intercept, Janssen, Merck, Mochida, Vertex; Scientific Consulting: Novartis; Advisory Boards: AbbVie, Gilead, Merck, Vertex Eric Lawitz: Research/Grant support: AbbVie Laboratories, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck & Co., Novartis, Pharmasset, Presidio, Roche, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Vertex Pharmaceuticals, ViroChem Pharma, ZymoGenetics, Speaker: Gilead, Kadmon, Merck, Vertex, Advisory Board Participation: AbbVie Laboratories, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, BioCryst, Biotica; Enanta; GlobeImmune, Idenix Pharmaceuticals, Inhibitex Pharmaceuticals, Janssen, Merck & Co., Novartis, Pharmasset, Santaris Pharmaceuticals, Tibotec, Theravance, Vertex Pharmaceuticals Fred Poordad: Grant/Research support: Vertex, AbbVie, Boehringer Ingelheim, Merck, Anadys, GlaxoSmithKline, Novartis, Roche/Genentech, Idenix, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Janssen, Pharmaceuticals, Achillion Pharmaceuticals, BMS, Gilead, Pharmasset; Speaker: Vertex, Merck, Genentech; Consultant/Advisor: Vertex, AbbVie, Merck, Anadys Pharmaceuticals, Achillion, BMS, Gilead, Kadmon David Nelson: Grant/Research support: AbbVie, BI, BMS, Genentech, Gilead, Merck, Vertex Stefan Zeuzem: Consultancies for AbbVie, Achillion, AstraZeneca, BMS, Boehringer Ingelheim, Gilead, Idenix, Janssen, Merck, Novartis, Presidio, Roche, Santaris, Vertex Gregory T. Everson: Grant/Research support: AbbVie, Vertex, BMS, Merck, Roche/Genentech, Gilead/Pharmasset, GSK, Novartis, Tibotec, Janssen. Consultant/Advisor: AbbVie, Vertex, BMS, Merck, Roche/Genentech, Gilead, GSK, Novartis, Esai, Biotest. Equity interest and manager - HepQuant LLC Paul Kwo: Grant/Research funding from AbbVie, Anadys, Bristol Myers Squibb, Conatus, Gilead, Merck, Novartis, Roche, and Vertex Consultant/Advisor: AbbVie, Bristol Myers Squibb, Gilead, Johnson and Johnson, Merck, Novartis, Vertex; Fees for Non-CME/CE services directly from Gilead, Merck, Vertex Graham R. Foster Grant/Research support AbbVie, BMS, Merck, Roche/Genentech, Gilead, Novartis, Janssen. Consultant/Advisor AbbVie, Vertex, BMS, Merck, Roche/Genentech, Gilead, GSK, Janssen, Virco, Novartis Mark Sulkowski: Grant/Research support: AbbVie, Boehringer Ingelheim, BMS, Gilead, Janssen, Merck, Roche, Vertex Pharmaceuticals, Consultant/Advisor: AbbVie, Boehringer Ingelheim, BMS, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Vertex Pharmaceuticals Daniel E. Cohen, Wangang Xie, Tami Pilot-Matias, George Liossis, Lois Larsen, Amit Khatri, Thomas Podsadecki, and Barry Bernstein are AbbVie employees and may hold AbbVie stock or options The design, study conduct, analysis, and financial support of the clinical trial were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the presentation. All authors had access to all relevant data. Rebecca Maag and Laurinda Cooker (AbbVie) provided medical writing services. Full author Disclosures will be provided with the presentation.

Treatment of chronic hepatitis C Genotype 1 (G1) infection with boceprevir (Victrelis®) in the German real-life setting: First results for treatment-naïve patients from the Novus observational study

Aims: Triple therapy with the HCV protease inhibitor boceprevir (Victrelis®) combined with pegylated interferons (PegIFN) and ribavirin (RBV) has recently been approved as new standard of care for patients (pts) with chronic HCV genotype 1 (G1) infection. As a consequent next step we conducted a non-interventional observational study (NOVUS) to investigate the efficacy and safety of this novel and more complex therapeutic approach in the German real-life setting.

Drug-Drug Interactions in the Treatment of HCV Among People Who Inject Drugs

Boceprevir and telaprevir are inhibitors and substrates of the cytochrome P450 3A4 family. With the use of these HCV protease inhibitors as part of standard therapy for chronic hepatitis C genotype 1 infection, drug-drug interactions with multiple medications being inductors, inhibitors, or substrates of cytochrome P450 3A4 can be expected. Due to the complexity of these interactions, predicting the expected magnitude and sometimes even the direction of the effect has proven to be difficult. Pharmacokinetic studies should be carried out to evaluate drugs with clinical relevance and possible interactions. This review focuses on the data available regarding drugs that are frequently used in the setting of addiction or used by patients with addiction. In addition to highlighting relevant drug-drug interactions, alternative drugs that can be safely used are suggested.

Telaprevir in HIV/HCV-coinfected Patients: A New Standard with a Short Half-Life

The licensing of the first HCV protease inhibitors will lead to a dramatic increase in cure rates for patients with chronic genotype 1 hepatitis C. The addition of a third drug, such as telaprevir, to the standard treatment with pegylated interferon and ribavirin has become the new standard of care in the western world. While a shortening of the treatment duration is often possible, side effects are likely to increase with these products. The experience with telaprevir in HIV/HCV-coinfected patients is limited to one Phase II trial. Nevertheless, HIV-positive patients are in urgent need for new treatment options, as they often have more aggressive liver disease and lower reponse rates with the current standard treatments. These initial results are very promising, and HIV/HCV-coinfected patients seem to now have equal response rates as monoinfected patients, as long as drug–drug interactions remain under control.

Deep Sequencing Analysis of HCV NS3 Resistance-Associated Variants and Mutation Linkage in Liver Transplant Recipients

Viral variants with decreased susceptibility to HCV protease inhibitors (PIs) occur naturally and preexist at low levels within HCV populations. In patients failing PI monotherapy, single and double mutants conferring intermediate to high-level resistance to PIs have been selected in vivo. The abundance, temporal dynamics and linkage of naturally occurring resistance-associated variants (RAVs), however, have not been characterized in detail. Here, using high-density pyrosequencing, we analyzed HCV NS3 gene segments from 20 subjects with chronic HCV infection, including 12 subjects before and after liver transplantation. Bioinformatics analysis revealed that Q80 substitution was a dominant variant in 40% of the subjects, whereas other RAVs circulate at low levels within quasispecies populations. Low frequency mutation linkage was detectable by Illumina paired-end sequencing in as low as 0.5% of the mock populations constructed from in vitro RNA transcripts but were uncommon in vivo. We show that naturally occurring RAVs are common and can persist long term following liver transplant at low levels not readily detectable by conventional sequencing. Our results indicate that mutation linkage at low levels could be identified using the Illumina paired-end approach. The methods described here should facilitate the analysis of low frequency HCV drug resistance, mutation linkage and evolution, which may inform future therapeutic strategies in patients undergoing direct acting antiviral therapies.

Treatment of Hepatitis C with An Interferon-Based Lead-In Phase: A Perspective from Mathematical Modelling

The standard of care for HCV genotype 1 is a protease inhibitor (telaprevir or boceprevir) combined with pegylated interferon (PEG-IFN) and ribavirin (RBV). A lead-in phase of PEG-IFN/RBV therapy before addition of the protease inhibitor has been used, with the aim of improving response rates by reducing the development of protease inhibitor resistance. However, whether such a strategy can bring benefit to patients is unclear. A viral dynamic model was used to compare in silico HCV dynamics in patients treated with a period of PEG-IFN/RBV lead-in therapy followed by the addition of a protease inhibitor versus immediate triple therapy without lead-in. The model predicts that both regimens result in a similar end-of-treatment viral load change (viral decline or breakthrough). Thus, the current lead-in strategy may not decrease the rate of viral breakthrough/relapse or increase the rate of sustained virological response. This agrees with available data from clinical trials of several HCV protease inhibitors, such as telaprevir, boceprevir and faldaprevir. These results suggest that current PEG-IFN/RBV lead-in strategies may not improve treatment outcomes. However, viral kinetics during a period of PEG-IFN/RBV therapy, combined with other factors, such as the IL28B polymorphism and baseline viral load, can identify IFN-sensitive patients and help develop response-guided therapies.

Abstract supplement: HIV Drug Therapy in the Americas Congress 13–15 June 2013, São Paulo, Brazil

Abstract supplement: HIV Drug Therapy in the Americas Congress 13–15 June 2013, São Paulo, Brazil

Development of Related HCV Protease Inhibitors: Macrocyclization of Two Highly Functionalized Dienyl-ureas via Ring-Closing Metathesis

A novel assembly of two structurally related 14-membered ring macrocyclic hepatitis C virus protease inhibitors is presented. Key to their successful construction was an ultimate ring-closing metathesis step on the respective highly functionalized dienyl-ureas. In the case of IDX316, this procedure significantly outperformed the original macrocyclizations in terms of reaction conditions, impurity profile, product isolation, and basic efficiency metrics. Simple nonchromatographic purification methods achieved sub-10-ppm ruthenium content in the isolated product. Overall yields to IDX316 from all five starting materials ranged from 11 to 40%, and the estimated process mass intensity was improved by a factor of 50 relative to the original unscalable discovery-based routes. Application of similar methodology in the case of IDX320 and first scale-up to half-kilogram batch sizes was demonstrated.

Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket

Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R(6) substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R(6) substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

1185 GENERATION OF SELECTIVE HIGH AFFINITY LIGANDS TO BLOCK CD81-LARGE EXTRACELLULAR LOOP: HEPATITIS C VIRUS–E2 GLYCOPROTEIN INTERACTION

Background and Aims: HCV infects around 3.3% of the world population. The standard of care HCV treatment (Peginterferon/Ribavirin) leads to serious side effects and SVR is <50% in genotype-1 patients. The newly FDA approved protease inhibitors (Telaprevir/Boceprevir) were found to be effective when each is combined with PR giving higher SVR rates in GT-1. However the poor safety profile of TVR and BOC reported in the Week 16 analysis of the French Early Access Program suggest there is still a need for better HCV drugs. Many companies have active programs developing HCV protease and polymerase inhibitors. We are developing drugs to block an earlier step in HCV infection, CD81 mediated invasion. In this study we are developing Selective High Affinity Ligands (SHALs) to target the E2 binding site on CD81 and block their interaction.

1201 NO CLINICALLY SIGNIFICANT PHARMACOKINETIC INTERACTION BETWEEN SOVAPREVIR AND ACH-3102 IN HEALTHY VOLUNTEERS

Background: This study evaluated the potential for a pharmacokinetic (PK) interaction when sovaprevir (formerly ACH-1625), a novel NS3 HCV protease inhibitor, and ACH-3102, a second generation NS5A inhibitor, were coadministered. Sovaprevir was administered as an oral tablet, while ACH-3102 was administered as an oral liquid-filled capsule (LFC). This study also investigated whether a PK interaction existed between sovaprevir and the excipients of the ACH-3102 LFC. Methods: Twenty-four (24) healthy volunteers were divided into 4 groups. Subjects in Groups 1 (n=6) and 2 (n=6) each received a single 300 mg dose of sovaprevir with a standard meal on Day 1, followed by a washout period (Days 2 to 4), and then a single 300 mg dose of sovaprevir, co-administered with either 300 mg ACH-3102 LFC (Group 1) or placebo (Group 2) while fed a standard meal (Day 5). Subjects in Groups 3 (n=6) and 4 (n=6) each received a single 300 mg dose of sovaprevir while fasted on Day 1, followed by a washout period (Days 2 to4), and then a single 300 mg dose of sovaprevir co-administered with either 300 mg ACH3102 LFC (Group 3) or placebo (Group 4) while fasted (Day 5). Results: For sovaprevir, the respective mean Day 5/Day 1 ratios (coadministered with ACH- 3102 versus dosed alone) of Cmax, AUC(0-24) and AUC(O-∞) were 0.96, 1.05 and 1.05 when fed, and 0.89, 0.77 and 0.77 when fasted. Similarly, for sovaprevir, the respective mean Day 5/Day 1 ratios (co-administered with placebo for ACH-3102 LFC versus dosed alone) of Cmax, AUC(0-24) and AUC(O-∞) were 0.84, 0.91 and 0.90 when fed, and 1.17, 1.12 and 1.08 when fasted. Mean observed Cmax, AUC(0-24) and AUC(0-192) of ACH-3102 when coadministered with sovaprevir were all within approximately 25% of values from previous studies. Conclusions: No clinically significant change was observed in the PK of either sovaprevir or ACH-3102 when co-administered in either the fed or fasted state. No clinically significant change was observed in the PK of sovaprevir when coadministered with the excipients of the ACH-3102 LFC. Co-administration of the two agents was safe and well-tolerated.

Pharmacokinetic Interaction between Telaprevir and Methadone

Hepatitis C virus (HCV) antibody is present in most patients enrolled in methadone maintenance programs. Therefore, interactions between the HCV protease inhibitor telaprevir and methadone were investigated. The pharmacokinetics of R- and S-methadone were measured after administration of methadone alone and after 7 days of telaprevir (750 mg every 8 h [q8h]) coadministration in HCV-negative subjects on stable, individualized methadone therapy. Unbound R-methadone was measured in predose plasma samples before and during telaprevir coadministration. Safety and symptoms of opioid withdrawal were evaluated throughout the study. In total, 18 subjects were enrolled; 2 discontinued prior to receiving telaprevir. The minimum plasma concentration in the dosing interval (C(min)), the maximum plasma concentration (Cmax), and the area under the plasma concentration-time curve from h 0 (time of administration) to 24 h postdose (AUC(0-24)) for R-methadone were reduced by 31%, 29%, and 29%, respectively, in the presence of telaprevir. The AUC0-24 ratio of S-methadone/R-methadone was not altered. The median unbound percentage of R-methadone increased by 26% in the presence of telaprevir. The R-methadone median (absolute) unbound C(min) values in the absence (10.63 ng/ml) and presence (10.45 ng/ml) of telaprevir were similar. There were no symptoms of opioid withdrawal and no discontinuations due to adverse events. In summary, exposure to total R-methadone was reduced by approximately 30% in the presence of telaprevir, while the exposure to unbound R-methadone was unchanged. No symptoms of opioid withdrawal were observed. These results suggest that dose adjustment of methadone is not required when initiating telaprevir treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT00933283.).

Multicenter Quality Control of Hepatitis C Virus Protease Inhibitor Resistance Genotyping

Hepatitis C virus (HCV) protease inhibitor resistance-associated substitutions are selected during triple-therapy breakthrough. This multicenter quality control study evaluated the expertise of 23 French laboratories in HCV protease inhibitor resistance genotyping. A panel of 12 well-defined blinded samples comprising two wild-type HCV strains, nine transcripts from synthetic NS3 mutant samples or from clinical strains, and one HCV RNA-negative sample was provided to the participating laboratories. The results showed that any laboratory with expertise in sequencing techniques should be able to provide reliable HCV protease inhibitor resistance genotyping. Only a 0.7% error rate was reported for the amino acid sites studied. The accuracy of substitution identification ranged from 75% to 100%, depending on the laboratory. Incorrect results were mainly related to the methodology used. The results could be improved by changing the primers and modifying the process in order to avoid cross-contamination. This study underlines the value of quality control programs for viral resistance genotyping, which is required prior to launching observational collaborative multicenter studies on HCV resistance to direct-acting antiviral agents.

Lack of a clinically significant drug-drug interaction in healthy volunteers between the HCV protease inhibitor boceprevir and the proton pump inhibitor omeprazole

Proton pump inhibitors (PPIs) can limit the solubility of concomitant drugs, which can lead to decreased absorption and exposure. Reduced efficacy can be a consequence and in the case of an antimicrobial agent this may contribute to development of resistance. Patients chronically infected with the hepatitis C virus can be treated with a boceprevir-containing regimen and it is relevant to know if interactions between PPIs and boceprevir exist. This study was designed to investigate the influence of a frequently used PPI, omeprazole, on the pharmacokinetics of boceprevir and vice versa. In this open-label, three-period, randomized, cross-over, Phase I study, healthy subjects were randomly assigned to 40 mg of omeprazole once daily for 5 days, 800 mg of boceprevir three times daily for 5 days and 40 mg of omeprazole once daily + 800 mg of boceprevir three times daily for 5 days, or the same treatment in a different order. Every treatment was followed by a wash-out period. At day 5 of every treatment pharmacokinetic blood sampling was performed for 8 h after medication intake. ClinicalTrials.gov: NCT01470690. All 24 subjects (15 males) completed the study and no serious adverse events were reported. Geometric mean ratios (90% CI) of the area under the plasma concentration-time curve up to 8 h (AUC0-8) and maximum plasma concentration (Cmax) of boceprevir with omeprazole versus boceprevir alone were 0.92 (0.87-0.97) and 0.94 (0.86-1.02), respectively. For omeprazole these values were 1.06 (0.90-1.25) for AUC0-8 and 1.03 (0.85-1.26) for Cmax for the combination versus omeprazole alone. Omeprazole did not have a clinically significant effect on boceprevir exposure, and boceprevir did not affect omeprazole exposure.

Future therapies for chronic hepatitis C

Therapy for hepatitis C has been fairly stagnant for the past decade, but the past few years have seen major progress and evolution, beginning with the approval of two HCV protease inhibitors in 2011. In spite of considerable improvements in response rates with these agents, a need for additional agents with improved potency and tolerability remains. Toward this goal and over the course of just a few months, the HCV therapy pipeline has already become crowded with direct-acting antivirals, host-targeted agents and unique interferons, all of which are positioned to be part of the next wave of therapeutic options. The ultimate goal of this push for new agents is to achieve a safe and straight forward yet highly effective therapy for hepatitis C that is widely embraced and readily available. Particularly among the 'baby boomer' population, it is predicted that over the next few years, more patients with currently quiescent infections will be newly diagnosed, and those currently diagnosed will be at increased risk of long-term complications of infection, and thus in need of treatment. A simple and safe treatment paradigm will become a necessity. This Review chronicles the latest developments in hepatitis C therapy and the potential effect these new treatments could have on delivery of care to patients infected with HCV.

Anemia Management in Patients with Chronic Viral Hepatitis C

To review the literature regarding current strategies for the management of anemia associated with treatment for chronic viral hepatitis C (HCV) in adults. The MEDLINE/PubMed, EMBASE, and Cochrane databases were searched (January 1980-October 2012) for articles in English using the search terms anemia, ribavirin, dose reduction, erythropoietin stimulating agents, hepatitis C, HIV, liver transplant, telaprevir, and boceprevir. All relevant original studies, meta-analyses, systematic reviews, guidelines, and review articles were assessed for inclusion. References from pertinent articles were examined for additional content not found during the initial search. Standard of care for patients infected with HCV genotype 1 now requires a triple therapy regimen including an HCV NS3 protease inhibitor. These regimens lead to significantly higher rates of anemia compared to prior dual therapy regimens. Development of an optimal management strategy should begin with risk stratification. Ribavirin dose reductions have been recommended in the package inserts for the pegylated interferon products and studies have demonstrated the need for maintenance of 80% of the initial ribavirin dose to achieve optimal sustained virologic response (SVR) with dual therapy. The use of erythropoietin-stimulating agents has been shown to be effective for anemia caused by peginterferon and ribavirin without compromising SVR rates. Limited data have been published regarding the management of anemia with triple therapy; however, efficacy studies for boceprevir and telaprevir have used ribavirin dose reduction and erythropoietin-stimulating agents to successfully manage anemia. Anemia is a common adverse event associated with the use of ribavirin, and, more recently, the new HCV protease inhibitors. Ribavirin dose reduction should continue to be used as an initial anemia management strategy, with the use of erythropoietin alfa 40,000 units once weekly reserved for patients whose hemoglobin does not adequately respond to initial management strategies.

Eligibility and Safety of Triple Therapy for Hepatitis C: Lessons Learned from the First Experience in a Real World Setting

BackgroundHCV protease inhibitors (PIs) boceprevir and telaprevir in combination with PEG-Interferon alfa and Ribavirin (P/R) is the new standard of care in the treatment of chronic HCV genotype 1 (GT1) infection. However, not every HCV GT1 infected patient is eligible for P/R/PI therapy. Furthermore phase III studies did not necessarily reflect real world as patients with advanced liver disease or comorbidities were underrepresented. The aim of our study was to analyze the eligibility and safety of P/R/PI treatment in a real world setting of a tertiary referral center.MethodsAll consecutive HCV GT1 infected patients who were referred to our hepatitis treatment unit between June and November 2011 were included. Patients were evaluated for P/R/PI according to their individual risk/benefit ratio based on 4 factors: Treatment-associated safety concerns, chance for SVR, treatment urgency and nonmedical patient related reasons. On treatment data were analyzed until week 12.Results208 patients were included (F3/F4 64%, mean platelet count 169/nl, 40% treatment-naïve). Treatment was not initiated in 103 patients most frequently due to safety concerns. 19 patients were treated in phase II/III trials or by local centers and a triple therapy concept was initiated at our unit in 86 patients. Hospitalization was required in 16 patients; one patient died due to a gastrointestinal infection possibly related to treatment. A platelet count of <110/nl was associated with hospitalization as well as treatment failure. Overall, 128 patients were either not eligible for therapy or experienced a treatment failure at week 12.ConclusionsP/R/PI therapies are complex, time-consuming and sometimes dangerous in a real world setting, especially in patients with advanced liver disease. A careful patient selection plays a crucial role to improve safety of PI based therapies. A significant number of patients are not eligible for P/R/PI, emphasizing the need for alternative therapeutic options.