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Background & Aims: Direct-acting antivirals (DAA) lead to high sustained virological response (SVR) rates and decrease the risk of disease progression. We compared SVR rates and all-cause, liver- and non-liver-related deaths, liver-related events, and non-liver-related cancers in HIV/HCV-coinfected and HCV-monoinfected participants from 2 French cohort studies after initiation of DAA treatment., Methods: Up to 4 HCV-monoinfected participants from the ANRS CO22 HEPATHER cohort were matched by age and sex to each HIV/HCV-coinfected patient from the ANRS CO13 HEPAVIH cohort; both are nationwide, prospective, multicentre, and observational. Participants were initiated on DAAs between March 2014 and December 2017. Cox proportional hazards models adjusted by age, sex, duration since HCV diagnosis, HCV transmission routes, HCV genotypes, cirrhosis, tobacco, alcohol consumption, and SVR (time dependent) were used., Results: A total of 592 HIV/HCV-coinfected and 2,049 HCV-monoinfected participants were included; median age was 53.3 years (inter-quartile range: 49.6-56.9) and 52.9 years (49.6; 56.7), 1,498 (73.1%) and 436 (73.6%) were men, and 159 (28.8%) and 793 (41.2%) had cirrhosis, respectively. SVR was observed in 92.9% and 94.6%, respectively. HIV coinfection was associated with higher risk of all-cause death (hazard ratio [HR] 1.93; 95% CI 1.01-3.69), non-liver-related death (HR 2.84; 95% CI 1.27-6.36), and non-liver-related cancer (HR 3.26; 95% CI 1.50-7.08), but not with liver-related-death (HR 1.04; 95% CI 0.34-3.15) or liver-related events (HR 0.66; 95% CI 0.31-1.44)., Conclusions: After DAA treatment, HIV-coinfected individuals had similar SVR rates and risk of liver-related deaths and events compared with HCV-monoinfected individuals, but had a higher risk of all-cause and non-liver-related deaths and non-liver-related cancers., Lay Summary: We compared the risk of several clinical events in participants infected by human immunodeficiency virus and hepatitis C virus with those infected with hepatitis C virus alone, matched on age and sex, after treatment with contemporary direct-acting antivirals. We found a higher risk of all-cause deaths, non-liver-related deaths, and non-liver-related cancers in participants coinfected with the human immunodeficiency virus and hepatitis C virus, and no differences for the risk of liver-related deaths or events., Competing Interests: Conflicts of interest S.P. has received consulting and lecturing fees from Bristol-Myers Squibb, Janssen, Gilead, Roche, MSD and Abbvie, Biotest, Shinogi, ViiV, and grants from Bristol-Myers Squibb, Gilead, Roche, and MSD. P.S. has received consulting and lecturing fees from AbbVie, Genfit, Gilead, Janssen, Mayoly-Spindler, and MSD. H.F. has received lecturing fees from Abbvie Gilead and MSD. D.S. has received lecturing fees from Abbvie and Gilead. The other authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: Because of the lack of evidence regarding long-term effectiveness and cost-effectiveness of first-generation direct-acting antivirals for chronic hepatitis C (CHC) treatment in Brazil, we performed a cost-utility analysis comparing standard dual therapy (peginterferon plus ribavirin [pegIFN/RBV]), boceprevir, and telaprevir for CHC patients., Methods: We developed a state-transition Markov model simulating the progression of CHC. Long-term outcomes included remaining life expectancy in life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Short-term outcomes included sustained virological response rates (SVR). Direct medical costs were obtained from Brazilian databases. A lifelong time horizon was considered and a 5% annual discount rate was applied for costs and clinical outcomes. A willingness-to-pay threshold of approximately $20 000 per QALY was used. We performed multiple sensitivity analyses., Results: For short- and long-term scenarios, therapy with boceprevir was dominated by telaprevir, which was more effective than standard dual therapy (75.0% vs 40.4% SVR rate, 13.47 vs 12.59 LYs, and 9.74 vs 8.49 QALYs, respectively) and was also more expensive ($15 742 vs $5413). The corresponding ICERs were $29 854/SVR, $11 803/LY, and $8277/QALY. Based on our model, triple therapy with telaprevir was the most cost-effective treatment for the Brazilian health system. Despite a lack of data regarding the Brazilian population, we incorporated as many applicable parameters as possible., Conclusions: Telaprevir is more effective and cost-effective than boceprevir. Our model may be applied for other settings with a few adjustments in the input parameters., (Copyright © 2019 ISPOR--The professional society for health economics and outcomes research. Published by Elsevier Inc. All rights reserved.)

Introduction: Chronic hepatitis C is a leading cause of liver disease. Infection triggers an immediate immune response in the host that is mediated by humoral/cellular mechanisms. T cells respond to infection via secretion of cytokines, which inhibit or stimulate one another, leading to cytokine imbalance and ultimately affecting treatment. Studies using interferon (IFN) and ribavirin (RBV) showed that TCD8+ cells and cytokine levels are associated with sustainable virological response (SVR). However, studies that investigated the effects of triple therapy (TT) are limited., Methods: The study included hepatitis C virus (HCV)+ RNA, naives, genotype 1, ≥18 years, and advanced fibrosis (F≥3) patients. Samples were collected at baseline and after 12 weeks (W12) of TT. Six cytokines were analyzed by flow cytometry., Results: Of 31 patients, four were excluded (two deaths, one interrupted TT, and one F2 patient). Of the 27 remaining patients, 21 (78%) were cirrhotic. SVR was achieved in 63% of the patients. The patients had a mean age of 55.11 ± 10.03 years. Analyses at baseline showed that the chemokine CCL5/Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) (p=0.04) and interleukin (IL)-6 (p=0.02), which was associated with SVR. RANTES (p=0.04) and IL-8 (p=0.01) levels were associated with SVR at W12., Conclusions: Similar to patterns observed during double therapy, IL-6, IL-8, and RANTES levels were associated with SVR in TT, indicating the potential role of interferon in immune response to hepatitis C virus.

In 2012, the first-generation protease inhibitors telaprevir (TVR) and boceprevir (BOC) were introduced in the Brazilian health system for treatment of chronic hepatitis C, after their approval by the National Committee for Health Technology Incorporation (CONITEC). However, these medicines were discontinued in 2015. The short period of use in therapy and their high cost require a discussion about the consequences for patients and for the health system of the early incorporation of new therapies. The article presents a qualitative analysis of the incorporation process of both medications in Brazil and the results of a multicenter study that included patients treated with BOC or TVR between January 2011 and December 2015 in five Brazilian cities. The study included 855 patients (BOC: n=247) and (TVR: n=608). The document analysis showed that CONITEC's decision to incorporate BOC and TVR was based on results of phase III clinical trials that compared sustained virologic response (SVR) rates of patients treated with BOC and TVR with rates of those that received placebo. However, these studies included a low percentage of cirrhotic patients. The SVR rates observed in this multicenter study were worse than clinical trials pointed out (BOC: 45.6%; TVR: 51.8%), but similar to those achieved with previously adopted therapies. The discontinuation rate due to adverse events was (BOC: 15.4%; TVR: 12.7%). Based on these unsatisfactory results, the study brings a discussion that goes beyond the therapy outcomes, exploring the incorporation of these high-cost medicines and the related decision-making process, contributing to future decisions in medicine policies and in the treatment of chronic hepatitis C.

Human endothelial progenitor cells (hEPCs) are promising therapeutic resources for wound repair through stimulating neovascularization. However, the hEPCs-based cell therapy has been hampered by poor engraftment of transplanted cells. In this study, we explored the effects of N-acetylated Proline-Glycine-Proline (Ac-PGP), a degradation product of collagen, on hEPC-mediated cutaneous wound healing and neovascularization. Treatment of hEPCs with Ac-PGP increased migration, proliferation, and tube-forming activity of hEPCs in vitro. Knockdown of CXCR2 expression in hEPCs abrogated the stimulatory effects of Ac-PGP on migration and tube formation. In a cutaneous wound healing model of rats and mice, topical application of Ac-PGP accelerated cutaneous wound healing with promotion of neovascularization. The positive effects of Ac-PGP on wound healing and neovascularization were blocked in CXCR2 knockout mice. In nude mice, the individual application of Ac-PGP treatment or hEPC injection accelerated wound healing by increasing neovascularization. Moreover, the combination of Ac-PGP treatment and hEPC injection further stimulated wound healing and neovascularization. Topical administration of Ac-PGP onto wound bed stimulated migration and engraftment of transplanted hEPCs into cutaneous dermal wounds. Therefore, these results suggest novel applications of Ac-PGP in promoting wound healing and augmenting the therapeutic efficacy of hEPCs.

The aim of this study was to determine risk factors for adverse events (AE)-related treatment discontinuation and severe anemia among patients with chronic hepatitis C virus (HCV) genotype 1 infection, treated with first-generation protease inhibitor (PI)-based therapy. We included all patients who initiated treatment with PI-based therapy at a Brazilian university hospital between November 2013 and December 2014. We prospectively collected data from medical records using standardized questionnaires and used Epi Info 6.0 for analysis. Severe anemia was defined as hemoglobin ≤8.5 mg/dL. We included 203 patients: 132 treated with telaprevir (TVR) and 71 treated with boceprevir (BOC). AE-related treatment discontinuation rate was 19.2% and anemia was the main reason (38.5%). Risk factors for treatment discontinuation were higher comorbidity index (OR=1.85, CI=1.05-3.25) for BOC, and higher bilirubin count (OR=1.02, CI=1.01-1.04) and lower BMI (OR=0.98, CI=0.96-0.99) for TVR. Severe anemia occurred in 35 (17.2%) patients. Risk factors for this outcome were lower estimated glomerular filtration rate (eGFR; OR=0.95, CI=0.91-0.98) for patients treated with TVR, and higher comorbidity index (OR=2.21, CI=1.04-4.67) and ribavirin dosage (OR=0.84, CI=0.72-0.99) for those treated with BOC. Fifty-five (57.3%) patients treated with TVR and 15 (27.3%) patients treated with BOC achieved sustained virological response (SVR). Among patients who received TVR and interrupted treatment due to AE (n=19), only 26.3% (n=5) achieved SVR (P=0.003). Higher number of comorbidities, lower eGFR and advanced liver disease are associated with severe anemia and early treatment cessation, which may compromise SVR achievement.

Background: Pivotal phase studies of telaprevir (TLV) and boceprevir (BOV) showed 10-56% rates of early treatment interruption. However, there have been no reports on the sustained virological response (SVR) rates of these patients., Aim: To assess the SVR rate in a large cohort of patients who discontinued triple therapy with TLV or BOV for reasons other than stopping rules and to identify variables predicting SVR., Material and Method: A survey was sent to 15 hospitals in Catalonia asking them to report all TLV/BOV treatments finished by 31 May 2014. Demographic, clinical, laboratory, liver fibrosis and therapeutic data were recorded for treatments with early discontinuation. Logistic regression analysis, ROC curves and prognostic assessment of the variables identified were calculated., Results: Twelve hospitals responded to the survey, representing 467 treatments and 121 (21.2%) early discontinuations, 76 (62.8%) due to stopping rules and 45 (37.2%) for other reasons. Early discontinuation was more frequent with BOV [38.2% (50/131) versus 21.1% (71/336) p<0.005], mainly due to stopping rules [78% (39/50) versus 52.1% (37/71); p=0.004]. SVR was achieved in 21/121 patients (17.4%), 19/71 (26.8%) treated with TLV and 2/50 (4.0%) treated with BOV. In patients discontinuing treatment for reasons other than stopping rules, SVR was achieved in 19/37 (55.9%) treated with TLV and in 2/11 (18.2%) treated with BOV. The SVR rate in patients treated with TLV who discontinued due to a severe adverse event was 61.5% (16/26). A logistic regression analysis was performed only with triple therapy with TLV and early discontinuation. The predictive variables of SVR were undetectable HCV-RNA at treatment week 4 and treatment length longer than 11 weeks. Treatment duration longer than 11 weeks showed the best accuracy (0.794), with a positive predictive value of 0.928., Conclusions: Early discontinuation of TLV-based triple therapy due to reasons other than stopping rules still have a significant SVR rate (55.9%). Undetectable HVC-RNA at week 4 of treatment and treatment duration longer than 11 weeks are predictive of SVR in this subset of patients., (Copyright © 2015 Elsevier España, S.L.U. y AEEH y AEG. All rights reserved.)

Background: For the last decade the backbone of hepatitis C (HCV) treatment was the pan-genotyping dual therapy with pegylated interferon alfa in combination with Ribavirin. This regimen was limited in achieving sustained virological response (SVR) and accompanied by serious adverse events. In 2010 there was overwhelming progress in the treatment options for HCV. This change began with the introduction of the first generation specific Direct Antiviral Agents (DAA's) that inhibit the viral protease, agents used in combination with the dual protocol for genotype 1 (triple therapy). In 2014 this revolution continued with the introduction of advanced DAA's targeting different non-structural viral proteins. These DAA's achieve an all oral regimen shorter in duration with outstanding SVR rates and mild side effects. Our liver clinic manages the treatment and follow-up of the vast majority of patients with HCV in southern Israel. As part of the unprecedented advance in the treatment regimen for HCV with the introduction of the first generation DAA's and especially after they were included by the national health care as an option for treatment, we started to treat HCV genotype 1 patients with the triple regimen. Now, in the era of advanced DAA's regimens, we look back, retrospectively, analyze and conclude our experience with a regimen that changed the conception of eradication for HCV by combining immune activation and specific inhibition of functional viral proteins. This was conducted in the hope that it will inspire the development of revolutionary regimens for eradication in other viral diseases., Methods: During the period between September 2011 to November 2013, 55 patients infected with HCV genotype 1 were treated in our outpatient liver clinic with the triple regimen. These patients finished a 6 month period of post-treatment follow-up allowing the evaluation of their viral PCR status at the latest in May 2014. The data were collected from the patient's computerized file and were statistically analyzed by the SMC clinical research center., Results: Out of the 55 patients, 39 received Telaprevir as the protease inhibitor and 16 were treated with Boceprevir. Of all the treated patients 34 achieved SVR; 47% of patients with genotype 1A reached SVR, whereas 71% of those with genotype 1B reached that endpoint. A total of 63.6% of patients with mild or no fibrosis (F 0-2) achieved SVR compared to 63% in patients with advanced fibrosis (F 3-4]. There were 6 patients with no METAVIR evaluation. A total of 57% of naïve patients, 83.3% of prior relapsers and 57.1% of previous non-responders reached SVR at 6 months in current triple therapy. There was no significant response difference in any sub-group when the two first generation PI's were compared., Conclusions: In our experience with first generation PI based triple regiment for HCV genotype 1, though more effective than previous dual treatment, it was still limited in its effectiveness, while creating some major safety issues. In light of this new era where much more effective and safe DAA's emerged and are now in routine use, the triple therapy in our view should be reviewed as a transitional phase that changed forever the concept of eradicating HCV and aimed at specific viral sites. This regimen paved the way for advanced DAA protocols achieving cures in overwhelming unprecedented rates.

Aim: To clarify the role of virus resistance in the efficiency of antiviral therapy with protease inhibitors (PIs) chronic hepatitis C (CHC) patients, with moderate sensitivity to interferon-α., Materials and Methods: Eight Caucasian patients (4 men and 4 women) aged 21 to 65 years (median 52.5 years) with genotype 1b hepatitis C virus (HCV) infection were included in the study. Two patients were diagnosed with liver cirrhosis; 4 had been ineffectively treated with peginterferon in combination with ribavirin. None of the patients had obesity and/or insulin resistance. All the 8 patients received triple therapy with PIs (boceprevir (n=3), telaprevir (n=4), and simeprevir (n=1)) and as a result failed to achieve a sustained virologic response. All the participants were studied to identify mutations in HCV NS3/4A region., Results: Five of the 8 patients were found to have mutations in HCV NS3/4A region (substantially reducing drug susceptibility in 3 cases)., Conclusion: In CHC patients who are moderately sensitive to interferon-α and receive therapy with PIs, resistance to the latter is critically important for the efficiency of therapy and the timely identification of resistance mutations can contribute to the choice of an optimal treatment policy.

No data have been reported yet on treatment outcome in persons who inject drugs (PWID) infected with hepatitis C virus treated with boceprevir or telaprevir in combination with peginterferon (Peg IFN) and ribavirin (RBV). Additionally, there are concerns about the safety of boceprevir and telaprevir in some subgroups of patients with hepatitis C (HCV). In a cohort of HCV patients infected with genotype 1 in Belgium, treatment outcome of patients infected due to IV drug use was analyzed and compared with patients who have no history of substance use. The study population consisted of 179 patients: 78 PWID and 101 controls treated with boceprevir (n = 79) or telaprevir (n = 100) additional to Peg IFN and RBV; 53 (30%) had advanced disease (F3, F4) and 79 (44%) had an antiviral therapy previously. There were no significant differences in the baseline characteristics between both groups, except that PWID patients were more frequently infected with genotype 1a (67% vs 21%), were younger and were predominantly male. Psychiatric complaints during follow-up occurred more frequently in the PWID patients: 24% versus 11% (P = .02). Treatment failure for other reasons than absence of viral response was 70% and 64% in PWID and non-PWID respectively. The sustained viral response (SVR) rates were similar in both groups (71% in PWID vs 72% in non-PWID); with a non-inferiority test with -5% margin there is a difference of -1% (95% CI [-15%, 13%]) and P = 0.30. There are no reasons to exclude PWID from treatment with boceprevir, telaprevir and novel antiviral therapies., (© 2015 Wiley Periodicals, Inc.)

Background & Aims: The addition of protease inhibitors, boceprevir (BOC) or telaprevir (TRV), to peg-interferon and ribavirin (PR) increases the incidence of anaemia in patients with chronic hepatitis C virus (HCV) infection. Although genetic variants in inosine triphosphatase (ITPA) gene have been linked to the haemolytic anaemia induced by PR, the mechanism sustaining severe anaemia during triple therapy is still unknown. This study aims to elucidate the molecular mechanisms underlying anaemia in chronic HCV patients with combined therapy., Methods: We studied 59 patients with chronic HCV genotype-1: 29 treated with TRV/PR and 30 with BOC/PR. We evaluated biochemical and haematological parameters, red cell index at baseline, 4, 12, 16 and 24 weeks of treatment; in a subgroup, we performed functional studies: osmotic fragility, red cell membrane protein separation, mass spectrometry analysis, quantification of erythroid microparticles release. IL28B and ITPA polymorphisms were also evaluated., Results: We found early acute normochromic normocytic haemolytic anaemia (4-8 weeks) followed by a late macrocytic hypo-regenerative anaemia with inappropriate low reticulocyte count (12-24 weeks). Studies on red cells revealed: (i) presence of spherocytes; (ii) increased osmotic fragility; (iii) abnormalities in red cell membrane protein composition; (iv) reduced membrane-cytoskeleton stability; (v) increased release of erythroid microparticles. ITPA polymorphisms impacted only the early phase of anaemia., Conclusions: The bimodal pattern of anaemia in chronic HCV patients on triple therapy might be because of acquired spherocytic-like anaemia in the early phase, followed by hyporegenerative anaemia, most likely related to the combined effects of PR and TRV or BOC on erythropoiesis., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Monitoring ribavirin concentrations during hepatitis C treatment with dual therapy can help optimize treatment response and minimize anaemia. A defined therapeutic range for ribavirin during direct-acting antiviral-based therapies is lacking. This analysis explores whether a therapeutic range for ribavirin concentrations can be defined in patients treated with boceprevir- or telaprevir-based triple therapies., Methods: Treatment-naive patients from ADVANCE, ILLUMINATE, OPTIMIZE and SPRINT-2, and treatment-experienced patients from RESPOND-2 were included. Multivariable logistic regression analyses were performed to evaluate whether ribavirin concentrations were an independent predictor of sustained virological response or anaemia. Optimal cutoff values and the percentage of patients within the proposed therapeutic range were determined, along with the associated chance of response., Results: Overall, 1,502 patients were included. In both regimens, ribavirin concentrations were significantly associated with anaemia (haemoglobin level <10 g/dl) at all time points (1.75 < odds ratio [OR] <2.45) and sustained virological response was associated with ribavirin concentrations at week 8 (OR=1.43 for telaprevir and 1.78 for boceprevir). A therapeutic range for ribavirin at week 8 of 2.2-3.5 mg/l was defined for telaprevir treatment. Of the 48% of patients with a concentration within this range, 81% achieved sustained virological response and only 5.1% reported anaemia. For boceprevir treatment, the week 8 optimal range was defined as 2.2-3.6 mg/l and 50% of patients had a concentration within this range, of whom 69% achieved sustained virological response and 46% developed anaemia., Conclusions: We established the therapeutic range for ribavirin in boceprevir- and telaprevir-based therapy that balances safety and efficacy.

Background: As first generation HCV-specific protease inhibitors, boceprevir (BOC) or telaprevir (TVR) can achieve 60% to 70% sustained virological response (SVR) for HCV infected patients with genotype 1 infections, they could remain temporary a therapeutic option in patients living in resources limited countries with limited access to the new anti-HCV direct acting antiviral (DAA) drugs, such as sofosbuvir., Objectives and Study Design: Here we evaluated in a routine practice setting, the treatment responses, tolerance and factors associated with SVR of a triple therapy with BOC or TVR, combined with pegylated interferon and ribavirin (PegIFN/RBV) in HIV/HCV co-infected patients, included in a large cohort of HIV/HCV coinfected patients (ANRS CO13-HEPAVIH)., Results: Among the 89 HIV/HCV coinfected patients treated, 65% of whom were previous non-responders to PegIFN/RBV therapy, 65%, 55% and 41% had at baseline genotype 1a, a high baseline HCV-RNA (≥800,000 IU/ml) and a cirrhosis, respectively. The SVR12 rate was 63% overall, 53% for BOC-based regimen and 66% for TVR-based regimen. In multivariate analysis, two factors were significantly associated with HCV SVR: HCV viral load <800,000 IU/mL at treatment initiation versus ≥800,000 IU/mL (OR 4.403, 95% CI 1.29-15.04; p=0.018) and virological response at W4 (HCV-RNA undetectable after 4 weeks of triple therapy) (OR 3.35, 95% CI 1.07-10.48; p=0.038)., Conclusions: Overall SVR12 was 63% and our results suggest that HIV/HCV coinfected patients with low HCV viral load (<800,000 IU/mL) and undetectable HCV-RNA after 4 weeks of triple therapy with TVR or BOC-based regimen have a higher probability of treatment success., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Introduction: Triple therapy with telaprevir or boceprevir has proven to be effective in the treatment of chronic hepatitis C with response rates of up to 88%. However, the treatment may be associated with important adverse effects and a high economic impact., Objective: To assess the cost-effectiveness and safety of triple therapy with telaprevir or boceprevir for the treatment of chronic hepatitis C., Methods: Retrospective observational study. We included all patients who had started treatment with protease inhibitors before July 31(st), 2013. We evaluated sustained virological response, the cost per patient achieving sustained virological response, and the cost of the supportive treatment for adverse events associated with triple therapy., Results: Fifty-nine patients were included; 35 had been treated with telaprevir (59.3%) and 24 with boceprevir (40.7%). Sustained virological response was achieved by 38 (64.4%) patients: 24 (68.6%) patients in the telaprevir treatment arm and 14 (58.3%) patients in the boceprevir treatment arm. The cost per patient with sustained virological response was 43,555 € (95% CI 35,389-51,722 €). There were no statistically significant differences between the overall costs of therapy with telaprevir, 43,494 € (95% CI 34,795 €-55,092 €) versus boceprevir, 42,005 € (95% CI 32,122-64,243€). The mean cost of supportive care per patient was 1,500 €, while the maximum cost was 11,374 €. Due to adverse events, 8 (13.6%) patients required hospital admission, 22 (37.3%) patients attended the accident and emergency department, and 26 (44.1%) patients needed additional medical consultations., Conclusions: The treatment of triple therapy with telaprevir or boceprevir resulted in high cost per patient with sustained virological response. Due to adverse events, a high number of patients required supportive care, whose costs should be added to those of triple therapy., (Copyright © 2015 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.)

Objectives: Vulnerable, urban populations with a history of substance use disorders have a high prevalence of hepatitis C virus (HCV). Primary care-based treatment has been proposed to improve access to care. In this study, we present outcomes from our urban, primary care-based HCV treatment program in patients treated with telaprevir or boceprevir in combination with pegylated-interferon and ribavirin ("triple therapy")., Methods: We collected data from 126 consecutive patients with genotype 1 HCV monoinfection seen in our treatment program (2011-2013). Among the 40 who initiated treatment, we analyzed factors associated with achieving a sustained viral response (SVR)., Results: During the study period, 40 patients initiated triple therapy (32%), 80% with recent or past substance use disorders. Patients initiating treatment were younger than untreated patients (P = 0.002), but otherwise did not differ demographically, or in the severity of their liver fibrosis (P > 0.05). An SVR was achieved in 18 patients (45%) and was less likely in patients with recent or past substance use disorders or psychiatric illness (both P < 0.01)., Conclusions: Nearly one third of patients initiated triple therapy with SVR rates comparable to other HCV treatment settings, despite a significant burden of mental illness and substance dependence. Our experience demonstrates that a primary care-based practice can successfully deliver HCV care to a vulnerable population. Additional interventions may be needed to improve outcomes in patients with recent or past substance use disorders or psychiatric illness.

Introduction: The aim of the study was to analyze the incidence, management and cost associated to hematological and dermatological adverse effects (AE) in chronic hepatitis C patients on triple therapy (TT) with telaprevir (TVR) or boceprevir (BOC)., Methods: An analysis was made on the data recorded on patients who started treatment with TVR or BOC associated with peginterferon alfa and ribavirin in a 12-week follow-up period., Results: Fifty-three patients were included (TVR n=36; BOC n=17). Thrombocytopenia (83% TVR vs. 88% BOC) followed by neutropenia (89% TVR vs. 82% BOC) were the most common AE. Dermatological AE were observed in 32% of patients. Eleven patients required treatment discontinuation (all of them received TVR), and toxicity was the main reason for discontinuation (64%). The percentage of patients who required supportive treatment for management of AE was 66%. The most used supportive treatment was erythropoietin. Eight patients required emergency health care, and 2 were hospitalized due to AE. Total cost of additional supportive resources was 32,522€ (625 [SD=876]€/patient) (TVR 759 [SD=1,022]€/patient vs. BOC 349 [SD=327]€/patient; P>.05). Patients with gradeiii-iv toxicity required greater supportive care with higher costs, compared to patients with gradei-ii toxicity (849 [SD=1,143]€/patient vs. 387 [SD=397]€/patient; P=.053)., Conclusion: The addition of new protease inhibitors to conventional treatment leads to a higher incidence of hematological AE in our study, compared to data described in clinical trials. The elevated incidence of AE involves the use of supportive care, increasing total costs of therapy., (Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.)

Background and Aims: Clinical trials of therapy against chronic hepatitis C virus (HCV) infection including boceprevir (BOC) or telaprevir (TVR) plus pegylated interferon and ribavirin (PR) have reported considerably higher response rates than those achieved with PR alone. This study sought to evaluate the efficacy and safety of triple therapy including BOC or TVR in combination with PR in HIV/HCV-coinfected patients under real-life conditions., Methods: In a multicentre study conducted in 24 sites throughout five European countries, all HIV/HCV-coinfected patients who initiated a combination of BOC or TVR plus PR and who had at least 60 weeks of follow-up, were analyzed. Sustained virologic response 12 weeks after the scheduled end of therapy date (SVR12) and the rate of discontinuations due to adverse events (AE) were evaluated., Results: Of the 159 subjects included, 127 (79.9%) were male, 45 (34.4%) were treatment-naïve for PR and 60 (45.4%) showed cirrhosis. SVR12 was observed in 31/46 (67.4%) patients treated with BOC and 69/113 (61.1%) patients treated with TVR. Overall discontinuations due to AE rates were 8.7% for BOC and 8% for TVR. Grade 3 or 4 hematological abnormalities were frequently observed; anemia 7%, thrombocytopenia 17.2% and neutropenia 16.4%., Conclusion: The efficacy and safety of triple therapy including BOC or TVR plus PR under real-life conditions of use in the HIV/HCV-coinfected population was similar to what is observed in clinical trials. Hematological side effects are frequent but manageable.

Background: HCV-TARGET is a longitudinal observational study of chronic hepatitis C virus (HCV) patients treated with direct-acting anti-viral agents (DAAs) in a US consortium of 90 academic and community medical centres., Aim: To assess utilisation of response-guided therapy (RGT) and sustained virological response (SVR) of a large cohort of patients., Methods: Patients received peginterferon (PEG-IFN), ribavirin and either telaprevir or boceprevir. Demographical, clinical and virological data were collected during treatment and follow-up. RGT and treatment futility stopping rules was assessed at key time points., Results: Of 2084 patients, 38% had cirrhosis and 56% had received prior treatment for HCV. SVR rates were 31% (95% CI: 24-40) and 50% (95% CI: 44-56) in boceprevir patients with and without cirrhosis, respectively. SVR rates were 46% (95% CI: 42-50) and 60% (95% CI: 57-64) in telaprevir patients with and without cirrhosis, respectively. Early clearance of virus, IL28B genotype, platelet counts and diabetes were identified as predictors of SVR among boceprevir patients, while early clearance of virus, IL28B, cirrhosis, HCV subtype, age, haemoglobin, bilirubin and albumin levels were identified as predictors of SVR for telaprevir patients., Conclusions: In academic and community centres, triple therapy including boceprevir or telaprevir led to SVR rates somewhat lower than those noted in large phase 3 clinical trials. Response rates were consistently higher among patients without cirrhosis compared to those with cirrhosis regardless of DAA used and prior treatment response. Trial registration clinicaltrials.gov NCT01474811., (© 2015 John Wiley & Sons Ltd.)

Goals: To examine the effect of provider type on outcomes and safety in a large hepatitis C virus (HCV)-infected cohort treated in routine medical practice., Background: Nonphysician providers (NPP) are uniquely positioned to expand health care infrastructure to meet HCV treatment demands., Study: Retrospective, observational cohort analysis of 820 HCV genotype 1-infected veterans initiated on peginterferon/ribavirin and boceprevir or telaprevir in routine medical practice at 94 VA facilities before January 1, 2012 and followed through July 30, 2013. Provider type was determined from prescription records and included physicians (MD) or NPPs (ie, nurse practitioners, physician assistants, and pharmacists). Inverse probability-of-treatment weighting and unweighted logistic regression analysis was used for comparison of sustained virologic response (SVR), treatment discontinuation rates, and adverse hematologic events., Results: There was no significant difference in SVR by provider type overall (NPPs 52% vs. MDs 49%, P=0.33) and within patient subgroups, or in treatment discontinuation rates. In multivariate analyses, provider type was not associated with any significant difference in the odds of achieving SVR (NPP vs. MD; odds ratio 1.17; 95% confidence interval, 0.84-1.63; P=0.37 inverse probability of treatment weighting; odds ration 1.16, 95% confidence interval, 0.84-1.59, P=0.38 unweighted). Hematologic adverse event rates were similar: anemia: 57% NPP, 62% MD; thrombocytopenia: 43% NPP, 40% MD; neutropenia: 40% NPP, 39% MD., Conclusions: Treatment prescribed by NPPs was as likely to result in SVR as treatment prescribed by MDs, even after accounting for patient differences. Engaging more NPPs as HCV treatment providers may allow wider access to HCV treatment.

Background & Aims: The safety profiles of boceprevir and telaprevir in the treatment of chronic hepatitis C, administered in academic and community centres across the United States, were evaluated., Methods: In 90 medical centres, patients with chronic HCV received pegylated interferon, ribavirin, and either telaprevir or boceprevir per local standard of care. Demographic, adverse event, clinical, and virological data were collected during treatment and follow-up., Results: A total of 2084 patients (97% HCV genotype 1) received at least one dose of a protease inhibitor. At baseline, 38% of patients had cirrhosis, and 57% had received at least one prior treatment for hepatitis C. Serious adverse events occurred in 12% of patients receiving protease inhibitor therapy. Overall, 66% of patients experienced anaemia, leading to frequent ribavirin dose reductions (42%) and erythropoietin use (37%); 11% received blood transfusion. More than 90% of patients had adverse events that led to a prescription, treatment, or dosage change, and 39% of patients discontinued treatment early, most commonly because of adverse events (18%) or lack of efficacy (16%). Hepatic decompensation events occurred in 3% of all patients. Age, female gender, cirrhosis, HCV genotype 1 subtype, creatinine clearance, platelet levels, albumin levels and haemoglobin levels were independent predictors of anaemia. Five deaths occurred. Overall, 52% of all patients achieved a sustained virologic response., Conclusions: In academic and community centres, where chronic hepatitis C patients commonly have advanced liver disease, triple therapy was associated with a high rate of adverse events and involved frequent treatment modifications and adverse event management., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aim: Hepatitis C virus (HCV) treatment in patients coinfected with HIV has historically been limited by poor efficacy and medication toxicities. Direct-acting antivirals (e.g. boceprevir and telaprevir) improve treatment results in clinical trials, but little is known about the outcomes in community-based coinfected populations. This project aimed to describe the real-world effectiveness of boceprevir-based or telaprevir-based therapies in HIV/HCV coinfected patients., Materials and Methods: We identified HIV/HCV coinfected patients of all genotypes in the Veterans Affairs healthcare system who initiated pegylated interferon and ribavirin with or without boceprevir or telaprevir from June 2011 to November 2012 (n = 134)., Results: Sustained virologic response (SVR) was higher in genotype 1 patients receiving boceprevir or telaprevir [n = 62, SVR = 50.0%, 95% confidence interval (CI) 37-63] versus pegylated interferon/ribavirin alone (n = 48, SVR = 33.3%, 95% CI 20-47). Patients with genotypes 2/3 treated with pegylated interferon/ribavirin (n = 24) achieved an SVR of 41.7% (95% CI 20-63). Only a few patients (15-25%) of each genotype completed more than 44 of 48 projected weeks. Treatment with boceprevir or telaprevir was the only characteristic independently associated with SVR in genotype 1 (adjusted odds ratio 2.2, 95% CI 1.1-4.7)., Conclusion: Addition of boceprevir or telaprevir to pegylated interferon/ribavirin improves treatment response in genotype 1 HIV/HCV coinfected patients. Treatment response is similar to reports from HCV monoinfected Veterans Affairs patients but lower than those reported in clinical trials. Early treatment discontinuation was common.

Background: In 2011, the FDA approved telaprevir (TVR) and boceprevir (BOC) for use with pegylated interferon and ribavirin to treat hepatitis C virus (HCV) genotype 1. We aimed to evaluate the real-world application, tolerability, and effectiveness of TVR- and BOC-based HCV treatment in a large integrated care setting., Methods: We utilized Northern California Kaiser Permanente Medical Care Program (KPNC) electronic databases and medical records to study the experience of all KPNC patients who initiated TVR or BOC from June 2011 to March 2012., Results: Compared with the pool of 5,194 treatment-eligible patients, the 352 treatment initiators were more likely to be cirrhotic (24 vs. 10%, p < 0.001) and treatment-experienced (44 vs. 22%, p < 0.001). Among the treatment initiators, 211 received TVR and 141 BOC. Overall, 31% discontinued treatment prematurely; 16% of patients stopped treatment early because of side effects. One patient with cirrhosis died of sepsis during treatment. Premature discontinuation was highest among TVR-treated cirrhotic patients (58%). Sustained virologic response (SVR) was achieved in 55% overall and was similar comparing the TVR (56%)- and BOC (53%)-treated groups. The only independent predictors of treatment failure were cirrhosis at baseline [odds ratio (OR) for SVR 0.44, p = 0.004] and prior partial or null response (OR for SVR 0.57, p = 0.02)., Conclusions: In the initial application of TVR and BOC, patients with cirrhosis and prior treatment failure were prioritized for treatment. In this real-world experience, most patients successfully completed a full treatment course. However, side effect-related premature discontinuations were common, and SVR rates were lower than reported in clinical trials.

Aims: The aim was to evaluate the effect of boceprevir and telaprevir on dolutegravir pharmacokinetics (PK); the effect of dolutegravir on boceprevir and telaprevir PK was assessed through comparison with historical data for each hepatitis C virus (HCV) drug's prescribing information alone., Methods: This was a single-centre, randomized, open-label, two-cohort, two-period, one-way study in healthy adult subjects. Dolutegravir 50 mg once daily was administered for 5 days in Period 1, and dolutegravir 50 mg once daily was coadministered with either boceprevir 800 mg every 8 h (Cohort 1) or telaprevir 750 mg every 8 h (Cohort 2) for 10 days in Period 2., Results: No deaths or serious adverse events were reported during the study. Four subjects were withdrawn from the study because of adverse events (elevated alanine aminotransferase, cellulitis, increased serum creatinine and dizziness). One subject became pregnant during the study. Coadministration of dolutegravir with boceprevir had no effect on dolutegravir area under the plasma concentration-time curve (AUC) and maximal plasma concentration (Cmax ) and caused a small increase in concentration at the end of the dosing interval (Cτ ; 8%). Coadministration of dolutegravir with telaprevir resulted in increased dolutegravir plasma exposures compared with those after administration of dolutegravir alone; AUC0- τ , Cmax and Cτ increased by 25, 19 and 37%, respectively. Coadministration of boceprevir or telaprevir with dolutegravir had no clinically significant effect on dolutegravir PK. Plasma boceprevir and telaprevir PK data for either combined treatment were similar to historical data, indicating no effect of dolutegravir on boceprevir or telaprevir exposure., Conclusions: Dolutegravir can be coadministered with boceprevir or telaprevir in patients coinfected with HIV and HCV with no dose adjustment., (© 2014 ViiV Healthcare/GSK. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

Boceprevir and telaprevir are both direct-acting antivirals indicated, as part of combination therapy for the management of chronic hepatitis C virus (HCV) genotype 1 infection. Transplanted patients treated with anticalcineurines (tacrolimus and cyclosporine) are confronted with major risks of interactions. Indeed, these antiviral are strong inhibitors of the enzyme cytochrome 3A4/A5, responsible for the metabolisme of ciclosprine and tacrolimus. The literature gives evidence of the dangerousness of this drug-drug interaction. We report four clinical cases illustrating the dosage adaptations at liver transplant patients and treated by telaprevir or boceprevir. To protect the immunosuppressive efficiency, a multidisciplinary care and narrow monitoring of the interaction between immunosuppressing agents and protease inhibitors were necessary., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

Triple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P=0.5), but there was a significant difference in the 50% effective concentrations (EC50) (P=0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively, P=0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day(-1)) and was higher in patients who subsequently eradicated HCV (P=0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

The aim of this study was to assess the therapeutic potential of telaprevir (TPV)/boceprevir (BOC)-based triple-therapy in a complete cohort of HIV/chronic hepatitis C co-infected patients (HIV/HCV). Moreover, a case series of four HIV/HCV genotype (HCV-GT)1 patients with rapid virologic response (RVR), who received only 28 weeks of BOC-based triple-therapy (BOCW28), was reported. 290/440 HIV-positive patients with positive HCV serology had at least one visit during the past 2 years, 142/290 had target detectable HCV-RNA with 64% (82/142) carrying HCV-GT1. While 18 HIV/HCV-GT1 displayed contraindications, 45% (64/142) of HIV/HCV were eligible for triple-therapy. Insufficiently controlled HIV-infection despite combined antiretroviral therapy (cART) (HIV-RNA <50 copies/mL: 73% vs. 22%; p<0.001) and liver cirrhosis (31% vs. 8%; p=0.025) were overrepresented among patients with contraindications for triple-therapy. Low treatment uptake rates (39% (25/64)) during the first 2 years of triple-therapy availability suggest that its benefit in HIV/HCV co-infected patients might fall short of expectations. Modification of cART or TPV dose adjustment would have been necessary in 61% and 84% of HIV/HCV-GT1 on cART eligible for triple-therapy using TPV and BOC, respectively, suggesting that drug-drug interactions with cART complicate management in the majority of patients. All four BOCW28 patients achieved a sustained virologic response. Prospective studies are necessary to validate our observations on the shortening of treatment duration in HIV/HCV-GT1 with RVR.

Objective: To evaluate the effects of boceprevir (BOC) and telaprevir (TVR) on the pharmacokinetics (PK) of maraviroc (MVC) in healthy volunteers., Methods: In this open-label, fixed-sequence study, 14 volunteers received MVC 150 mg twice daily alone for 5 days (period 1), followed by MVC + BOC 800 mg 3 times daily and MVC + TVR 750 mg 3 times daily, each for 10 days in periods 2 and 3, respectively, with a ≥10-day wash-out. PK was analyzed on day 5 of period 1 and day 10 of periods 2 and 3. Safety was also assessed., Results: Ratios of the adjusted geometric means (90% confidence intervals) for MVC area under the curve from predose to 12 hours, maximum plasma concentration, and plasma concentration at 12 hours were 3.02 (2.53 to 3.59), 3.33 (2.54 to 4.36), and 2.78 (2.40 to 3.23), respectively, for MVC + BOC versus MVC alone, and 9.49 (7.94 to 11.34), 7.81 (5.92 to 10.32), and 10.17 (8.73 to 11.85), respectively, for MVC + TVR versus MVC alone. PK profiles for MVC + BOC or TVR were consistent with historic values for BOC and TVR monotherapy. Adverse event incidence was higher with MVC + BOC and MVC + TVR versus MVC alone. Dysgeusia (50%) and pruritus (29%) occurred most commonly with MVC + BOC, and fatigue (46%) and headache (31%) with MVC + TVR. There were no serious adverse events., Conclusions: MVC exposures were significantly increased with BOC or TVR, therefore MVC should be dosed at 150 mg twice daily when coadministered with these newly approved hepatitis C protease inhibitors. No dose adjustment for BOC or TVR is warranted with MVC. MVC + BOC or TVR was generally well tolerated with no unexpected safety findings.

Background: Drug-drug interactions (DDIs) in the treatment of chronic hepatitis C infection became a potential challenge with the introduction of direct-acting anti-virals (DAAs). Both currently approved DAAs, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), are substrates and inhibitors of P-glycoprotein and the cytochrome P450 3A4, which are regularly involved in DDIs., Aim: To analyse the risk for DDIs in patients with chronic HCV genotype 1 infection considered for PI treatment at a tertiary referral centre., Methods: The first 115 consecutive patients selected for a PI therapy at Hannover Medical School were included. All changes to co-medication before and during PI treatment were documented. Drugs were checked for DDIs with TVR and BOC using DDI websites and the respective prescribing information., Results: Out-patient medication contained 116 different drugs. Median number of drugs/patient was 2 (range 0-11). The risk for DDIs was substantial for 38% of the drugs affecting 49% of patients. Only 4% of the drugs were strictly contraindicated. DDIs between a PI and drugs newly prescribed during anti-viral therapy were considerable in 42% of the patients. Suspected DDIs were managed by dose adjustments and discontinuation of co-medication in 7% and 21% of the patients respectively., Conclusions: Many patients with chronic HCV genotype 1 infection are affected by potential DDIs if treated with a protease inhibitor, but only in a minority of cases co-medication is strictly incompatible. Overall, the challenge of DDIs is time-consuming, but well manageable by a careful review of the patient's drug chart and monitoring during treatment., (© 2013 John Wiley & Sons Ltd.)

Background and Aims: The protease inhibitors (PIs) boceprevir and telaprevir are currently standard treatment as part of triple therapy regimens (TTx) for chronic HCV genotype 1 (GT1) patients. In this preliminary analysis, we have compared demographic variables, polypharmacy, and Charlson's comorbid index (CCI) with Rapid Virological Response (RVR) and extended RVR (eRVR) rates in HCV GT1 patients receiving PI containing TTx., Methods: Retrospective descriptive cohort study., Results: Among 74 HCV patients (46 M, 28 F; age: 54.43 ± 9.52 years; African Americans: 59.5 %) in this initial analysis, 44 % achieved RVR. All these RVR patients also achieved eRVR. Patients achieving RVR and eRVR were 50 ± 11.7 (mean ± SD) years old, compared to 58 ± 5.2 years without an RVR (p < 0.005). The average number of medications taken by patients achieving RVR and eRVR was 5 ± 2.7 compared to 9.24 ± 3.4 in patients not achieving RVR and eRVR (p < 0.005). Twenty-five percent of patients who were not on CYP3A4 inhibitors had an RVR and eRVR compared to 63.2 % who were taking CYP3A4 inhibitors (p = 0.001). Patients achieving RVR and eRVR had a lower CCI (1.61 ± 1.37) compared to those not achieving RVR and eRVR (2.8 ± 2.7; p = 0.02). Multivariate analysis also revealed a significant correlation between increased polypharmacy and CCI with lower RVR and eRVR rates., Conclusions: These preliminary treatment data demonstrate that increased polypharmacy and higher degrees of comorbidity decrease RVR and eRVR rates among patients receiving first generation PI-containing TTx regimens.

Background & Aims: In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme., Methods: 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16., Results: A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high., Conclusions: The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy., (Copyright © 2013. Published by Elsevier B.V.)

Background & Aims: Protease inhibitor triple therapy for hepatitis C virus (HCV) infection (boceprevir or telaprevir with pegylated interferon and ribavirin) has been shown to increase rates of sustained virologic response in phase 3 trials. We investigated the proportion of patients who began therapy with this regimen in the 12 months after the Food and Drug Administration approval of boceprevir and telaprevir in the United States., Methods: We performed a retrospective cross-sectional study of 487 patients with HCV genotype 1 infection (396 did not receive triple therapy, and 91 had begun triple therapy with boceprevir or telaprevir), who were seen at hepatology practices in Dallas and Miami from June 2011 through February 2012. The subjects were predominantly middle-aged, non-Hispanic white, and privately insured; 50% were treatment-naive, and most had advanced fibrosis. We compared features of patients who initiated triple therapy with those who deferred it. Treated patients were followed to determine the discontinuation rate in the first 12 weeks of treatment., Results: Of patients assessed, only 18.7% began triple therapy, the same percentage as those receiving dual therapy (pegylated interferon and ribavirin) before boceprevir or telaprevir was approved for treatment of HCV infection in the United States. Reasons for deferring treatment included relative contraindications (50.5%), patient choice (22.5%), and less advanced liver disease (17.4%). Among treated patients, 15% discontinued prematurely because of serious adverse events. On the basis of multivariate analysis, factors associated with initiation of triple therapy included prior treatment relapse (odds ratio [OR], 4.6; 95% confidence interval [CI], 2.1-9.9) and liver fibrosis of stage 3 (OR, 9.1; 95% CI, 3.1-27) or stage 4 (OR, 9.0; 95% CI, 3.3-25) but not hepatic decompensation., Conclusions: Only 18.7% of patients with HCV genotype 1 infection received triple therapy in the 12 months after Food and Drug Administration approval of boceprevir and telaprevir. This low percentage might result from concerns of side effects and recognition that more effective medications could be available in the future., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The safety, efficacy, and effect on immunosuppression levels of telaprevir (TVR) or boceprevir (BOC) in combination with peginterferon (PEG-IFN) and ribavirin (RBV) in recipients of liver transplantation (LT) with hepatitis C virus (HCV) genotype 1 have not been defined. We report our 3 centers' preliminary experiences with administering triple antiviral treatment protocols containing PEG-IFN, RBV, and TVR or BOC. Patients with biopsy-proven HCV recurrence (METAVIR grade ≥ 3 and/or stage ≥ 2) received TVR with PEG-IFN/RBV for 12 weeks and then PEG-IFN/RBV for 36 weeks or BOC with PEG-IFN/RBV for 44 weeks after 4 weeks of lead-in PEG-IFN/RBV. Maintenance immunosuppression was changed to cyclosporine whenever possible, and the levels were followed closely. PEG-IFN/RBV dose adjustments were based on patients' tolerance. Sixty patients started triple antiviral treatment, and they were followed for up to 66 weeks (mean = 35 weeks); all were followed at least 12 weeks. Thirty of the 35 patients treated with TVR (86%) achieved undetectable HCV RNA levels after an average of 6 weeks, whereas 12 patients (48%) in the BOC-treated group achieved undetectable HCV RNA levels after a mean of 11 weeks. According to an intention-to-treat analysis, 14 of 21 TVR-treated patients (67%) and 10 of 22 patients who received BOC (45%) achieved undetectable HCV RNA levels at week 24 without viral breakthrough at the last follow-up. Cytopenias complicated both regimens; all patients required dose reductions of PEG-IFN and/or RBV or the administration of hematological growth factors. One death occurred in each group on triple antiviral treatment. In conclusion, TVR or BOC combined with PEG-IFN/RBV achieved on-treatment virological response rates of approximately 50% to 60% in patients with recurrent HCV after LT, but significant side effects were common., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Summary.  Directly acting antiviral (DAA) agents are currently revolutionizing the treatment of chronic hepatitis C infection. The first generation of these agents have significant limitations including cost issues that are of particular concern in the developing world and a lack of efficacy in genotype 3 patients. Both of these concerns are of particular relevance in Pakistan., (© 2012 Blackwell Publishing Ltd.)

Background: Telaprevir and boceprevir are protease inhibitors now added to therapy for patients with chronic hepatitis C virus (HCV) genotype 1 infection who either are treatment naive or have a history of relapse or recurrence following a previous course of treatment with pegylated interferon + ribavirin (Peg-IFN + RBV). Because these agents are fairly new to the market, providers may have limited experience with them in the management of chronic HCV., Objective: This meta-analysis compared 24- and 48-week sustained viral responses (SVR) and drug-related adverse events (AEs) between telaprevir and boceprevir triple-therapy regimens in the treatment of chronic HCV infection., Methods: MEDLINE, EMBASE, and Cochrane databases were searched for articles published from January 1995 to October 2012 on randomized controlled trials that reported SVR at ≥24 weeks in patients with HCV receiving triple-therapy regimens that included telaprevir or boceprevir or placebo + pegylated interferon + ribavirin (Peg-IFN + RBV). Pooled odds ratios (ORs) were calculated and used to compare SVR at 24 and 48 weeks. Secondary end points included common drug-related AEs and treatment discontinuations., Results: Eight studies were included in this meta-analysis (N = 4144 treatment-naive and treatment-experienced patients). With telaprevir, the ORs (95% CI) for SVR at 24 weeks in treatment-naive and treatment-experienced patients were 3.31 (2.27-4.82; P < 0.0001) and 4.21 (1.83-9.72; P = 0.001), respectively. Telaprevir triple therapy did not result in more drug-related discontinuations but did cause additional rash, pruritis, and anemia. With boceprevir, the ORs (95% CI) were improved in both treatment-naive and treatment experienced patients (3.55 [2.66-4.56; P < 0.0001] and 7.34 [3.92-13.9; P < 0.0001]), but with more treatment-related anemia and dysgeusia., Conclusions: Based on the findings from this meta-analysis, telaprevir or boceprevir combined with Peg-IFN + RBV had favorable short-term data on SVR while resulting in more drug-related AEs. Extended follow-up is required to determine whether these agents offer a reduction in the risk for chronic hepatitis C genotype 1-related mortality and/or hospitalization., (Copyright © 2013 Elsevier HS Journals, Inc. All rights reserved.)

The approval of the first protease inhibitors as treatment for hepatitis C virus (HCV) infection is rapidly transforming the way patients with chronic hepatitis C are managed. Treatment regimens are moving to combinations given for shortened periods, excluding poorly tolerated subcutaneous interferon, and providing rates of cure exceeding 75%. The recognition of HCV infection as a systemic disease, not limited to producing liver damage, in which extrahepatic complications play a major role as the cause of morbidity and mortality, is prompting the treatment of a growing number of HCV-infected individuals. However, new challenges are emerging, including the need to diagnose a substantial proportion of asymptomatic carriers, the risk of potentially harmful drug-drug interactions and the high cost of medications. The future will probably see a progressive marginalization of residual HCV populations, with increasing over-representation of illegal immigrants, alcohol abusers, intravenous drug users and the mentally disabled., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background and Aims: To indirectly compare the efficacy of telaprevir (TVR) and boceprevir (BOC) combined with peginterferon/ribavirin α-2a/2b (PR) in achieving sustained viral response (SVR) in treatment-naïve and treatment-experienced patients with genotype 1 chronic hepatitis C virus (HCV) infection., Methods: A systematic literature review was conducted to identify randomized controlled trials reporting the efficacy of PR-based treatment in genotype 1 chronic HCV patients. A Bayesian network meta-analysis was performed on the endpoint of SVR, assuming fixed study effects. For treatment-experienced patients, only previous relapsers and partial responders were included, as no results in prior null responders were available for boceprevir., Results: Eleven publications were included. In treatment-naïve patients, the odds ratios (OR) (posterior median [95% credible interval]) for telaprevir (12 weeks + response guided treatment [RGT] 24/48 weeks PR) and boceprevir (24 weeks + RGT 28/48 weeks PR) versus PR were respectively 3.80 (2.78-5.22) and 2.99 (2.23-4.01). The OR for telaprevir versus boceprevir was 1.42 (0.89-2.25), with a probability for telaprevir being more effective (P[OR > 1]) of 0.93. In treatment-experienced patients, the OR of telaprevir (12 weeks + 48 weeks PR) and boceprevir (32 weeks + RGT 36/48 weeks PR) versus PR were respectively 13.11 (7.30-24.43) and 5.36 (2.90-10.30). The OR for telaprevir versus boceprevir was 2.45 (1.02-5.80), with telaprevir having a probability of 0.98 of being more effective., Limitations: The main limitation of this study is the low number of trials included in the analysis, especially for the treatment-experienced patient population, which only allowed random-effect models to be explored. We tried to identify potential biases due to study heterogeneity., Conclusions: In the absence of direct comparative head-to-head studies between telaprevir and boceprevir for the treatment of chronic HCV genotype 1 patients, an indirect comparison based on Bayesian network meta-analysis suggests better efficacy for telaprevir than boceprevir in both treatment-naïve and treatment-experienced patients.

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., (© 2012 John Wiley & Sons A/S.)

Telaprevir and boceprevir have received US Food and Drug Administration approval for use as triple therapy with pegylated interferon and ribavirin in genotype 1 chronic hepatitis C virus (HCV) infection. Clinical trials of these agents included few African Americans, despite the overwhelming need for improved therapies in this racial group. Although African Americans are predicted to have improved response rates with this new treatment paradigm, clinical trials illustrate lower rates of sustained virologic response for this racial group versus whites. African Americans with genotype 1 HCV infection appear to require longer durations of therapy than do whites to achieve a sustained virologic response. Further investigation is required to adequately counsel African Americans with genotype 1 chronic HCV infection on the efficacy of telaprevir and boceprevir in their racial group. Increased participation of this racial group in HCV clinical trials is needed to improve therapies in this difficult-to-treat population.

Recently developed drugs and innovative strategies for the treatment of chronic infection with genotype 1 hepatitis C virus (HCV) have become the standard of care. The protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) are the first direct-acting antiviral (DAA) agents approved, and many more are being developed. These drugs substantially increased rates of sustained virologic response in treatment-naïve and -experienced patients, in conjunction with peginterferon and ribavirin (triple therapy), in phase 3 trials. The efficacy of triple therapy depends on appropriate selection of patients, although the population of patients that receive triple therapy could be expanded as the risk/benefit ratio improves. Attention to details that reflect the standard of care, such as appropriate dosing, anticipation of adverse effects, and strict adherence to stopping rules, will insure the success of these drugs and lead the way for new combination therapies., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: We review here the recent literature regarding hepatitis C treatment through January 2012. We discuss newly approved therapies and their clinical trial data and discuss what can be expected in this rapidly changing field., Recent Findings: Two new directly acting antiviral agents were approved in 2011 for use in hepatitis C treatment, bringing shortened treatment durations, and increased treatment success to some patients with genotype 1 hepatitis C. Additional drugs using different viral targets are in development to further improve response rates, tolerance, and increase access to therapy., Summary: Telaprevir and boceprevir were approved in 2011 for use against genotype 1 hepatitis C, in combination with pegylated interferon and ribavirin. In most populations of genotype 1 patients, response rates are much improved but increased treatment related anemia has been seen. Additional options for therapy, including interferon-free regimens, are still needed and are under development.

Boceprevir (BOC) and telaprevir (TPV), when added to pegylated interferon and ribavirin for the treatment of chronic hepatitis C virus (HCV) infection, increase the rates of sustained virologic response in treatment-naïve persons to approximately 70%. Though these agents represent an important advance in the treatment of chronic HCV, they present new treatment challenges to the hepatology community. BOC and TPV are both substrates and inhibitors of the hepatic enzyme, cytochrome P450 3A, and the drug transporter, P-glycoprotein, which predisposes these agents to many drug interactions. Identification and appropriate management of potential drug interactions with TPV and BOC is critical for optimizing therapeutic outcomes during hepatitis C treatment. This review highlights the pharmacologic characteristics and drug-interaction potential of BOC and TPV and provides guidance on the management of drug interactions with these agents., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Objective: To summarize and evaluate the published literature pertaining to boceprevir and telaprevir, and to provide clinicians with suggestions for use in patients with chronic hepatitis C infection., Methods: A standardized search strategy was performed using the MEDLINE, EMBASE, Google Scholar and International Pharmaceuticals Abstracts databases using the search terms "boceprevir", "telaprevir", "boceprevir and hepatitis C", and "telaprevir and hepatitis C". A manual search of references was performed to identify articles missed by the electronic search. Studies were included in the review if they assessed either boceprevir or telaprevir in comparison with standard of care in chronic hepatitis C patients., Results: The studies identified assessed boceprevir and telaprevir in genotype-1 hepatitis C patients. In both treatment-naive and treatment-experienced patients, sustained virological response rates were achieved more often with boceprevir or telaprevir in combination with pegylated interferon and ribavirin compared with pegylated interferon and ribavirin alone. Both medications were well tolerated, with anemia presenting as the most treatment-limiting adverse effect., Conclusions: Boceprevir and telaprevir will revolutionize the management of hepatitis C genotype 1 patients and will most likely decrease the burden of end-stage disease worldwide. However, current clinical limitations include establishing appropriate and cost-effective treatment durations, and use in special populations such as transplant patients and patients coinfected with HIV. Future research will need to clarify these clinical obstacles to clearly define the role of these agents in hepatitis C management.

Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. Two first-generation protease inhibitors, telaprevir and boceprevir, have recently been approved for the treatment of chronic hepatitis C genotype 1. Triple therapy comprising pegylated interferon-α, ribavirin and telaprevir or boceprevir increases sustained virological response rates to ~70% and allows to shorten treatment duration in ~½ of treatment-naïve patients with chronic hepatitis C genotype 1. Sustained virological response rates in treatment-experienced patients depend on the response to previous treatment, ranging from >80% in previous relapsers to ~30% in previous null responders. These advances come at the expense of new adverse effects and increased cost. In addition, treatment of chronic hepatitis C will become more complex. In these times of changing medical practice, the present expert opinion statement by the Swiss Association for the Study of the Liver shall provide guidance on the treatment of chronic hepatitis C with triple therapy comprising telaprevir or boceprevir.

Direct acting antiviral agents for the management of chronic hepatitis C infection have recently been licensed. These new protease inhibitors are combined with pegylated interferon and ribavirin and markedly increase the proportion of patients who respond to antiviral therapy. The protease inhibitors may be used with a 'lead-in' phase of pegylated interferon and ribavirin and the value of this approach has been much debated with those supporting 'lead in' citing the advantages of assessing the early response to therapy before commencing the direct acting antiviral agent. Those opposed to the 'lead-in' phase cite the complexity of the regime and the lack of robust evidence showing an improvement in clinical outcome in those treated in this fashion., (© 2012 John Wiley & Sons A/S.)

With the approval of boceprevir and telaprevir the standard treatment of chronic hepatitis C virus (HCV) genotype 1 infection will be the triple therapy of a HCV protease inhibitor together with pegylated interferon alfa and ribavirin. In clinical studies a significant increase of sustained virological response rates from 38 - 44 % to 63 - 75 % for treatment-naïve and from 17 - 21 % to 59 - 66 % in treatment-experienced patients in comparison to the dual combination therapy with pegylated interferon alfa and ribavirin alone has been demonstrated. In addition, a large number of treatment-naïve patients and relapsers benefit from shorten treatment durations to 24 - 28 weeks. However, important differences exist between the administration of boceprevir and telaprevir in terms of a pegylated interferon alfa/ribavirin lead-in phase, the duration of dosing of the protease inhibitor, the overall treatment duration, HCV RNA measurements for response guided treatment durations and stopping rules. Furthermore, triple therapies with boceprevir and telaprevir may be associated with selection of resistant viral variants, new adverse events and clinically relevant drug-drug interactions. The present review gives an overview on the results of underlying clinical studies together with a guideline for the practical management of boceprevir- and telaprevir-based triple therapies., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Telaprevir and boceprevir are highly selective hepatitis C virus (HCV) NS3/4A proteaseinhibitors in phase 3 development. Viral breakthrough during mono- and triple-therapies with PEG-interferon and ribavirin and relapse is associated with resistance., Objectives: Potential persistence of resistance mutations during long-term follow-up should be analyzed., Study Design: Clonal sequence analysis of the NS3-protease gene was performed at long-term follow-up in HCV genotyp-1 infected patients who received telaprevir or boceprevir within phase-1b studies for comparison with resistant variants present directly after the end-of-treatment., Results: After a median follow-up of 4.2 years in 28 of 82 patients HCV-RNA was still detectable. Resistance variants were detected in two of 14 telaprevir- and in four of 14 boceprevir-treated patients. For telaprevir patients two low-level (V36M, V36A) and one high-level (A156T) mutation associated with resistance were detected at low frequencies (4-9% of the clones). In five boceprevir-treated patients four low level mutations (V36A, T54A/S, V55A) were observed at low frequencies (1-10%) while in one patient additionally a combined variant (T54S+R155K) was detected at 94%. Presence of resistant variants at long-term follow-up was not predictable by variants detected at the end-of-treatment. In one patient a V55A variant which was dominant already at baseline was still detectable at long-term follow-up., Conclusions: In the majority of patients after short-term treatment with telaprevir or boceprevir wild-type NS3-protease isolates are detectable by clonal sequencing at long-term follow-up. Detectable resistance mutations in single patients are not predictable by initial frequencies of variants., (Copyright © 2011 Elsevier B.V. All rights reserved.)