HCV Protease Inhibitors Research Articles

On the fast track towards IFN-free therapy for hepatitis C?

With the first HCV protease inhibitors approved in 2011, we are currently in a transition phase towards a shift in treatment paradigm. Within the next 3 years, the vast majority of patients with hepatitis C will probably be treated with completely different drugs in most Western countries.

Pharmacokinetic Interaction Between Boceprevir and Etravirine in HIV/HCV Seronegative Volunteers

The primary aim of this study was to determine the bioequivalence of boceprevir, an HCV protease inhibitor and etravirine, an HIV non-nucleoside reverse transcriptase inhibitor; area under the concentration time curve (AUC(0,τ)); maximum concentration (C(max)); and trough concentration (C(8) or C(min)) when administered in combination versus alone. Open-label crossover study in healthy volunteers. Boceprevir, etravirine, and the combination were administered for 11-14 days with intensive sampling between days 11 and 14 of each sequence. Boceprevir and etravirine were quantified using validated liquid chromatography coupled with tandem mass spectrometry and high-performance liquid chromatography/ultraviolet assays, respectively and pharmacokinetics determined using noncompartmental methods. Geometric mean ratios (GMRs) and 90% confidence interval (CI) for the combination versus each drug alone were evaluated using 2 one-sided t tests. The hypothesis of equivalence was rejected if 90% GMR CI was not contained in the interval (0.8-1.25). Twenty subjects completed study. GMRs (90% CI) for etravirine AUC(o,τ), C(max), and C(min) were 0.77 (0.66 to 0.91), 0.76 (0.68 to 0.85), and 0.71 (0.54 to 0.95), respectively, in combination versus alone. Boceprevir GMRs (90% CI) for AUC(o,τ), C(max), and C(8) were 1.10 (0.94 to 1.28), 1.10 (0.94 to 1.29), and 0.88 (0.66 to 1.17), respectively, in combination versus alone. All adverse events (n = 112) were mild or moderate. Six subjects discontinued: 4 due to rash, 1 due to central nervous system effects, and 1 for a presumed viral illness. Etravirine AUC(o,τ), C(max), and C(min)decreased 23%, 24%, and 29%, respectively, with boceprevir. Boceprevir AUC(0,τ) and C(max) increased 10% and C(8) decreased 12% by etravirine. Additional research is needed to elucidate the mechanism(s) and therapeutic implications of the observed interaction.

Hepatitis C treatment with a focus on HCV protease inhibitors (Part Two)

Hepatitis C treatment with a focus on HCV protease inhibitors (Part Two)

Hepatitis C treatment with a focus on HCV protease inhibitors (Part Three)

Hepatitis C treatment with a focus on HCV protease inhibitors (Part Three)

Stereoselective Addition of 2-Phenyloxazol-4-yl Trifluoromethanesulfonate to N-Sulfinyl Imines: Application to the Synthesis of the HCV Protease Inhibitor Boceprevir

The stereoselective addition of 2-phenyloxazol-4-yl trifluoromethanesulfonate to N-sulfinylimines is described. Vinyl anions derived from enol triflate 2 undergo 1,2-addition with a variety of aldimines to afford the corresponding secondary sulfonamides as single diastereomers. The absolute stereochemistry was confirmed by X-ray crystallography which provides support that the reaction proceeds through an open, nonchelate transition state. This methodology has been applied to the synthesis of the ketoamide fragment of the protease inhibitor boceprevir.

Hepatitis B and C in liver transplantation: new strategies to combat the enemies

Hepatitis B immune globulin-free therapeutic regimens with a nucleos(t)ide analogue (NUC) or NUC combinations after liver transplantation (LT) are currently being investigated for their efficacy and safety as HBV re-infection prophylaxis in clinical studies. Recurrence rates differ among these studies as most of them are limited by a non-randomised study design, small sample size, lack of long-term data and varying time intervals for the switch from combined to purely virostatic prophylaxis. Post-transplant pre-emptive antiviral therapy with pegylated IFN and ribavirin is associated with low sustained virological response rates and was found to have no advantage over treatment of manifest HCV re-infection. Safety and efficacy of triple antiviral therapy including boceprevir or telaprevir in patients with manifest HCV re-infection are currently under investigation in clinical trials. Relevant drug interactions have been shown to occur during calcineurin inhibitor (CNI) and concomitant triple antiviral therapy, which vary with type of CNI and choice of HCV protease inhibitor. Newer direct-acting antivirals with lower or minimal toxicity, when used in combination with immunosuppressives, are worthy of further study in LT patients. This review focuses on hot topics in the management of hepatitis B and C patients before and after LT and offers a critical summarised selection of the corresponding relevant studies published in the current literature or presented at recent liver congresses.

Estimates of HCV-1 Patients Attaining RVR Following Dual Therapy with Peg-Interferon and Ribavirin

Given the significant side-effects and healthcare costs associated with telaprevir- or boceprevir-combination therapy, identifying patients likely to respond to dual therapy peg-interferon (Peg-IFN)/ribavirin is highly desirable. Since the perception of how large the pool of patients who may achieve rapid virologic response (RVR) is vaguely ascertained, we searched the literature for this information. Studies on patients treated with Peg-IFN/ribavirin were identified by searching MEDLINE and analyzed by meta-analysis. The primary end point was weighted estimates of RVR. The influence on race/ethnicity, baseline viremia, type of Peg-IFN, ribavirin dosage, and significant hepatic fibrosis on the results was evaluated. Across 38 studies on 13,219 patients, the fraction of RVR patients was 19.6 %. The only baseline factor influencing RVR was race/ethnicity, with higher rates in Asian (26.7 %) and Caucasian patients (22.5 %). Of the 1,735 RVR patients, 85.1 % attained sustained virologic response (SVR). In these, SVR was influenced by ribavirin dose (86.8 vs. 72.8 % for high or low), type of Peg-IFN (91.8 % for alpha-2b vs. 82.9 % for alpha-2a), and treatment duration (91.7 % for 48 weeks vs. 79.4 % for 24 weeks). One fifth to one fourth of hepatitis C virus genotype 1 (HCV-1) patients can be safely treated with dual therapy of Peg-IFN/ribavirin, and may be spared from cost and inconvenience of regimens considering the addition of HCV protease inhibitors.

Boceprevir in combination with HIV protease inhibitors in patients with advanced fibrosis‐altered drug‐drug interactions?

In HIV/HCV co‐infected patients improved treatment outcomes have been reported for the HCV protease inhibitors (PIs) boceprevir (BOC) and telaprevir (TVR), reaching SVR rates of up to 70% in pilot trials. Due to complex drug‐drug‐interactions triple therapy is substantially limited in HIV/HCV‐coinfected individuals. Co‐administration of BOC with the commonly available HIV PIs has been reported not only to decrease the level of BOC but also to lead to relevant decreases in the respective HIV PI. Here, we report on two patients who received BOC‐containing HCV triple therapy in combination with a HIV PI. Patient 1 was on darunavir 800 mg/ritonavir 100 mg once‐daily mono‐therapy. Using FibroScan a liver stiffness of 34 kPa suggested liver cirrhosis prior to start of HCV triple therapy. At week 5 of HCV triple therapy darunavir trough concentration was measured in the reference range with 3777 ng/ml (reference trough concentration 2400–4600 ng/ml). HCV‐RNA became negative at week 10 and HIV‐RNA was below detection limit (<40 copies/ml) at all times. Patient 2 was on a simplified FTC qd and fos‐amprenavir 700 mg/ritonavir 100 mg bid regimen. Liver disease had also progressed to liver cirrhosis, confirmed in FibroScan, with a liver stiffness of 32 kPa. At week 8 of HCV triple therapy fos‐amprenavir trough level was measured in the normal reference range with 1699 ng/ml (reference trough concentration 750–2500 ng/ml). At week 11 HCV‐RNA was <12 IU/ml and HIV viral load was below detection limit of <40 copies/ml at all times. Our clinical data suggest that in patients with advanced liver disease possibly drug levels of HIV PIs which are coadministered with BOC may be within the normal range. In order to better understand the true amount of drug interactions between BOC and commonly used HIV PIs in HIV/HCV‐coinfected patients with more advanced liver fibrosis, urgently more PK studies are required to make HCV triple therapy accessible for a wider number of HIV/HCV‐coinfected patients in desperate need of these drugs.

New agents for hepatitis C and the challenges in treating co‐infected patients

More recently, the improved understanding of the hepatitis C viral life cycle has led to the identification of numerous potential targets for novel, direct‐acting antiviral compounds. Two NS3/4A protease inhibitors, telaprevir and boceprevir, were the first oral HCV protease inhibitors which were approved in Europe and the United States in 2011 in combination with pegylated interferon (IFN)‐α and ribavirin for the treatment of chronic hepatitis C related to HCV genotype 1, in both treatment‐naïve and treatment‐experienced patients. Sustained virological response rates in the range of 66–75% and 59–66% have been achieved in these two patient populations, respectively, with treatment durations of 24 to 48 weeks. Despite these significant advances the high rate of adverse events and the high costs of these regimens have limited the uptake of these new regimens. In particular, the quest for removal of interferon from HCV therapy remains one of the great unmet medical needs in HCV therapy development. With an increasing number of other DAAs in clinical development including second‐wave, first‐generation, and second‐generation NS3/4A protease inhibitors, nucleoside/nucleotide analogue inhibitors and non‐nucleoside inhibitors of HCV‐RNA‐dependent RNA polymerase, inhibitors of nonstructural protein 5A (NS5A) and host‐targeted compounds such as cyclophilin inhibitors and silibinin, the hope for better tolerated HCV therapies and potentially interferon‐free HCV combination therapies has grown considerably. The proof of concept that IFN‐free regimens may lead to HCV eradication has recently been brought in GT2/3 patients treated with PSI‐7977 and ribavirin for 12 weeks as well as in GT1b patients treated with BMS‐790052 + BMS‐650032 for 24 weeks. Although some patients with GT1a infection were also cured under this regimen, the majority of patients relapsed after treatment discontinuation, suggesting that at least for the 1a HCV genotype more effective interferon‐free regimens still need to be developed. Interestingly, also GT1 non‐responders treated with GS‐7977+ribavirin showed a high relapse rate, again underlining that more challenging patient populations will still exist which either need broader oral combinations or longer treatment durations. Overall, the dramatic increase in efficacy has also been seen in DAA‐based HCV therapy in HIV/HCV‐coinfected patients. However, complex drug‐drug interactions and tolerability issues remain a concern for all HCV patients, but particularly for HIV patients receiving antiretroviral therapy with a high potential for drug interactions.

Naturally occurring mutations to HCV protease inhibitors in treatment-naïve patients

BackgroundProtease inhibitors (PIs) to treat hepatitis C (HCV) virus infection have been approved and others are under development.ResultsThe aims of this study were to illustrate natural polymorphisms in the HCV protease and measure the frequency of PI resistance mutations in different HCV genotypes from PI-naïve patients.Direct sequencing of HCV NS3/4A protease was performed in 156 HCV patients naïve to PIs who were infected with genotype 1a (n = 31), 1b (n = 39), 2 (n = 30), 3 (n = 33) and 4 (n = 23).Amino acid (aa) substitutions associated with HCV PI resistance were found in 17/156 (10.8%) sequences. Mutations V36L, T54S, V55A/I, and Q80K/L were observed in 29% of patients with genotype 1a, and V55F, Q80L/N and M175L in 10% of patients with genotype 1b. The mutation V158M was found in 3% of patients with genotype 2, D168Q was present in 100% of patients with genotype 3 and D168E was observed in 13% of patients with genotype 4. In addition, multiple aa polymorphisms not associated with PI resistance were detected in patients with genotypes 1a, 1b and 4.ConclusionsAlthough major PI resistance mutations were not detected, other resistance mutations conferring low level resistance to PIs together with a number of natural polymorphisms were observed in proteases of PI naïve HCV patients. A more extensive analysis is needed to better evaluate the impact of baseline resistance and compensatory mutations in the efficacy of HCV PI treatment.

Interchanging of Direct Acting Antiviral Agents in the Treatment of Hepatitis C Infection: Are All Protease Inhibitors Created Equal?

Purpose: The standard of care (SOC) therapy for patients with chronic Hepatitis C has changed due to the emergence of direct acting antiviral agents (DAA). These novel serine NS3/4A protease inhibitors are now used in combination with pegylated interferon and ribavirin in the treatment of genotype 1 chronic hepatitis C infection in adult patients with liver diseases (including cirrhosis) who are treatment naïve or who have failed previous treatment. Although pegylated interferon and ribavirin remain core components of therapy, these DAAs have led to a substantial improvement in SVR rates and the option of abbreviated therapy in many patients. However, the efficacy of these medications has not been established for patients who have failed previous treatment regimens that contained HCV protease inhibitors. We report the case of a 48-year-old male with stage 2 fibrosis, Hep C genotype 1b infection who had previously completed a 60 week course of pegylated interferon and ribavirin therapy and proved to be a partial responder with HCV RNA detectable at week 24. The patient subsequently had a course of consensus interferon and ribavirin therapy for an additional 26 weeks that proved to be a null responder. In our clinical setting, the patient was started on triple therapy comprising of pegylated interferon, ribavirin and boceprevir. Unfortunately, the patient met treatment futility rule at week 12 with a HCV RNA PCR assay of 190 IU which was confirmed on repeat testing. The patient's treatment strategy was reinstituted with the substitution of boceprevir for telaprevir, in addition to pegylated interferon and ribavirin. The patient obtained a rapid virological response (RVR) with undetectable HCV RNA by PCR at week 4 of treatment. The patient has currently received 10 weeks of treatment on this new regimen. This is potentially the first case reported of induction of virologic response with one protease inhibitor in a patient who failed treatment with another one. The emergence of antiviral resistance Hep C variants (conferred by substitutions of the NS3 amino acid sequence) was observed in phase 2 and 3 clinical trials of both protease inhibitors and was associated clinically with virological failure and relapse. A cohort of these substitutions was found common to both protease inhibitors, suggesting that some degree of cross resistance may exist. This has led to weak evidence not recommending the initiation of one protease inhibitors in the face of failure of treatment on another. Further studies are needed to assess this and the potential for substitutions of HCV protease inhibitors in patients with an inadequate viral response.

Compensatory substitutions in the HCV NS3/4A protease cleavage sites are not observed in patients treated unsuccessfully with telaprevir combination treatment

BackgroundDevelopment of compensatory mutations within the HIV p7/p1 and p1/p6 protease cleavage site region has been observed in HIV-infected patients treated with protease inhibitors. Mechanisms of fitness compensation may occur in HCV populations upon treatment of HCV protease inhibitors as well.FindingsIn this study, we investigated whether substitutions in protease cleavage site regions of HCV occur in response to a treatment regimen containing the NS3/4A protease inhibitor telaprevir (TVR). Evaluation of viral populations from 569 patients prior to treatment showed that the four NS3/4A cleavage sites were well conserved. Few changes in the cleavage site regions were observed in the 159 patients who failed TVR combination treatment, and no residues displayed evidence of directional selection after the acquisition of TVR-resistance.ConclusionsCleavage site mutations did not occur after treatment with the HCV protease inhibitor telaprevir.

Crystal structures of HCV NS3/4A protease complex with HCV protease inhibitors

Crystal structures of HCV NS3/4A protease complex with HCV protease inhibitors

Probing the cation binding modes of macrocyclic HCV Protease inhibitor BILN 2061 by multinuclear NMR

The ability of the macrocyclic HCV protease inhibitor BILN 2061 to bind different classes of cations has been studied by (15)N, (13)C, and (1)H NMR. (15)N NMR experiments were performed at natural abundance or with isotopically labeled materials. Three classes of cations: alkali metals, alkaline earth metals, and transition metals, were examined, using two members of each class. The behavior of each cation class was found to be different, and provided insight into how metal ions interact with the molecular scaffold. These specific interactions were uncovered by examining coordination shifts, NOE correlations, and line broadening across all three nuclei.

PMO-166 Early experience with telaprevir for patients with advanced fibrosis or cirrhosis

IntroductionThe direct-acting HCV protease inhibitor telaprevir has recently been licensed for treatment of chronic genotype 1 HCV infection, and promises significant improvements in sustained virological response for these patients. However...

Hepatitis C and HIV Co-Infection: New Drugs in Practice and in the Pipeline

HCV/HIV coinfection continues to represent a serious health issue with risk of liver disease progression and development of hepatocellular carcinoma. Pegylated interferon with ribavirin is approved for treatment but results are suboptimal and tolerability poor. First-generation HCV protease inhibitors appear to significantly improve HCV treatment response in the setting of HIV infection. Interactions with HIV protease inhibitors have been documented, but the significance of this in terms of adverse reactions and HCV or HIV viral breakthrough remains uncertain. Next generation agents hold the promise of even better efficacy, with improved dosing schedules and perhaps decreased risk of drug:drug interactions.

New drug interactions in HIV and HCV

Drug-drug interactions (DDIs) remain one of the challenges faced by health care professionals involved in patient management and by researchers seeking to understand the many different mechanisms that may be involved. While in HIV treatment there has been an understanding that checking for DDIs is part of routine management, the development of directly acting antiviral (DAA) drugs is changing the whole approach to the treatment of HCV. DDIs have not really been high on the agenda while pegylated interferon and ribavirin have been the standard of care for Hepatitis C; however the first generation HCV protease inhibitors while representing a huge advance, also present new treatment challenge of awareness and management of DDIs. In this presentation, some of the key areas of DDIs with a) HIV drugs, b) HCV drugs and c) co infected patients receiving both HIV and HCV drugs will be discussed. While it has long been established that boosted HIV protease inhibitors are likely to interact with other medications metabolised by CYP3A4 (and other enzymes/transporters) to increase drug exposure and that drugs like efavirenz, nevirapine and etravirine are inducers of drug metabolism some of the current challenges are to determine i) the likelihood of interactions where there are no study data to guide us and ii) what happens when a patient switches therapy off an enzyme inducing drug. In relation to the new DAAs, Boceprevir is primarily metabolised by the enzyme aldo-ketoreductase (AKR) but also undergoes metabolism by CYP3A4; telaprevir is metabolised by CYP3A4. In addition, both boceprevir and telaprevir are strong inhibitors of CYP3A4 and are substrates for P-glycoprotein. Co administration of drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious or life threatening events means a contraindication with boceprevir and/or telaprevir. However, many other interactions require close monitoring, alteration of drug dosage or timing of administration and here we clearly need help to understand the potential magnitude of an interaction and strategies for patient management. Since targeted drug interaction studies are done in the development programme and then post-licensing there are a limited number of drugs for which there are actual study data. Where there are no data, guidance can only be given based on knowledge of the pharmacology of the respective drugs. This is the approach being used in the resource http://www.hep-druginteractions.org. One particular area of concern is HIV positive patients who are receiving antiretrovirals (ARVs) since they are relatively highly represented among patients with HCV infection, and are at a high risk of DDIs. Recent drug interaction data presented on telaprevir and boceprevir have reinforced the initial suspicions that we are faced with a whole new challenge of managing multiple interactions in co-infected patients. Management of DDIs with these exciting new agents certainly poses a challenge and awareness of the potential for DDIs is fundamental for safe prescribing. Think DDIs for the DAAs. But we are still on a steep learning curve and there are unanswered questions.

Rapid Decline of Viral RNA in Chronic Hepatitis C Patients Treated Once Daily with IDX320: A Novel Macrocyclic HCV Protease Inhibitor

The addition of direct-acting antivirals to pegylated interferon-α plus ribavirin for the treatment of chronic HCV infection can result in an increased sustained viral response rate and may permit reduction in treatment duration. IDX320 is a potent non-covalent macrocyclic inhibitor of the HCV NS3/4A protease. This was a randomized double-blind placebo-controlled single- and multiple-dose study to assess the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in healthy volunteers (HV) and patients with chronic HCV genotype 1 infection. HV (n=48) received single or multiple ascending doses of IDX320. Two HCV-infected patients received a single dose of 200 mg IDX320. Dosages for other HCV-infected patients were as follows: placebo, 50, 100, 200 or 400 mg of IDX320 orally once daily for 3 days (n=30) or placebo/200 mg of IDX320 twice-daily for 3 days (n=8). In total, 48 HV and 40 HCV-infected patients were enrolled and all completed the study. There were no serious adverse events. The majority of adverse events were of mild or moderate intensity. Pharmacokinetics supported a once-daily dosing regimen. A rapid decline in plasma HCV RNA was observed in all patients. In the multiple-dose study, mean HCV RNA reductions were 2.6, 3.1, 3.1, 3.3 and 3.8 log(10) IU/ml after 3 days in the IDX320 50, 100, 200, 400 mg once-daily and 200 mg twice-daily treatment groups, respectively. This compared to a mean HCV RNA reduction of 0.04 log(10) in the placebo group. Once-daily IDX320 dosing demonstrated potent dose-dependent antiviral activity in treatment-naive HCV genotype-1-infected patients.

HIV‐HCV co‐infection facing HCV protease inhibitor licensing: implications for clinicians

With the licensing of the first hepatitis C (HCV) protease inhibitors (PI), telaprevir (TVR) and boceprevir (BOC), cure rates for chronic HCV infection will substantially improve. Human immunodeficiency virus- chronic hepatitis C (HIV-HCV) co-infected patients are in urgent need for these new drugs, because they are facing both severe liver disease and lower response rates than HCV monoinfected patients. The currently available efficacy data are however, limited to two phase II trials. Fortunately, TVR and BOC appear to be able to improve cure rates in co-infected patients. A major challenge for clinicians will be the management of drug-drug interactions of antiretroviral drugs and new PI. As HCV PI are also metabolized by the cytochrome P450 3A4 system interactions are probable as well with non-nucleoside reverse transcriptase inhibitors as with HIV PI. To our knowledge, TVR can only be safely used with one protease inhibitor, boosted atazanavir, and also with efavirenz (EFV), although this combination requires TVR dose adjustments. Boceprevir should not be combined with HIV PI and should not be combined with EFV. The approval of TVR and BOC will create new chances of cure also for HIV-HCV co-infected patients. However, the decision who to treat or not has to be taken carefully on the basis of fibrosis stage and previous treatment outcomes. In addition, HIV therapy needs to be optimized according to the available drug-drug interaction data.

Discovery of Novel Urea-Based Hepatitis C Protease Inhibitors with High Potency against Protease-Inhibitor-Resistant Mutants

The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.