Telaprevir-based Triple Therapy Research Articles

Ruptured hepatocellular carcinoma in a patient with chronic hepatitis C and a sustained viral response

Hepatitis C virus (HCV) is one of the most common causes of chronic liver disease in the world (1). The goal of chronic hepatitis C therapy is to prevent cirrhosis of the liver and hepatocellular carcinoma (HCC) by achieving a sustained virologic response (SVR). It has been reported that telaprevir-based triple therapy enabled 60%–70% SVR in genotype 1 (G1) patients (2,3). The 74-year-old male patient was diagnosed with chronic hepatitis C 6 years ago, and peginterferon (P) + ribavirin (R) therapy was initiated. As HCV-RNA positivity continued in the 24th week of treatment, the patient was considered unresponsive, and his treatment was concluded. With the introduction of telaprevir into the therapy approximately one year later, the G1b patient was started on a triple therapy (telaprevir, PR) for 12 weeks followed by a 36-week course of double therapy (PR); thereby, his treatment was completed in a total of 48 weeks. The patient, who now had SVR, has been followed up in the 4 years since the completion of his therapy by carrying out tests on his HCV-RNA and alpha-fetoprotein (AFP) levels, alongside abdominal ultrasonography (ABD USG) performed every 6 months. The patient, who presented to the emergency department with a complaint of severe abdominal pain reflecting on his right shoulder about 4 months after his latest follow-up, had a heterogeneous solid mass about 6 cm in size in his eighth liver segment alongside free fluid in the perihepatic and pelvic areas, as revealed by ABD USG. The results of testing showed that the patient had a high AFP level of 36 ng/mL (0–8.1). The results of all abdominal computed tomography scans carried out in view of these findings showed that the patient’s liver was of a normal size with no pronounced undulation of the contours. A heterogeneous solid mass lesion about 67 × 73 × 68 mm in size growing toward the subdiaphragmatic space in liver segment 8 was observed to reveal a hyperdense, possibly arterial contrasting image; the presence of high-density fluid around the mass in the subdiaphragmatic space was also visualized. Consequently, the rapidly contrasting arterial mass on the hepatic dome was diagnosed as HCC (?), hepatic adenoma (?), and a ruptured mass, and it was recommended that the patient undergo dynamic magnetic resonance (MR). A T1A hypointense, T2A mildly hyperintense heterogeneous solid mass, 63 × 70 mm in size with fine borders and irregular contours, was visualized on the dome level of the eighth segment of the right lobe (Figure 1). As a result, the patient was diagnosed with spontaneous rupture of the mass because of his high AFP levels, the presence of a solid mass concordant with HCC, contour irregularity neighboring the superior, and signs of hemoperitoneum observed in the perihepatic area. The patient was taken into surgery and died in the perioperative period. The risk of HCC development in patients with SVR through direct-acting antiviral (DAA) has proven to be a controversial issue (4,5). Patients with SVR through DAA administration should be followed up every 6 months with regards to ABD USG results and AFP levels.

Efficacy of telaprevir-based therapy in stable liver transplant patients with chronic genotype 1 hepatitis C

Background and rationale. The REPLACE study (NCT01571583) investigated telaprevir-based triple therapy in patients who have recurrent genotype 1 hepatitis C virus (HCV) infection following liver transplantation and are on a stable immunosuppressant regimen of tacrolimus or cyclosporin A. Patients received telaprevir 750 mg 8-hourly with pegylated interferon 180 μg weekly and ribavirin 600 mg daily, followed by a further 36 weeks of pegylated interferon and ribavirin alone and 24 weeks of follow-up. Efficacy (sustained virological response [SVR] 12 weeks after last planned study dose), safety and tolerability of telaprevir throughout the study were assessed. Pharmacokinetics of telaprevir, tacrolimus and cyclosporin A were also examined.Results. In total, 74 patients were recruited. Overall, 72% (53/74; 95% CI: 59.9 to 81.5) of patients achieved SVR at 12 weeks following completion of treatment. Anticipated increases in plasma concentrations of tacrolimus and cyclosporin A occurred during telaprevir treatment and were successfully managed through immunosuppressant dose reduction and, for tacrolimus, reduced dosing frequency. Safety and tolerability of telaprevir-based triple therapy were generally comparable with previous data in non-transplant patients, although rates of reported anemia (55% [41/74]) were higher. Elevated plasma creatinine (46% [34/74]) was observed during REPLACE - consistent with the post-liver transplant population and the co-administered immunosuppressants.Conclusion. Telaprevir-based triple therapy in patients with recurrent genotype 1 HCV infection following liver transplantation produced high rates of SVR. Therapeutic concentrations of immunosuppressants were maintained successfully through dose modification during telaprevir treatment.

Regional Differences in the Safety of Telaprevir-Based Triple Therapy for Chronic Hepatitis C in Japan:

Regional Differences in the Safety of Telaprevir-Based Triple Therapy for Chronic Hepatitis C in Japan:

Dendritic cells activation is associated with sustained virological response to telaprevir treatment of HCV-infected patients

First anti-HCV treatments, that include protease inhibitors in conjunction with IFN-α and Ribavirin, increase the sustained virological response (SVR) up to 80% in patients infected with HCV genotype 1. The effects of triple therapies on dendritic cell (DC) compartment have not been investigated. In this study we evaluated the effect of telaprevir-based triple therapy on DC phenotype and function, and their possible association with treatment outcome.HCV+ patients eligible for telaprevir-based therapy were enrolled, and circulating DC frequency, phenotype, and function were evaluated by flow-cytometry. The antiviral activity of plasmacytoid DC was also tested.In SVR patients, myeloid DC frequency transiently decreased, and returned to baseline level when telaprevir was stopped. Moreover, an up-regulation of CD80 and CD86 on mDC was observed in SVR patients as well as an improvement of IFN-α production by plasmacytoid DC, able to inhibit in vitro HCV replication.

The Safety Profile of Telaprevir-Based Triple Therapy in Clinical Practice: A Retrospective Cohort Study.

This study was designed to evaluate the safety profile of adding telaprevir to therapy using pegylated interferon-alfa-2b and ribavirin (PR) using real world patient data obtained from a nationwide Japanese interferon database. This retrospective cohort study compared telaprevir-based triple therapy (T/PR) with PR therapy. The study population comprised patients with genotype 1 chronic hepatitis C represented in the database between December 2009 and August 2015. The primary endpoint was dropout from treatment due to adverse events during the relevant standard treatment duration based on guidelines from the Japan Society of Hepatology. The dropout odds ratio (OR) and 95% confidence interval (95% CI) were calculated using univariate logistic regression analysis. Covariates were detected using a stepwise logistic regression analysis, and the adjusted OR and 95% CI were calculated. A total of 25989 patients were registered, and 4619 patients (T/PR: 1334, PR: 3285) were appropriate for primary endpoint analysis. The dropout rate due to adverse events was lower in the T/PR group (13.4%) than in the PR group (22.6%) (OR: 0.530; 95% CI, 0.444-0.633). After adjustment for the covariates detected by stepwise selection, the OR was 0.529 (95% CI, 0.441-0.634). Our study showed that there was a difference in dropout rate between real world T/PR and PR therapy in Japan. Although the addition of telaprevir to PR therapy may improve treatment continuity under the care of hepatologists, this study could not fully determine which therapy was safer or the factors influencing this result. Therefore, additional research will be required to confirm this.

Telaprevir-based triple therapy for re-treatment Chronic HCV patients with Genotype 1, including the Null-Response: A single center experience from Turkey

Telaprevir-based triple therapy for re-treatment Chronic HCV patients with Genotype 1, including the Null-Response: A single center experience from Turkey

Liver Apparent Diffusion Coefficient Changes during Telaprevir-Based Therapy for Chronic Hepatitis C.

Diffusion-weighted imaging (DWI) has become an established diagnostic modality for the evaluation of liver parenchymal changes in diseases such as diffuse liver fibrosis. To evaluate the parenchymal apparent diffusion coefficient value (ADC) changes using diffusion-weighted imaging (DWI) during telaprevir-based triple therapy. Diagnostic accuracy study. Seventeen patients with chronic hepatitis C virus (HCV) virus and twenty-five normal volunteers were included. All of the patients took 12-weeks of telaprevir-based triple therapy followed by 12-weeks of PEGylated interferon and ribavirin therapy. They were examined before treatment (BT), as well as 12-weeks (W12) and 24-weeks (W24) after treatment by 3 Tesla magnetic resonance imaging (MRI). DWI was obtained using a breath-hold single-shot echo-planar spin echo sequence. Histopathologically, liver fibrosis was classified in accordance with the modified Knodell score described by Ishak. Quantitatively, liver ADCs were compared between patients and normal volunteers to detect the contribution of DWI in the detection of fibrosis. In addition, liver ADCs were compared during the therapy to analyze the effect of antiviral medication on liver parenchyma. The liver ADC values of fibrotic liver parenchyma were significantly lower than those of the healthy liver parenchyma (p<0.001). However, we were not able to reach a sufficiently discriminative threshold value. The ADC values showed a declining trend with increasing fibrotic stage. No statistically significant correlation (p=0.204) was observed. Compared with those before treatment, the liver ADC values after telaprevir-based triple therapy were significantly decreased at W12. A significant increase in the liver ADC values was also observed after the cessation of telaprevir therapy at W24 with a return to initial values. Liver ADC values appear to indicate the present but not the stage of liver fibrosis. DWI may be a helpful research tool for the assessment of antiviral drug effects.

Ultra-deep sequencing analysis of resistance-associated variants during retreatment with simeprevir-based triple therapy after failure of telaprevir-based triple therapy in patients with genotype 1 hepatitis C virus infection.

Simeprevir (SMV)-based triple therapy is an effective retreatment option following failure of telaprevir (TVR)-based triple therapy. However, it is unclear whether the persistence of resistance-associated variants (RAVs) induced by TVR-based therapy may reduce the treatment effect of SMV-based therapy. The factors associated with the treatment effect, including RAVs in the NS3 region, were examined in 21 patients with genotype 1b HCV infection who were treated with SMV-based therapy after failure of TVR-based therapy. Ultra-deep sequencing was carried out to detect RAVs. With the exception of one patient who discontinued treatment owing to adverse events, the sustained virologic response (SVR) rate was 50% (10/20). Ultra-deep sequencing at the start of SMV-based therapy revealed that TVR-resistant variants were detected in six patients (29%), and no variants were observed at position 168. Cross-resistance between TVR and SMV with low frequency was detected in only one patient, and this patient achieved SVR. Higher SVRs for SMV-based therapy were attained in patients who discontinued treatment owing to the adverse effects of prior TVR-based therapy (discontinuation 100% vs. non-discontinuation 29%, P = 0.005), and patients who relapsed following prior pegylated interferon plus ribavirin therapy (relapse 100% vs. non-response 20%, P = 0.007). In this study, ultra-deep sequencing analysis revealed that TVR and/or SMV-resistant variants may have no influence on the effect of SMV-based therapy after failure of TVR-based therapy. Patients who discontinued treatment owing to adverse effects of TVR-based therapy and relapsers to previous pegylated interferon/ribavirin therapy would be good candidates for retreatment with SMV-based therapy.

Telaprevir-based Triple Therapy for Retreatment of Chronic Hepatitis C Patients with Genotype Four Followed in Our Clinic

OZ Objective: Telaprevir-based triple therapy for chronic hepatitis C virus (HCV) patients with genotype 4 is not recommended potently by the guidelines. There are few studies in the literature related to this issue. This study showed the antiviral activity and safety of telaprevir-based regimens in the treatment of treatmentexperienced genotype 4 chronic HCV-infected patients. Materials and Methods: This retrospective study consisted of 12 genotype 4 HCV-infected patients. All patients received 12 weeks of telaprevir in combination with 24 weeks of pegylated interferon (PEG-IFN) alpha and ribavirin (RBV). Results: The sustained virological response (SVR) rate was six of 12 (50%). Notably, the rate of SVR in prior relapsers was 75% (6 of 8). SVR could not be achieved in non-responders. Conclusion: Telaprevir, a potent HCV NS3-4A protease inhibitor, has been used as monotherapy and in combination with PEG-IFN/RBV in patients infected with genotype 1, 2 and 3 HCV. Limited clinical data suggest that telaprevir has activity against genotype 4 HCV. In this study, it was observed that the addition of telaprevir to the standard regimen had a greater activity on treatment relapse patients with genotype 4.

Two-Year Follow-Up Analysis of Telaprevir-Based Antiviral Triple Therapy for HCV Recurrence in Genotype 1 Infected Liver Graft Recipients as a First Step towards Modern HCV Therapy.

Objective. The introduction of protease inhibitors telaprevir and boceprevir in 2011 had extended the antiviral treatment options especially in genotype 1 infected hepatitis C relapsers and nonresponders to interferon/ribavirin therapy. The aim of this study was to analyze the long-term treatment efficiency of telaprevir-based triple therapy for patients with hepatitis C reinfection after orthotopic liver transplantation. Patients and Methods. We included 12 patients with histologically confirmed graft fibrosis due to hepatitis C reinfection. The treatment duration was scheduled as 12 weeks of telaprevir-based antiviral triple therapy followed by 36 weeks of dual therapy with pegylated interferon/ribavirin. The patients were followed up for two years after the end of triple therapy. Results. Of the 12 patients, 6 (50%) completed the full 48 weeks of antiviral treatment. An end of treatment response and a sustained virological response 52 weeks after the end of the antiviral treatment course were achieved in 8/12 (67%) and 7/12 (58%) patients, respectively. Conclusion. Telaprevir-based triple therapy was shown to be a long-term effective but complex treatment option for individual patients with hepatitis C graft. With the recent improvements in hepatitis C therapy options telaprevir may not be recommended as a standard therapy for this indication anymore.

Simeprevir or telaprevir with peginterferon and ribavirin for recurrent hepatitis C after living-donor liver transplantation: A Japanese multicenter experience.

This study aimed to clarify the efficacy and safety of simeprevir, a second-generation NS3/4A inhibitor, with peginterferon and ribavirin for recurrent hepatitis C after liver transplantation. A retrospective cohort study of living-donor liver transplant recipients with recurrent hepatitis C with the hepatitis C virus genotype 1 treated with either simeprevir- or telaprevir-based triple therapy was carried out at eight Japanese liver transplant centers. Simeprevir- and telaprevir-based triple therapies were given to 79 and 36 patients, respectively. Of the 79 patients treated with simeprevir-based triple therapy, 44 (56%) achieved sustained virological response 12weeks (SVR12) after treatment ended, and there was no significant difference in the SVR12 between the simeprevir- and telaprevir-based triple therapy groups (69%). The rates of adverse events were not significantly different between the simeprevir- and telaprevir-based triple therapy groups, although the rate of patients who received blood cell transfusion and erythropoietin due to anemia and had renal insufficiency were significantly higher in the telaprevir group than in the simeprevir group. Three baseline factors, the presence of prior dual therapy with peginterferon and ribavirin (P = 0.001), a non-responder to the prior dual therapy (P <0.001), and male sex (P = 0.040), were identified as significant predictive factors for non-SVR with simeprevir-based triple therapy. Simeprevir-based triple therapy for recurrent hepatitis C after living-donor liver transplantation resulted in a high SVR rate and good tolerability, especially in treatment-naïve patients.

Analysis of renal function during telaprevir-based triple therapy for chronic hepatitis C.

Telaprevir (TVR) is used for the treatment of chronic hepatitis C in a combination therapy with pegylated-interferon and ribavirin. Although renal dysfunction is one of the critical adverse outcomes of this treatment, little is known regarding the mechanism of its onset. The present study assessed the association of renal function with TVR dose and viral response. Hematological, biochemical, urinary and virological parameters of renal function were examined during the TVR-based triple therapy of patients infected with hepatitis C virus (HCV) genotype 1b. Serum creatinine levels were increased and the estimated glomerular filtration rate (eGFR) was decreased in every patient during TVR administration, but these values recovered to normal levels following cessation of TVR. Fractional excretion of sodium was <1% at days 3 and 7, appearing similar regardless of baseline renal function. Urinary β2-microglobulin levels were elevated and were significantly higher in patients with renal dysfunction, as compared with those not exhibiting renal dysfunction (P<0.05). The reduction in renal function was milder in patients treated with a reduced TVR dose, and these patients had a significantly lower risk of developing renal dysfunction (P<0.05). Using a multivariate analysis, TVR dose and eGFR at the initiation of treatment were identified as significant contributory factors in the development of renal dysfunction. Reduction in TVR dose did not lead to a significant increase in the viral kinetics of HCV or detrimental effects on the sustained viral response (SVR) rate. It is hypothesized that renal dysfunction during TVR treatment is caused by damage of the renal tubule, in addition to pre-renal dysfunction, and that reduction in TVR dose reduces the rate of renal dysfunction without causing a significant decrease in the SVR rate.

Telaprevir-based triple therapy following partial splenic arterial embolization for chronic hepatitis C with thrombocytopenia can reduce carcinogenesis and improve hepatic function reserve.

Thrombocytopenia in patients with chronic hepatitis C negatively impacts interferon (IFN)-based treatment. The aim of this study was to evaluate the efficacy and safety of telaprevir (TVR)-based triple therapy including IFN for patients who have undergone partial splenic arterial embolization (PSE). Ten patients with thrombocytopenia who were infected with hepatitis C virus (HCV) genotype 1b received 12 weeks of TVR in combination with 24 weeks of pegylated interferon (PEG-IFN)α2b and ribavirin following PSE. A sustained virological response (SVR) was seen in 9 of the 10 patients who could be assessed. Early relapse was seen in 1 patient who had the IL-28B minor allele and a null response to pretreatment. The α-fetoprotein levels of the patients decreased from 17.94±7.30 ng/ml prior to PSE to 4.33±2.41 ng/ml at 6 months after triple therapy (P=0.08). Furthermore, serum albumin levels improved significantly from 3.68±0.49 g/dl pre-PSE to 4.13±0.34 g/dl at 12 months after triple therapy (P=0.043). PSE contributed to the treatment success of triple therapy, particularly for patients who were either treatment-naïve, had a history of relapse or the IL28B major allele. This strategy can reduce carcinogenesis and improve hepatic function reserve.

The Effect on Gastric Emptying of Telaprevir-Based Triple Therapy for Chronic Hepatitis C Patients

Aim: We evaluated food intake in telaprevir-based triple therapy (telaprevir, pegylated-interferon, and ribavirin) and its relation to Gastric Emptying (GE). Methods: 17 patients received telaprevir combined with pegylated interferon plus ribavirin. The GE study was carried out using the 13C-acetate breath test and GE time was expressed as the peak time of 13CO2 excretion (Tmax).

Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure.

Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG-IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir-based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir-based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG-IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG-IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct-acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG-IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir-based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG-IFNα and ribavirin. For patients with prior null response to PEG-IFNα and ribavirin, retreatment with simeprevir-based triple therapy is not a useful option.

Daily Low-dose Tacrolimus Is a Safe and Effective Immunosuppressive Regimen During Telaprevir-based Triple Therapy for Hepatitis C Virus Recurrence After Liver Transplant

Graft loss because of hepatitis C virus recurrence is a serious problem after liver transplantation (LT), and the response to pegylated interferon (PEG-IFN) and ribavirin (RBV) is poor. The significantly better response rates achieved with telaprevir (TVR)-based triple therapy have led to better graft and patient survival rates, but severe drug interactions may limit the usefulness of this therapy for LT patients. We report our single-center experience with a specially developed protocol that involved administering a low daily dose of tacrolimus (TAC) to a cohort of 17 patients with a recurrence of hepatitis C virus genotype 1 after LT. Patients were treated with TVR, PEG-IFN, and RBV for 12 weeks, followed by 12 or 36 weeks of dual therapy with PEG-IFN and RBV. After TVR administration was initiated, the TAC dosage was skipped until trough levels began to decline; it was then administered at a dose of 0.1 mg once or twice daily. Tacrolimus trough levels and laboratory values were closely monitored during the TVR phase. Deviations in trough levels were avoided, thus preventing any clinically evident renal toxicity related to TAC. In addition, histologic studies performed at the end of therapy showed that no rejection episodes had occurred. All patients tolerated the medication. Sustained virologic response was documented for 10 of 17 patients (58%) 24 weeks after end of treatment. In conclusion, substantial dose reduction and daily administration of low doses of TAC compose a safe and efficient immunosuppressive regimen during TVR-based triple therapy.

Postmarketing surveillance of telaprevir-based triple therapy for chronic hepatitis C in Japan.

An observational postmarketing study was conducted to evaluate the real-world safety and efficacy of an NS3-4A protease inhibitor, telaprevir (TVR), in combination with pegylated interferon-α-2b (PEG IFN) and ribavirin (RBV), for patients with chronic hepatitis C (CHC). Here, we report an interim analysis of data from 3563 patients. Patients were treated with TVR, PEG IFN and RBV for 12 weeks, followed by PEG IFN and RBV for 12 weeks (triple therapy). Safety was evaluated throughout the 24-week treatment period. Risk factors for development of the three important adverse drug reactions (ADR), skin disorders, grade 3 anemia (hemoglobin level <8 g/dL) and serious renal dysfunction, were analyzed using a multivariate logistic regression model. Efficacy was assessed on the basis of sustained virological response (SVR) after treatment completion. Total and serious ADR were observed in 96.5% and 35.7% of patients, respectively. ADR related to skin disorders and anemia were frequently observed in this study and in the phase III clinical studies, whereas those related to serious renal dysfunction were new observations. Concomitantly, various predictive risk factors for development of the three important ADR were identified. The SVR rate was 87.7% in all patients. When patients were grouped by previous treatment history, SVR rates were 91.8% in naive patients, 91.0% in relapsers and 70.6% in non-responders. Although many ADR were observed, they can be controllable with appropriate risk management strategies based on the predictive risk factors for important ADR. Furthermore, the efficacy of the triple therapy was found to be favorable.

The birth and potential death of IL28B genotyping for hepatitis C therapy.

The birth and potential death of IL28B genotyping for hepatitis C therapy.

Evolution of hepatitis C virus quasispecies during repeated treatment with the NS3/4A protease inhibitor telaprevir.

In treating hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections, the rapid reselection of resistance-associated variants (RAVs) is well known in patients with repeated exposure to the same class of antiviral agents. For chronic hepatitis C patients who have experienced virologic failure with direct-acting antiviral drugs, the potential for the reselection of persistent RAVs is unknown. Nine patients who received 14 days of telaprevir monotherapy were retreated with telaprevir-based triple therapy 4.3 to 5.7 years later. In four patients with virologic failure with both telaprevir-containing regimens, population-based and deep sequencing (454 GS-FLX) of the NS3 protease gene were performed before and at treatment failure (median coverage, 4,651 reads). Using deep sequencing, with a threshold of 1.0% for variant calling, no isolates were found harboring RAVs at the baseline time points. While population-based sequencing uncovered similar resistance patterns (V36M plus R155K for subtype 1a and V36A for subtype 1b) in all four patients after the first and second telaprevir treatments, deep sequencing analysis revealed a median of 7 (range, 4 to 23) nucleotide substitutions on the NS3 backbone of the resistant strains, together with large phylogenetic differences between viral quasispecies, making the survival of resistant isolates highly unlikely. In contrast, in a comparison of the two baseline time points, the median number of nucleotide exchanges in the wild-type isolates was only 3 (range, 2 to 8), reflecting the natural evolution of the NS3 gene. In patients with repeated direct antiviral treatment, a continuous evolution of HCV quasispecies was observed, with no clear evidence of persistence and reselection but strong signs of independent de novo generation of resistance. Antiviral therapy for chronic viral infections, like HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV), faces several challenges. These viruses have evolved survival strategies and proliferate by escaping the host's immune system. The development of direct-acting antiviral agents is an important achievement in fighting these infections. Viral variants conferring resistance to direct antiviral drugs lead to treatment failure. For HIV/HBV, it is well known that viral variants associated with treatment failure will be archived and reselected rapidly during retreatment with the same drug/class of drugs. We explored the mechanisms and rules of how resistant variants are selected and potentially reselected during repeated direct antiviral therapies in chronically HCV-infected patients. Interestingly, in contrast to HIV and HBV, we could not prove long-term persistence and reselection of resistant variants in HCV patients who failed protease inhibitor-based therapy. This may have important implications for the potential to reuse direct-acting antivirals in patients who failed the initial direct antiviral treatment. (The phase IIIb study described in this paper is registered at ClinicalTrials.gov under registration number NCT01054573.).

No correspondence between resistance mutations in the HCV-NS3 protease at baseline and early telaprevir-based triple therapy

Direct-acting antiviral (DAA)-based therapy is the new standard treatment for chronic hepatitis C virus (HCV) infection. However, protease inhibitor (PI)-resistant viral variants have been often described. This study aimed to examine HCV-NS3 protease variants at baseline and at 4weeks under triple therapy. To this end, we analyzed the presence of variants in HCV-NS3 protease region from peripheral blood samples of 16 patients infected with HCV-1 at baseline and at 4weeks of combined therapy with telaprevir, pegylated interferon, and ribavirin, using next-generation sequencing. Several variants with synonymous and non-synonymous amino acid substitutions were detected at both time points. Variants detected at low frequency corresponded to 74% (HCV-1a) and 35% (HCV-1b) of non-synonymous substitutions. We found nine PI-resistance-associated variants (V36A, T54S, V55I, Q80K, Q80R, V107I, I132V, D168E, M175L) in HCV-NS3 of 10 patients. There was no correspondence of resistance-associated variant profile between baseline and at 4weeks. Moreover, these resistance variants at baseline and short-term treatment are not good predictors of outcome under triple therapy. Our study also shows a large number of others minor and major non-synonymous variants in HCV-NS3 early in telaprevir-based therapy that can be important for further drug resistance association studies with newly developed PI agents.