Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial – Full Text

(Since this study was first presented at AASLD 2013 Gilead has released results from 3 different Phase 3 studies including a larger patient pool: Gilead Announces SVR12 Rates From Three Phase 3 Studies Evaluating a Once-Daily Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients)

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The Lancet, Volume 383, Issue 9916, Pages 515 - 523, 8 February 2014 
doi:10.1016/S0140-6736(13)62121-2Cite or Link Using DOI
This article can be found in the following collections: Gastroenterology (Hepatobiliary disease); Infectious Diseases (Anti-infective therapy)
Published Online: 05 November 2013

Copyright © 2014 Elsevier Ltd All rights reserved.

Prof Eric Lawitz MD a, Prof Fred F Poordad MD a, Phillip S Pang MD b, Robert H Hyland DPhil b, Xiao Ding PhD b, Hongmei MoPhD b, William T Symonds PharmD b, John G McHutchison MD b, Fernando E Membreno MD a

Summary

Background

Interferon-based treatment is not suitable for many patients with hepatitis C virus (HCV) infection because of contraindications such as psychiatric illness, and a high burden of adverse events. We assessed the efficacy and safety of an interferon-free regimen—a fixed-dose combination of the nucleotide polymerase inhibitor sofosbuvir (400 mg) and the HCV NS5A inhibitor ledipasvir (90 mg), with and without ribavirin—in patients with genotype-1 hepatitis C infection who were treatment-naive or previously treated with a protease-inhibitor regimen.

Methods

For this open-label study, we enrolled 100 adult patients (>18 years) with HCV infection at a centre in the USA between Nov 2, 2012, and Dec 21, 2012. In cohort A, we used a computer-generated sequence to randomly assign (1:1:1; stratified by HCV genotype [1a vs 1b]) 60 non-cirrhotic, treatment-naive patients to receive sofosbuvir plus ledipasvir for 8 weeks (group 1), sofosbuvir plus ledipasvir and ribavirin for 8 weeks (group 2), or sofosbuvir plus ledipasvir for 12 weeks (group 3). In cohort B, we randomly allocated (1:1; stratified by genotype and presence or absence of cirrhosis) 40 patients who previously had virological failure after receiving a protease inhibitor regimen to receive sofosbuvir plus ledipasvir for 12 weeks (group 4) or sofosbuvir plus ledipasvir and ribavirin for 12 weeks (group 5). 22 (55%) of 40 patients in cohort B had compensated cirrhosis. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329978.

Results

In cohort A, SVR12 was achieved by 19 (95%) of 20 patients (95% CI 75—100) in group 1, by 21 (100%) of 21 patients (84—100) in group 2, and by 18 (95%) of 19 patients (74—100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74—100) in group 4 and by all 21 (100%) of 21 patients (84—100) in group 5. Two patients had viral relapse; one patient was lost to follow-up after achieving sustained virological response 8 weeks after treatment. The most common adverse events were nausea, anaemia, upper respiratory tract infection, and headache. One patient in group five had a serious adverse event of anaemia, thought to be related to ribavirin treatment.

Interpretation

These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis. Further clinical trials are needed to establish the best treatment duration and to further assess the contribution of ribavirin.

Funding

Gilead Sciences.

Introduction

The treatment of patients with chronic hepatitis C virus (HCV) infection has evolved substantially since results from the first clinical trial of recombinant human interferon alfa for this disorder were published in 1986,1 but one element of treatment has remained constant: regular injections of recombinant interferon alfa for durations of 6 months to 1 year. The disadvantages of interferon treatment are well known, from its onerous side-effects (asthenia, myalgia, influenza-like symptoms, cytopenia, and depression) to the inconvenience of weekly injections, and the many potential medical contraindications and other reasons for ineligibility, including the unwillingness of many patients to receive interferon treatment because of side-effects.2, 3 Although protease inhibitor-containing regimens for patients with genotype 1 HCV (both approved in 2011)—24—48 weeks of peginterferon and ribavirin with 12—44 weeks of a protease inhibitor—have achieved high rates of sustained virological response (SVR) in clinical trials, these trials excluded, by definition, the population of patients for whom interferon is not an option because of contraindications or intolerability.4—7 Moreover, HCV protease inhibitors can sometimes cause additional and specific adverse events. In their wider clinical use outside of clinical trials, they have been shown to exacerbate the side-effects normally seen with peginterferon and ribavirin treatment. Serious adverse events associated with these regimens, especially in patients with cirrhosis, can also lead to premature treatment discontinuation.8, 9 Other limitations of protease inhibitors include their low barrier to the development of resistance, high pill burden, complex response-guided regimens, and drug—drug interactions. Overall, less than half of diagnosed patients are eligible to receive protease inhibitor regimens. Those who do not achieve SVR with a protease inhibitor regimen have no treatment options at present.10

Sofosbuvir (formerly known as GS-7977; Gilead Sciences, Foster City, CA, USA) is a nucleotide analogue inhibitor of the HCV NS5B polymerase that has been extensively studied in combination with peginterferon and ribavirin, as well as with other direct-acting antiviral agents in treatment-naive patients with genotype-1 HCV infection.11—15 Ledipasvir (formerly known as GS-5885; Gilead Sciences) is a novel HCV NS5A inhibitor that has shown potent antiviral activity against genotypes 1a and 1b HCV infection,16 and is active against HCV with the S282T mutation, the only variant known to reduce susceptibility to sofosbuvir.17 Findings from a drug interaction study showed no clinically significant pharmacokinetic interactions between sofosbuvir and ledipasvir, with the investigators concluding that the two drugs could be given together without any dose adjustments.18 The combination of sofosbuvir and ledipasvir with ribavirin was first assessed in treatment-naive and prior null responder patients with genotype-1 infection in the ELECTRON trial.19 All 25 treatment-naive patients and all nine prior null responder patients who received 12 weeks of sofosbuvir and ledipasvir plus ribavirin in ELECTRON achieved SVR 12 weeks after discontinuation of treatment (SVR12). However, none of these patients had cirrhosis.

The primary objective of the LONESTAR study was to assess the antiviral efficacy of a fixed-dose single-tablet combination of sofosbuvir and ledipasvir (sofosbuvir plus ledipasvir) with and without ribavirin, for 8 weeks or 12 weeks in treatment-naive patients with genotype-1 HCV, and for 12 weeks in patients with genotype 1 HCV who had not achieved SVR after receiving a protease-inhibitor-containing regimen, half of whom had compensated cirrhosis.

Methods

Study design and participants

For this two-cohort study, we enrolled patients with chronic genotype-1 HCV infection at one clinical site in the USA (Texas Liver Institute, San Antonio, TX). Screening for the trial began on Nov 2, 2012, with the last patient enrolled on Dec 21, 2012. Eligible patients were at least 18 years of age and had chronic genotype-1 HCV infection with serum HCV RNA concentrations of 10 000 IU/mL or greater. Exclusion criteria included hepatic decompensation (as evidenced by the presence of ascites, encephalopathy, or a history of variceal haemorrhage), a body-mass index of 18 kg/m2 or lower, or co-infection with hepatitis B virus or HIV. Patients in cohort A had not received any previous treatment for HCV. Patients in cohort B had had virological failure after treatment with an approved or investigational protease inhibitor regimen (which included peginterferon and ribavirin), but had not discontinued treatment due to an adverse event. About 50% of patients enrolled in cohort B could have compensated cirrhosis. We established the presence of cirrhosis by liver biopsy (eg, a Metavir score of 4 or an Ishak score of ≥5). For all patients, IL28Bwas determined by PCR amplification and sequencing of the rs12979860 single-nucleotide polymorphism.

Before enrolment and before any study procedures were undertaken, written informed consent was obtained from all patients. The study was done in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice.

Randomisation and masking

We used a computer-generated randomisation sequence; allocation to treatment was done sequentially and communicated to the site by email based on the randomisation sequence. XD (Gilead Sciences) generated the randomisation sequence and remained on the study as lead statistician. In cohort A, in which treatment-naive patients with HCV genotype-1 were randomly allocated in a 1:1:1 ratio to treatment groups 1, 2, or 3, randomisation was stratified by HCV genotype (1a vs 1b). In cohort B, in which patients with HCV genotype-1 who had failed a previous protease inhibitor regimen were randomly allocated in a 1:1 ratio to groups 4 or 5, randomisation was stratified by HCV genotype (1a vs 1b) and presence or absence of compensated cirrhosis. This was an open-label study, so patients and investigators were not masked to treatment allocation.

Procedures

Patients in all treatment groups received a fixed-dose combination tablet containing 400 mg of sofosbuvir and 90 mg of ledipasvir (sofosbuvir plus ledipasvir) once daily with or without food. Ribavirin was given orally as a divided, weight-based daily dose (ie, patients weighing <75 kg received 1000 mg and those weighing ≥75 kg received 1200 mg). In cohort A, patients in group 1 received sofosbuvir plus ledipasvir for 8 weeks; those in group 2 received sofosbuvir plus ledipasvir and ribavirin for 8 weeks; patients in group 3 received sofosbuvir plus ledipasvir for 12 weeks. In cohort B, patients in group 4 received sofosbuvir plus ledipasvir without ribavirin for 12 weeks and those in group 5 received sofosbuvir plus ledipasvir with ribavirin for 12 weeks. After completion or early discontinuation of treatment, we followed-up patients for 24 weeks.

We measured plasma HCV RNA concentrations using the COBAS TaqMan HCV Test (version 2.0) for use with the High Pure System (Roche; Indianapolis, IN, USA) with a lower limit of quantification for HCV RNA of less than 25 IU/mL. We defined virological breakthrough as the presence, during treatment, of HCV RNA concentrations greater than 25 IU/mL in serum samples after previous documentation of on-treatment concentrations of HCV RNA concentrations less than 25 IU/mL. We defined relapse as the presence of HCV RNA concentrations greater than 25 IU/mL at any time during the post-treatment follow-up period after documentation of HCV RNA less than 25 IU/mL in a serum sample at the end of treatment.

Deep sequencing of the NS3 and NS5A regions of the HCV RNA was done for all patients at baseline. We established the presence of baseline resistance-associated variants (RAVs) by comparison with wild-type reference sequences (1a-H77 for genotype 1a samples and 1b-Con-1 for genotype 1b samples). NS3 protease RAVs for genotypes 1a and 1b were assessed at aminoacid positions 36, 54, 55, 155, 156, 168, and 170. We also assessed the presence of Q80 polymorphisms. NS5A RAVs was assessed at aminoacids 28, 30, 31, 58, and 93 for genotype 1a, and at positions 31 and 93 for genotype 1b. For all patients who had virological failure, deep sequencing of the NA5A and NS5B regions was done with samples obtained at the time of failure. We compared the resulting sequences with sequences from baseline samples to detect emergent RAVs. We reported RAVs present at greater than 1% of sequence reads.

Patients allocated to groups 1 or 2 who completed 8 weeks of treatment and had post-treatment virological failure at or before the post-treatment week 12 visit were offered a 24-week regimen of sofosbuvir plus ledipasvir with weight-based ribavirin.

We encouraged all patients who achieved SVR 24 weeks after discontinuation of treatment to enrol in the SVR Registry Study (NCT01457755), which is intended to assess durability of SVR for up to 3 years post-treatment. Patients who did not achieve SVR were eligible to enrol in the Sequence Registry Study (NCT01457768), for the purpose of monitoring the persistence of HCV-resistant mutations for up to 3 years post-treatment.

Safety was assessed by review of adverse events and concomitant drugs, blood samples for clinical laboratory testing including haematological assessments, and physical examinations. Patients in groups 2 and 5 (ie, those receiving ribavirin) with decreases in haemoglobin concentrations to lower than 100 g/L during treatment had the option to reduce the daily dose of ribavirin. The use of erythropoiesis-stimulating agents was not permitted.

Statistical analysis

The primary efficacy endpoint of the study was the proportion of patients achieving SVR12, analysed by intention to treat. We did the primary analysis after all patients had been followed-up through 12 weeks post-treatment or after premature discontinuation from the study. The SVR12 rate was calculated for each treatment group along with the 2-sided 95% CI using the exact binomial distribution (the Clopper-Pearson method). The study was exploratory and not powered to allow for comparisons among groups. Therefore, we did no statistical hypothesis testing. With a sample size of 20 patients in each treatment group, a two-sided 95% exact CI will extend at most 46% in length. We used SAS (version 9.2) for all statistical analyses.

This study is registered with ClinicalTrials.gov, number NCT01329978.

Role of the funding source

The study sponsor oversaw trial management, data collection, statistical analyses, and the writing and review of the report. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication.

Results

We screened 116 patients, of whom 100 were deemed eligible and enrolled in the study (figure 1, appendix). Baseline characteristics of patients within each of the two cohorts were similar among groups (table 1). Most patients were non-black. In cohort A, 53 (88%) of 60 patients had HCV genotype 1a, and 40 (80%) had non-CC IL28B genotypes. A similar proportion of patients in cohort B (34 [85%] of 40 patients) had genotype 1a infection, but a larger proportion (37 patients [93%]) carried non-CC IL28B genotypes, as would be expected given their failure to respond to previous interferon-based treatment combined with a protease inhibitor. More than half of patients (22 patients [55%]) in cohort B had compensated cirrhosis. At baseline, 22 patients with cirrhosis had mean total bilirubin of 0·9 mg/dL, mean albumin of 3·8 g/dL, mean platelet count of 107 × 103, and mean prothrombin time international normalised ratio of 1·27. Most patients in cohort B had shown non-response to previous treatment with protease inhibitor regimens (27 [68%] of 40 patients) whereas about a third (13 patients [33%]) had had virological breakthrough or relapse.

Figure 1 Trial profile *This patient, who discontinued treatment due to withdrawal of consent, had HCV RNA <LLOQ at post-treatment weeks 4 and 8, but was lost to follow-up after week 8.

  Table 1 Table image Baseline characteristics

All patients had rapid reductions in serum HCV RNA after beginning treatment, with most having serum HCV RNA reductions of about four logs by the end of week 1 of treatment (figure 2). By the end of the second week of dosing, 90 [90%] of 100 patients had HCV RNA below the limit of quantification, and by the end of the fourth week of dosing 99 (99%) of these patients had concentrations below the limit of quantification (appendix).

Figure 2 Mean hepatitis C virus (HCV) RNA in serum samples by visit through week 8 of treatment Error bars are SD.

Most patients in all dose groups achieved SVR12 (table 2), irrespective of previous treatment history (treatment naive vspreviously treated), the presence or absence of ribavirin in the regimen, the presence or absence of cirrhosis, or race (black vsnon-black). Early viral response during treatment was not predictive of the likelihood of SVR12 achievement. Post-treatment week 24 data are available for all of 97 patients who achieved SVR12. All 97 patients also achieved SVR24.

  Table 2 Table image Response during and after treatment

No patient in any treatment group had virological breakthrough during study treatment. Of the 100 patients enrolled and treated, two (2%) had virological relapse after receiving a full course of treatment: one non-cirrhotic 60-year-old white man with genotype 1a infection and the CT IL28b genotype in treatment group 1 relapsed between post-treatment weeks 4 and 8, and one cirrhotic 54-year-old white woman with genotype 1a infection and the CT IL28b genotype in treatment group 4 relapsed between post-treatment weeks 2 and 4—this patient was a non-responder to prior treatment with boceprevir-peginterferon-ribavirin triple therapy.

At baseline, NS3 protease inhibitor RAVs were detected in 33 patients: four (7%) of 60 treatment-naive patients and 29 (73) of 40 previously treated patients (table 1). R155K, the most prevalent protease inhibitor RAV, was detected in 19 patients (all of whom were previously treated with protease inhibitors). All 33 patients with baseline NS3 RAVs achieved SVR12.

At baseline, NS5A RAVs were detected in nine patients, seven of whom achieved SVR12. Two patients, one each in groups 1 and 4, had virological relapse as described above. The patient in group 1 had an L31M RAV at baseline; additionally NS5A RAVs (Y93H, Q30L, and L31V) were detected at relapse timepoints. NS5B sequencing also detected the S282T mutation in this patient at relapse. In more than 1900 patients treated to date,20, 21 the S282T mutation, which is associated with reduced susceptibility to sofosbuvir, has been detected once before, in a patient with HCV genotype 2b infection who relapsed after receiving sofosbuvir monotherapy in a phase 2 trial.22 In the second patient who relapsed in this study, the NS5A RAVs Q30H and Y93H were detected at baseline and relapse. The NS5B RAV S282T was not detected in this patient at any post-baseline timepoint.

Overall, 48 (48%) of 100 patients had at least one adverse event during the study (table 3). Patients in groups 2 and 5, who were receiving ribavirin with sofosbuvir plus ledipasvir, had the highest rates of adverse events: 12 (57%) of 21 patients in group 2 and 12 (57%) of 21 patients in group 5. Nine (45%) of 20 patients in group 1, eight (42%) of 19 patients in group 3, and seven (37%) of 19 patients in group 4 had an adverse event. The most common adverse events were nausea, anaemia, upper respiratory tract infection, and headache, with most of these events rated by the treating physician as mild in severity. Anaemia was noted only in patients given ribavirin. Eight patients received ribavirin dose reductions to manage anaemia; all eight achieved SVR12. No patient in any group discontinued treatment because of an adverse event. Four patients had serious adverse events: one patient in group 2 had delirium, one patient in group 3 had an exacerbation of peptic ulcer disease, one patient in group 4 was diagnosed with a spinal compression fracture, and one patient in group 5 had anaemia and suicidal ideation; this serious adverse event of anaemia was the only serious adverse event considered related to study treatment. The only grade 3 or 4 haematological abnormality that occurred during treatment was decreased haemoglobin in four patients, all of whom had received ribavirin (two patients in group 2 and one in group 5 had grade 3 reductions in haemoglobin and one patient in group 5 had a grade 4 reduction). In the ribavirin-containing groups, mean change from baseline values in haemoglobin at the end of treatment was −1·8 g/dL in group 2 and −2·0 g/dL in group 5 versus −0·2 g/dL in group 1, 0·0 g/dL in group 3, and −0·2 g/dL in group 4 (figure 3). We recorded no grade 2, 3, or 4 liver chemistry abnormalities in any patient. No patient in any group had abnormal (grade 1—4) increased creatinine concentrations. Patients in the ribavirin-containing groups had mild increases in total bilirubin during treatment (figure 3).

 Table 3 Table image Treatment-emergent adverse events in more than two patients

Figure 3 Median haemoglobin (A) and total bilirubin (B) concentrations during treatment Error bars are SD.

Discussion

In this randomised, open-label study, treatment with the fixed-dose combination of sofosbuvir and ledipasvir with and without ribavirin was well tolerated and resulted in high rates of SVR12 (95—100%) in both treatment-naive and previously treated patients with genotype-1 HCV. Patients in the 12-week group of cohort A had a similar response to patients in the 8-week groups, suggesting that 8 weeks of treatment might be sufficient for non-cirrhotic patients who have not previously been treated for HCV. The results in cohort B indicate that 12 weeks of the sofosbuvir plus ledipasvir combination might be an effective treatment for patients who had not achieved sustained virological response with a protease-inhibitor regimen, even in those with compensated cirrhosis.

The rate of response in all patients in the study was much the same. In both cohorts, patients with baseline characteristics historically associated with poor response to interferon-based treatment—non-CC IL28b genotype, black race, high baseline viral load—had SVR12 rates similar to patients without those characteristics. Additionally, cohort B included many patients with two other characteristics that have been associated with poor response—over half had compensated cirrhosis and more than two thirds had shown non-response to previous treatment. Rates of SVR12 in these patients were similar to response rates in non-cirrhotic and treatment-naive patients. Overall, only two of the 100 patients treated had virological failure (both relapses), even though nine patients harboured viruses with NS5A baseline variants associated with resistance to treatment. Thus, the presence of these baseline NS5A RAVs (in nine patients) did not preclude the ability of a patient to achieve an SVR12, nor did it accurately predict virological failure.

No clinically significant treatment-emergent safety issues were noted in patients receiving the sofosbuvir plus ledipasvir fixed-dose combination. We did not see the haematological abnormalities typically associated with interferon-based treatments, except for the mild anaemia seen in patients receiving ribavirin. The low incidence of adverse events coupled with the brief duration of this regimen contrast favourably with interferon-based treatment, which might mean that this combination treatment could improve treatment adherence and completion compared with interferon-based treatment.

Findings from several phase 2 clinical trials assessing various combinations of direct-acting antiviral agents for 12—24 weeks have established the potential of interferon-free regimens for both treatment-naive and previously treated patients with HCV genotype 1 infection.14,15,23—28 Sofosbuvir has been assessed in combination with other direct-acting antiviral agents. In the COSMOS trial,15 in which sofosbuvir was given with the NS3/4A protease inhibitor simeprevir (Janssen Research and Development, Raritan, NJ, USA) with and without ribavirin, sustained virological response rates of 93—96% were reported. In the AI444040 trial,29 investigators treated a broad range of patients—treatment-naive patients with genotypes 1, 2, or 3 infection, as well as patients with genotype-1 infection who had not responded to a previous protease inhibitor regimen—with 12 or 24 weeks of sofosbuvir plus the NS5A inhibitor daclatasvir (Bristol-Myers Squibb, New York, NY, USA). Rates of sustained virological response at 12 weeks after treatment ranged from 86% to 100%.29 The COSMOS trial did not include patients who had not responded to a previous protease inhibitor regimen, whereas the AI444040 trial did not include patients with cirrhosis. LONESTAR is one of the few early phase trials assessing an interferon-free treatment regimen that includes patients with compensated cirrhosis. In view of the high prevalence of advanced fibrosis in patients with chronic HCV infection and the poor response rates with currently approved therapies, this regimen could fill an important unmet medical need. In terms of safety and efficacy, this regimen compares favourably with other all-oral combinations tested in treatment-naive and previously treated patients with genotype-1 HCV infection and cirrhosis (panel). Other possible advantages of this regimen are its high barrier to viral resistance, short duration, once-daily dosing as a single tablet, absence of food restrictions, few clinically significant drug interactions, and its similar efficacy in genotypes 1a and 1b HCV infections.

Panel
research in context
Systematic review

We searched PubMed up to July 22, 2013, using the search term “HCV treatment” for clinical trials for patients with genotype-1 hepatitis C virus (HCV). We also searched the reference list of reviews of the treatment of hepatitis C with direct-acting antiviral agents,30, 31 which systematically surveyed a large body of evidence concerning outcomes of clinical trials.

Interpretation

The standard-of-care regimens for patients with genotype-1 hepatitis C consist of a protease inhibitor—telaprevir or boceprevir—in combination with peginterferon and ribavirin. Among the disadvantages of these regimens are their long duration (24—48 weeks), unfavourable safety and tolerability profiles, poor efficacy in prior null responders with cirrhosis, exclusio n of a large proportion of the patient population because of interferon ineligibility, and complicated regimens with high pill burdens. Many direct-acting agents are in development, and many trials of interferon-free regimens are being done. Data from very few of these trials have been published in peer-reviewed journals to date, but several of these experimental regimens have shown promising efficacy and safety.14,15,23—28 To our knowledge, this trial is the first to report data for cirrhotic genotype-1 patients who had not responded to prior treatment with a protease inhibitor regimen, a population without treatment options at present. Our data lend support to the possibility of effectively treating all patients with genotype-1 HCV with a brief, all-oral, once-daily regimen that has no known safety issues.

The main limitations of this trial are the small size and that it was done at only one centre. This study was not powered to detect small differences in response by characteristics of patients or by treatment groups. Thus, whether 8 weeks of treatment is as efficacious as 12 weeks of treatment or whether ribavirin is necessary in all patients or in only specific populations remain open questions. Three large multicentre phase 3 trials are underway, ION-1 (NCT01701401), ION-2 (NCT01768286), and ION-3 (NCT01851330), and are designed to address the role of treatment duration, the contribution of ribavirin in the regimen, and the effect of compensated cirrhosis in both treatment-naive and previously treated patients. Studies are also planned to assess the sofosbuvir plus ledipasvir fixed-dose combination in patients with more advanced liver cirrhosis (Child-Pugh class B and C), patients with HIV and HCV co-infection, and patients with HCV genotypes 3, 4, 5, and 6.

The results of this trial suggest that the fixed-dose combination of sofosbuvir and ledipasvir could offer a short, all-oral treatment that is effective in both treatment-naive and previously treated patients. Further large scale trials are underway, the findings from which could substantiate those from this trial. Importantly, the sofosbuvir plus ledipasvir combination might be highly effective and safe in patients with multiple negative traditional predictors of response, including cirrhosis, black race, non-CC IL28B variants, and in those who have not responded to standard-of-care protease inhibitor regimens.

Contributors

EL, FFP, PSP, RHH, XD, HM, WTS, JGM, and FEM contributed to the writing and review of the report. EL, FFP, and FEM contributed the recruitment of patients and served as investigators in this study. EL, PSP, RHH, XD, HM, WTS, JGM, and FEM contributed to the data collection or interpretation. PSP, RHH, XD, HM, WTS, and JGM contributed to the study design.

Conflicts of interest

EL has received research support and grants from AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medtronic, Merck and Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals; was on the speakers' bureau for Gilead Sciences, Kadmon, Merck, and Vertex; and has served on advisory boards for AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Gilead Sciences, Idenix Pharmaceuticals, Janssen, Merck and Co, Novartis, Santaris Pharmaceuticals, Theravance, and Vertex Pharmaceuticals. FFP has received research support and grants from AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medtronic, Merck and Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals; has served as a consultant or adviser to Gilead Sciences; and was on the speakers' bureau for Gilead Sciences. FEM has received research support and grants from AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medtronic, Merck and Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, and Vertex Pharmaceuticals; and has served on the speakers' bureau for Merck, Salix, Onyx/Bayer, and Otsuka. PSP, RHH, XD, HM, JGM, and WTS are employees and stockholders of Gilead Sciences.

Acknowledgments

This study was sponsored by Gilead Sciences. Editorial assistance was provided by David McNeel and Kellie Chu of Gilead Sciences. We thank the patients who took part in this study, as well as Juan Betular and Meredith Gonzalez of Gilead Sciences for their contributions to study conduct.

Supplementary Material

Supplementary appendix

 PDF (360K)

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13 Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878-1887. CrossRef | PubMed

14 Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naive patients chronically infected with HCV GT1, 2, or 3. 63rd annual meeting of the American Association for the Study of Liver Diseases; Boston, Massachusetts, USA; Nov 9—13, 2012.

15 Lawitz E, Ghalib R, Rodriguez-Torres M, et al. COSMOS Study: SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders. 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, Georgia, USA; March 3—6, 2013.

16 Lawitz EJ, Gruener D, Hill JM, et al. A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C. J Hepatol 2012; 57: 24-31. CrossRef | PubMed

17 Cheng G, Peng B, Corsa A, et al. Antiviral activity and resistance profile of the novel HCV NS5A inhibitor GS-5885. EASL 2012.

18 German P, Mathias A, Pang PS, et al. Lack of clinically significant pharmacokinetic drug-drug interaction between sofosbuvir (GS-7977) and GS-5885 or GS-9669 in healthy volunteers. 63rd annual meeting of the American Association for the Study of Liver Diseases; Boston, Massachusetts, United States; November 9—13, 2012.

19 Gane EJ, Stedman CA, Hyland RH, et al. ELECTRON: all-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV GT 1 infection. 48th annual meeting of the European Association for the Study of the Liver; Amsterdam, The Netherlands; April 24—28, 2013.

20 Svarovskaia ES, Dvory-Sobol H, Gontcharova V, et al. Comprehensive resistance testing in patients who relapsed after treatment with sofosbuvir (GS-7977)-containing regimens in phase 2 studies. 63rd annual meeting of the American Association for the Study of Liver Diseases; Boston, Massachusetts, USA; Nov 9—13, 2012.

21 Svarovskaia WS, Dvory-Sobol H, Hebner C, et al. No resistance detected in four phase 3 clinical studies in HCV genotype 1-6 of sofosbuvir + ribavirin with or without peginterferon. 64th annual meeting of the American Association for the Study of Liver Diseases; Washington, DC, USA; Nov 1—5, 2013.

22 Gane EJ, Stedman CA, Hyland RHH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013; 368: 34-44. CrossRef | PubMed

23 Poordad F, Lawitz E, Kowdley KV, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med2013; 368: 45-53. CrossRef | PubMed

24 Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012;366: 216-224. CrossRef | PubMed

25 Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2010; 376: 1467-1475. Summary | Full Text | PDF(316KB) | CrossRef | PubMed

26 Chayama K, Takahashi S, Toyota J, et al. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology2012; 55: 742-748. CrossRef | PubMed

27 Lawitz E, Poordad F, Kowdley KV, et al. A phase 2a trial of 12-week interferon-free therapy with two direct-acting antivirals (ABT-450/r, ABT-072) and ribavirin in IL28B C/C patients with chronic hepatitis C genotype 1. J Hepatol 2013; 59: 18-23.CrossRef | PubMed

28 Sulkowski M, Gardiner D, Lawitz E, et al. Potent viral suppression with the all-oral combination of daclatasvir (NS5A inhibitor) and GS-7977 (nucleotide NS5B inhibitor), +/− ribavirin, in treatment-naïve patients with chronic HCV GT1, 2, or 3. EASL 2012.

29 Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Sustained virologic response with daclatasvir plus sofosbuvir ± ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC). 48th annual meeting of the European Association for the Study of the Liver; Amsterdam, Netherlands; April 24—28, 2013.

30 Shah N, Pierce T, Kowdley KV. Review of direct-acting antiviral agents for the treatment of chronic hepatitis C. Expert Opin Investig Drugs 2013; 22: 1107-1121. CrossRef | PubMed

31 Manns MP, von Hahn T. Novel therapies for hepatitis C—one pill fits all?. Nat Rev Drug Disc 201310.1038/nrd4050. published online June 28. PubMed

a Texas Liver Institute and the University of Texas Health Science Center, San Antonio, TX, USA

b Gilead Sciences Inc, Foster City, CA, USA

Correspondence to: Prof Eric Lawitz, Texas Liver Institute, University of Texas Health Science Center, 607 Camden Street, San Antonio, TX 78215; USA

Source

Fair Pricing Coalition Highlights Major Barriers to Life-Saving Treatment in Affordable Care Act Health Insurance Marketplace Plans

New report offers short- and long-term solutions to minimize out-of-pocket expenses and maximize access to treatment for all Qualified Health Plan beneficiaries living with HIV and/or hepatitis C

For Immediate Release
February 6, 2014
Contact: Lynda Dee 410-332-1170 or lyndamdee@aol.com

Discriminatory practices by Qualified Health Plans (QHPs) in the health insurance marketplaces, exorbitant drug pricing by the pharmaceutical industry, and a lack of clear guidance from the federal government regarding the legality of co-payment assistance programs for QHP beneficiaries are proving to be major barriers to affordable treatment for HIV and hepatitis C, according to a new policy guide produced by the Fair Pricing Coalition (FPC).

“The QHPs mandated by the Affordable Care Act are good news for many people living with HIV and/or hepatitis C, as it means they can’t be denied health insurance, because of pre-existing conditions,” explained FPC Co-Chair Lynda Dee. “This ensures the provision of essential health benefits, including important primary care services, access to specialists, and prescription drug benefits.”

“However, many plans are proving financially disastrous for people living HIV, hepatitis C, and other chronic diseases,” Dee added. “This situation is made worse by high drug prices being set and increased annually by manufacturers, along with an inexcusable lack of direction from the U.S. Department of Health and Human Services regarding co-pay assistance programs for people receiving care under ACA-mandated plans.”

According to FPC’s policy guide, Health Insurance Marketplace Plans and People Living with HIV and/or Viral Hepatitis: The Success of the Affordable Care Act Requires Fair Drug Pricing and Access, numerous drug pricing and access issues are becoming increasingly apparent:

• Some health insurance companies are not including certain standard-of-care HIV medications in their formularies, essentially circumventing the non-discrimination backbone of ACA.
• Many QHPs are placing prescription medications for HIV and hepatitis C in “specialty drug” tiers (Tier 4 or 5), which impose extremely high out-of-pocket costs.
• High prices of drugs used to treat HIV and hepatitis C are a key driver of QHPs placing standard-of-care medications in the highest tiers, resulting in prohibitive out-of-pocket costs.
• QHPs are failing to be transparent regarding their drug formularies and the associated cost sharing, thereby prohibiting people living with HIV and/or hepatitis C from making educated plan choices.
• Some manufacturers and not-for-profit payers have indicated that they are unwilling to extend their co-payment assistance programs to QHP beneficiaries because of conflicting government guidance.

“These are major barriers to life-saving treatment, when in fact we need to be making access to affordable treatment as easy as possible,” said Tim Horn, an FPC member. “Nationally, only 25 percent of people living with HIV are receiving HIV treatment and keeping the virus in their blood in check. This is essential in terms of protecting their own health and preventing ongoing transmission of the virus. We need to get more people on treatment, not fewer, which won’t be possible if they cannot afford their costly medications.”

Among the possible short- and long-term solutions offered by the FPC:

1. Require access to all U.S. Department of Health and Human Services (HHS)- preferred and HHS-alternative antiretrovirals for HIV and all FDA-approved treatments for hepatitis C.
2. Monitor tiering of HIV and hepatitis C drugs for discriminatory practices, such as placing all recommended treatment options on the highest cost-sharing or specialty tiers.
3. Mandate QHP benefits and drug formulary transparency.
4. Confirm Secretary of Health Kathleen Sebelius’ indication that manufacturers and non-profit payers may help defray out-of-pocket costs for medications under ACA through co-payment assistance programs.
5. Lower the out-of-pocket spending caps for individuals and families with incomes up to 250 percent of the federal poverty level.
6. Insist that insurance companies include HIV and hepatitis C expertise on their pharmacy and therapeutics committees or that they consult disease experts regarding formulary and tiering decisions.

“The problems outlined in the policy report are not insurmountable,” said Dee. “The FPC believes that the Affordable Care Act, while not perfect, has tremendous potential to redress disparities for U.S. residents whose access to healthcare has previously been at the whim of conflicting political and economic forces. This applies not only to HIV/AIDS and viral hepatitis, but also to many other chronic, debilitating, and costly health challenges beyond the capacity of individuals to manage on their own.”

The FPC supports urgent attention to these matters for all U.S. residents at this moment of new hope for achieving universal, affordable, quality health care.

The FPC policy guide can be accessed here:

http://fairpricingcoalition.org/wp-content/uploads/2014/02/FPC-QHP-Policy-Guide-Feb-2014-1.pdf

_______________

The Fair Pricing Coalition (FPC), founded by the late Martin Delaney of Project Inform, is a national coalition of activists who work on HIV and viral hepatitis drug pricing issues and to help control drug costs for patients who are privately insured, underinsured and uninsured.  The FPC also works to ensure access for recipients of state ADAPs, Medicare, and Medicaid as well as for other underinsured and uninsured individuals.

Source

Sustained Drug Use Changes After Hepatitis C Screening and Counseling Among Recently Infected Persons Who Inject Drugs: A Longitudinal Study

Clin Infect Dis. 2014 Feb 5. [Epub ahead of print]

Bruneau J, Zang G, Abrahamowicz M, Jutras-Aswad D, Daniel M, Roy E.

Abstract

Background. Notification of hepatitis C virus (HCV) positive status is known to have short-term impacts on subsequent alcohol, drug use and injection behaviors among persons who inject drugs (PWID). It remains to be established whether postscreening behavioral changes extend over time for PWID and whether screening test notification has behavioral impacts among HCV-negative PWID. This study sought to longitudinally assess substance use and injection behaviors after HCV status notification among HCV seroconverters and HCV-negative PWID. Methods. Initially HCV-seronegative PWID (n = 208) were followed prospectively between 2004 and 2011 in Montreal, Canada. Semiannual screening visits included blood sampling and an interview-administered questionnaire assessing substance use and injection behaviors. Multivariable generalized estimating equation analyses were conducted to assess substance use and behavior changes over time and compare changes between HCV seroconverters and HCV-seronegative participants while adjusting for baseline characteristics. Results. Of the 208 participants (83% male; mean age, 34.7 years, mean follow-up time, 39 months), 69 (33.2%) seroconverted to HCV. A linear decrease in syringe sharing behavior was observed over time after HCV and status notification, whereas a 10% decrease for each additional 3 months of follow-up was observed for injection cocaine and heroin use among HCV seroconverters but not among HCV-seronegative PWID (P < .05). No significant changes were observed in alcohol use. Conclusions. Our results indicate that notification of HCV-positive status is associated with reduced injection drug use among seroconverters. Among PWID deemed seronegative after screening, there is no sustained trend for change in risk behavior.

KEYWORDS: behavior change, hepatitis C, injection drug use, screening

PMID: 24363333 [PubMed - as supplied by publisher]

Source

Georgia Launches Programme to Curb Hepatitis

By Manana Vardiashvili - Caucasus

CRS Issue 722, 7 Feb 14

Cut-price medication for many patients, and free treatment for the prison population.

Georgia's deputy prisons minister Archil Talakvadze (left). (Photo: Georgian prisons ministry website)

Under a nationwide programme which Georgia’s government has launched to tackle hepatitis C, 10,000 people will become eligible for subsidised medicines, and treatment will be free in the prison system, where the disease is common.

Experts say the programme could be a major step towards reducing infection rates. Prisoners with hepatitis C will start receiving free treatment from March.

Official statistics dating from 2004 showed 200,000 people infected with the disease, or between six and seven per cent of the population. Some believe the current total could be higher, close to 300,000. The equivalent rate is 2.5 per cent in the United States, and under one per cent in northwestern Europe. (See Hepatitis Unchecked in Georgia from last year.) Around 20,000 people, under ten per cent of the total number infected, have undergone treatment.

Archil Talakvadze, the deputy prisons minister, told IWPR that “international experts say Georgia will become a global leader in the fight against hepatitis C. The creation of the programme for prisoners, and the provision of lower prices to 10,000 citizens is the biggest boost to making treatment accessible in Georgia’s modern history.

“For comparison, only 300 to 400 patients were receiving treatment every year, and at their own expense.”

Until now, many have been unable to afford the medicines. In a country where the average monthly wage is 700 laris (400 dollars) and 17 per cent of the population is unemployed, many could not even afford to pay for a diagnosis costing 1,600 laris. Health insurance companies refused to pay for treatment even when people had cover.

The two drugs used to treat hepatitis C – Ribavirin and Pegylated Interferon – normally cost 6,000 US dollars for a 24-week course, and sometimes a 48-week course is needed.

Certain forms of the disease require a third medicine, Boceprevir, which increases the changes of success but adds 28,000 dollars to the cost of treatment. Until now, the government has not provided this to prisoners free of charge.

In December, the health ministry announced a tender for the purchase of medicines, after a similar attempt failed in October. This time it was successful, and secured supplies of the drugs at 60 per cent below the normal cost.

“Georgia is now has the second-lowest prices in the world after Egypt,” Talakvadze said.

The prisons ministry says the level of hepatitis C infection in the penal system is around three times higher than among the general populace, and 18 per cent of deaths among convicts are attributed to the disease.

Some 12,000 prisoners will be screened for the disease, and the ministry plans to treat 500 of the most serious cases this year, and another 500 in 2015, at a total cost of six million laris.

Only those serving sentences longer than 18 months will be eligible, since treatment is not free once they are released. “We’ve done that to stop people going to prison for hooliganism [disorderly behaviour] just to get a free course of treatment,” Talakvadze said.

He noted that free hepatitis treatment would put an end to a situation where Georgia had lost four cases at the European Court for Human Rights because of restrictions on diagnosis and medical treatment in the penal system.

“The court in Strasbourg compared the lack of treatment in prison to torture,” he added.

On February 1, the government began registering members of the public to assess their eligibility for treatment at the reduced rate.

Dato, a 40-year-old man who has had hepatitis C for several years, is now preparing the documents he needs to sign up for the programme.

“I have already undergone several tests. Now I’m having my liver tested and if the doctor considers it necessary for me to start treatment, I’ll do so,” he told IWPR. “If need be, I’ll collect the money I need for the treatment. A few months ago, I couldn’t even have dreamed of this.”

Applicants like Dato will need to submit their diagnosis, information about previous tests and their results, and what course of treatment they need. A commission will examine the applications and rule whether a discount is applicable.

The aim is to get people started on treatment on July 1. Some 200 people have submitted their documents so far.

“This is a good start, although of course we can’t say all the problems have been resolved,” said Paata Sabelashvili, head of the Georgian Harm Reduction Network. “It’s very good that the state is going to treat prisoners with hepatitis C for free. And the provision of medicines at an accessible price to people who need immediate treatment is a very major benefit.”

Sabelashvili said there were still issues to be addressed.

“People remain very under-informed – they don’t know how to get treatment, and many don’t even know they are infected,” he explained. “There are too few doctors able to treat patients according to modern medical standards. And the tender has cut cost of the medicines, but hasn’t reduced the cost of diagnosis, which remains high.

“Most important of all, we are hoping the government will initiate a programme of free treatment for the general population.”

Manana Vardiashvili works for Liberali magazine in Georgia.

Source

New HCV Interim Treatment Recommendations Available

Medscape Medical News

Troy Brown, RN
February 07, 2014

The latest treatment recommendations for hepatitis C virus (HCV) infection are now available on HCVguidelines.org, the result of a collaboration between the American Association for the Study of Liver Diseases (AASLD), the Infectious Diseases Society of America (IDSA), and the International Antiviral Society-USA.

The evidence-based consensus recommendations for the screening, treatment, and management of patients with HCV were developed by a panel of 27 liver disease and infectious disease specialists and a patient advocate.

Between 3 and 4 million Americans have HCV that may progress to advanced liver disease and/or hepatocellular cancer, according to information on the Web site.

Because of recent changes in HCV testing guidelines, increasing numbers of patients are being diagnosed with HCV who were unaware they have the disease, Adrian Di Bisceglie, MD, president of AASLD, explained in a joint statement from the AASLD and the IDSA. "The guidance provided through HCVguidelines.org comes at a critical time as more and more of these patients seek treatment that has the potential to effectively 'cure' them," Dr. Di Bisceglie said.

Rapidly Changing Field

Drug development for HCV is progressing rapidly, with new direct-acting antiviral medications capable of essentially curing HCV.

Eugene Schiff, MD, director, Schiff Center for Liver Disease at the University of Miami Miller School of Medicine in Florida, commented on the development of the Web site in an interview with Medscape Medical News. "The reason [for the development of the Web site] is that the field is moving so rapidly...the [US Food and Drug Administration] is trying to advance some of these [medications] faster than they have traditionally in the past, which is wonderful for the patients," Dr. Schiff said.

"Because of all this, the average clinician can't keep up with it, and they're trying to be more in sync with the advances," he added.

"In just the past 3 months, 2 new medications became available for treating HCV that hold a great deal of promise for patients living with this disease, and more are expected. HCVguidelines.org provides physicians with the latest information and informed guidance on the available treatment options based on a rigorous review of data," Barbara Murray, MD, president of IDSA, explained in the statement.

"[The development of newer drugs is] of historical significance. We are quickly approaching 100% cure rates of this disease with treatment," Dr. Schiff explained.

"The presence of a readily available, frequently updated guidance document is a great service to providers and their patients, who will benefit from modern treatments that result in cure of HCV up to 95% of the time," Michael Saag, MD, a member of the board of directors of the International Antiviral Society-USA and a cochair of the guidance panel, said in the statement.

"The site will be updated regularly to keep pace with improved diagnostic tools and new drug options as they meet [US Food and Drug Administration] approval," according to the statement.

The Web site will include an ongoing summary of recent changes.

Guidance for Insurance Carriers Also

The rapid development of medications has made insurance companies as well as clinicians unsure of the best treatment options, the statement explains.

The newer drugs are expensive, and not all insurance carriers are willing to pay for them. The guidelines may help insurance carriers evaluate the appropriateness of these drugs for patients with HCV. As the drugs become more available to patients, the cost may go down, Dr. Schiff said.

Even though the newer drugs are expensive, they may still be cost-effective if they are curing patients, he added.

Dr. Schiff reports a variety of relationships with pharmaceutical companies, including receipt of consulting fees, membership on scientific advisory boards and the Data and Safety Monitoring Board, and receipt of grants/research support for clinical trials.

Source

Also See: Online Expert Advice for Clinicians Treating Hepatitis C Now Available

Sticker Shock and the Price of New Therapies for Hepatitis C: Is it worth it?

Provided by NATAP

Download the PDF here

"Thus, although DAA therapy may be $1000 a pill, SVR is arguably priceless......if these individuals fail to be linked to a provider willing to administer HCV therapy, or if HCV therapy is out of reach due to barriers such as cost, the potential health care burden in the long run is even higher......expensive for society.21 It is difficult, however, to justify an intervention simply by a price tag. Some treatments may be equally effective but toxicity and complexity may make one a much better value......Cost is important, but effective safe therapy is paramount."

Hepatology Feb 3 2014

Nancy S. Reau, MD, Donald M. Jensen, MD

The Center for Liver Disease
The Section of Gastroenterology, Hepatology and Nutrition
The University of Chicago Medicine

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record.

The new era of antiviral therapy for hepatitis C holds great promise to finally reign in a public health nightmare, but at what expense? It has been estimated that a 12 week course of therapy could cost in excess of $84,000. Much has been written in the lay press regarding the price of these newer therapies which has led to concerns about the ability of our health care system to effectively implement and deliver these treatments to those in greatest need.1Can we justify these costs? To better understand this, it is necessary frame the discussion in the context of the economic burden of chronic liver disease against the retail cost of therapy. Product price also reflects drug development and productions expense; however this is very difficult to access.

What is success and what is it worth? According to Oxford dictionary, success is the accomplishment of an aim or purpose.2 In medicine, success can be hard to define. However, when it comes to hepatitis C therapy, sustained viral response (SVR) is a well-established surrogate for treatment success, and has been equated with a cure. Not only is SVR durable, with a less than 1% chance for late relapse, SVR has been associated with lower rates of liver cancer, cirrhosis, transplant and all-cause mortality. It leads to improved quality of life, lower risk of metabolic complications such as insulin resistance, improves glycemic control in those that are diabetic and recovers neurocognitive function. It is difficult to argue this is not success- both for the patient as well as society. How much is this worth? What is the price of prevention?

HCV is generally asymptomatic (and thus not a significant economic burden) until advanced liver disease occurs. This was confirmed by a recent study that compared the economic burden for U.S. patients with chronic hepatitis C, stratified by severity of liver disease, in a large private health insurance claims database from 2003 to 2010. The database included claims for all prescription medications and all medical services submitted for payment. Researchers examined claims from 53,796 patients with chronic hepatitis C: 41,858 (78%) without cirrhosis, 3,718 (7%) with compensated cirrhosis, and 8,220 (15%) with end-stage liver disease. Overall, the annual health care costs were estimated to be $24,176 for patients with chronic hepatitis C infection. However, when examined by disease stage, advanced disease consumed a substantially larger proportion of the total. Average annual costs were $17,277 for patients with no cirrhosis, $22,752 among patients with well-compensated cirrhosis, and $59,995 among patients with end-stage liver disease - most of which was driven by inpatient care.3 Patients with compensated cirrhosis may live for over a decade, accruing (by this model) over $270,000 in expense prior to developing end-stage liver disease. When HCV disease progresses to decompensated cirrhosis, transplant offers the best long-term prognosis, but this is not cheap. According to the United Network for Organ Sharing (UNOS)' Transplant Living Web site, the estimated U.S. average of billed charges per liver transplant in 2011 was $577,100.4, 5

Despite the risk of progression to advanced disease, most patients remain untreated. Based on two large US cohorts (Chronic Hepatitis Cohort Study: CHeCS and the National Health and Nutrition Examination Survey: NHANES) analyzed by the Division of Viral Hepatitis at the Centers for Disease Control and Prevention (CDC) only 13-18% of individuals chronically infected with HCV receive treatment.6 Other studies support this abysmal treatment uptake. In another recent interrogation of a large healthcare payer database showed that only 10.9% of 57,084 HCV infected patients have received HCV therapy.7

It is possible that many of these patients are simply waiting for better treatment options. A common quandary is when to begin therapy. Traditionally, it is felt that a cirrhotic patient has the most to gain from viral eradication, as SVR is associated with a lower risk of hepatic decompensation, liver cancer and need for transplantation.8,9 Yet, at least with 2011 triple therapy, patients with cirrhosis are more likely to experience treatment-related side effects, early termination, and are least likely to attain SVR.10 This experience is likely to improve with newer therapies. Alternatively, treating all patients with minimal fibrosis could prevent progression to advanced disease. This subset has a high probability of cure; yet, these patients are also least likely to develop HCV induced complications in the immediate future and some may never develop advanced disease. Predicting disease progression would be ideal, and baseline factors do contribute to the risk of disease progression. However, the absence of these factors cannot guarantee disease stability.

Still, it is well recognized that SVR can mitigate disease complications and, theoretically, the cost of end stage liver disease. Traditional interferon-based therapy has never been inexpensive. HCV therapy has evolved from standard interferon-alfa for 24 weeks, which offered a 6% SVR rate and would cost less than 20 thousand dollars today, to peginterferon and ribavirin (PEG/RBV) for 48 weeks, with SVR rates increasing to 40-60%11, but also with doubled the price. With the approval in 2011 of HCV protease inhibitor direct-acting antivirals (DAA), efficacy improved, but the cost increased substantially to over 70 thousand dollars. Still, this price tag is out of context. When the total cost of therapy to achieve SVR is considered, including management of complications, the price of treatment actually increases to $172,889 to $188,859 per SVR.11,12 The treatment cost per SVR may therefore be the most reasonable way to estimate the total cost impact of a new therapy. Those patients who relapse (become HCV negative but the disease recurs once treatment is discontinued) therefore cost the most - as they experience the longest duration of therapy for the least return.

The next wave of therapy (simeprevir and sofsbuvir) has again increased treatment efficacy, but the price tag is daunting. These agents shorten therapy and are much more tolerable, but are only approved in combination with PEG and RBV for genotype 1. They are expected to accumulate some additional cost driven by side effects but monitoring and management of adverse events will likely be attenuated. Sofosbuvir is also available as an all oral therapy in combination along with RBV for genotype 2 and 3, and those genotype 1 that are interferon intolerant. But the longer duration necessary for many will further increase the treatment cost.

Is this cost exorbitant?

The price of medical care in the United States has never been a bargain. According to the World Health Organization (WHO), total health care spending in the U.S. was 17.9% of its GDP in 2011, the highest in the world 14 Of each dollar spent on health care in the United States, 31% goes to hospital care, 21% goes to physician/clinical services, and only 10% to pharmaceuticals.15 Still prescription drug prices are higher in the U.S. than anywhere else in the world, and the pharmaceutical industry remains a highly profitable business.16 Manufacturing costs do not drive drug prices, as the cost of producing a drug exclusive of development) is relatively low. Companies typically price a medication based on development costs and demand, but largely demand. The logic is circular in that the escalated cost helps offset drug development and clinical trials. Investing in drug development ultimately saves money by saving lives and preventing hospitalizations.17

Although HCV treatment induces a fair amount of sticker shock, other approved medications are equally costly. HIV therapy averages 2000-5000 dollars a month, and given that it is a lifelong treatment, lifetime drug costs are more than one-half million dollars.18 Several other drugs, including treatment for multiple sclerosis and anti-neoplastic agents, “cost more than a car”. However, the majority of these high-end agents are used for niche indications such as rare enzyme defects (Gaucher Disease) or uncommon conditions such as Hunter Syndrome and paroxysmal nocturnal hemoglobinuria.19

So how can appropriate costs be determined? The cost-effectiveness of an intervention can be calculated by applying a well-being scale, where a unit of health status expresses the output of a health intervention in the number of years and the health-related “quality of life” produced by a treatment.20 Understanding both cost-effectiveness, as well as impact on the quality of life, is imperative for health policy and cost containment. Although this measure has not been performed for current HCV therapy, evaluation of other medical and surgical procedures suggest that very cost-effectiveinterventions typically include those procedures costing less than $20,000; those ranging from $20,000 to $100,000 are moderately cost-effective; and interventions costing more than $100,000 are possibly cost-effective, but expensive for society.21 It is difficult, however, to justify an intervention simply by a price tag. Some treatments may be equally effective but toxicity and complexity may make one a much better value.

Can we negotiate a better price? Although consumers have little ability to impact drug prices, drug companies do negotiate with payers and pharmacy benefit plans. Medicaid also negotiates lower prices, which is then offset by the manufacturer by increasing retail prices. Although other federal agencies can bargain with drug companies, by design Medicare is not permitted to negotiate prices.22 In addition, Medicare participants often assume some out of pocket expense. Other payers receive rebates from companies, effectively lowering the price of the medication. Rebates are not reported, but they are one factor that explains the difference between a company’s gross sales and net sales. There is no standardization for rebates, but the average size is approximately 30% of gross sales. Naturally, rebates are larger for drugs close to patent expiration or those with more significant competition.23

Most consumers are fortunate if their insurer negotiates a better price for them, and then, based on their plan, provides coverage for the medication with affordable co-pays and premiums. For consumers without insurance, or those who cannot afford their portion of the charges, assistance programs and co-pay coupon programs often exist.[(www.MySupportPath.com)]

Still, it remains unanswered if the new agents are worth their price. In some conditions, first line therapy may be a less effective agent that is escalated to a superior but more expensive therapy if it fails to control the disease. When treating viral hepatitis, this strategy is irresponsible. As described above, patients who relapse or fail a course acquire the most cost. They pay for a full course of therapy and experience all of the side effects, but fail to clear the infection. Although we have learned to use interferon and ribavirin effectively, these agents have side effects that can be life threatening. Failing therapy may also make future treatment more difficult, either through possible viral resistance or lack of approved treatment options. Cost is important, but effective safe therapy is paramount.

HCV therapy is most effective if there is adequate treatment uptake, but several barriers exist in addition to the price tag. Patients and providers do not want interferon-based therapy. Until an all-oral-option is widely available, access to physicians willing to treat HCV will be a barrier. Even if a doctor is interested in prescribing interferon, the inevitable availability of all-oral options is widely publicized and patients will be resistant to starting older stigmatized treatments. The primary consumer of HCV therapy will shift as birth cohort screening increases HCV recognition. Most baby boomers will be insured through Medicare, which is financed through U.S. Treasury trust funds, payroll taxes, income taxes and funds authorized by congress (again tax dollars) .24 HCV is also more prevalent in lower socioeconomic groups which are either uninsured or insured through Medicaid- also a tax burden. The University of Alabama recently undertook a massive screening project in their emergency room. Here HCV testing was offered to all birth cohort ER customers who were unaware of their HCV status. After the first 1287 subjects, they found a 12% prevalence of positive anti-HCV of which 72.5% were HCV RNA positive. They also found that the prevalence was much higher in those either uninsured or insured with public/Medicaid (17% for each). Those with Medicare had an 11% prevalence where as those privately insured had only a 4% prevalence. They hope to screen over 7000 individuals and identify over 800 with positive HCV antibody.25 It is easy to see how this will be a financial burden on our health care system. But if these individuals fail to be linked to a provider willing to administer HCV therapy, or if HCV therapy is out of reach due to barriers such as cost, the potential health care burden in the long run is even higher.

Thus, although DAA therapy may be $1000 a pill, SVR is arguably priceless.

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Gender Differences in the Quality of Life of Patients with Liver Cirrhosis Related to Hepatitis C after Liver Transplantation

Blood Purification

Vol. 36, No. 3-4, 2013
Issue release date: January 2014

Free Access

Blood Purif 2013;36:231-236
(DOI:10.1159/000356362)

Bianco T.^d · Cillo U.^b · Amodio P.^c · Zanus G.^b · Salari A.^d · Neri D.^b ·Bombonato G.^c · Schiff S.^c · Baggio G.^a · Ronco C.^{e, f} · Brocca A.^{e, f} · Soni S.^f ·Minazzato L.^d

^aStudy Center of National Health and Gender Medicine, Padua Operating Unit, ^bUnit of Hepatobiliary Surgery, ^cDepartment of Clinical and Experimental Medicine, and^dAntalgic Therapy, Institute of Anesthesiology and Reanimation, University of Padua, Padua, ^eDepartment of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, and ^fInternational Renal Research Institute Vicenza (IRRIV), Vicenza, Italy

Key Words Gender differences  Hepatitis C  Liver transplantation  Pain perception Quality of life  SF-36

Abstract

Background: Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, which adversely affects the quality of life (QoL) of the patient. The gender of the patient may be an important variable in the way severity of the disease is perceived. The aim of our study is to evaluate the effect of the gender variable on QoL in HCV-positive patients.Methods: This study included a total of 52 patients (26 men and 26 women) whocompleted a 1-year follow-up after liver transplantation. QoL was assessed using the SF-36 questionnaire. Results: Male subjects have significantly higher scores on physical role functioning, bodily pain and physical activity compared with females. Females have a better QoL compared to males with regard to the emotional state and mental health.Conclusions: These results show a significant effect of the gender variable on QoL in HCV patients.

© 2013 S. Karger AG, Basel

Introduction

The diagnosis of chronic liver disease has important implications on the patient's life, as it often marks the beginning of frequent medical checkups and treatment. It also involves the formalities related to enrolment into the liver transplant waiting list. In addition to the clinical effects of the liver disease, the psychological stress related to the continuous monitoring and assessments can affect health-related quality of life (HRQoL).

The World Health Organization (WHO) refers to ‘quality of life' as an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns [1]. In this sense, the HRQoL is defined as the set of physical, mental and social diseases assessed by somatic symptoms, psychological status and social interactions from the perspective of the patient, regardless of their medical condition. The international scientific community is increasingly interested in the QoL concept, particularly for the patients with chronic diseases. QoL studies can involve many different factors, ranging from the evaluation of the different effects of different diseases on daily activities and the identification of problems specific to each disease, to evaluate the effectiveness of different treatments and the specific factors that, in addition to patient compliance, determine treatment effectiveness.

In recent years, there have been numerous investigations on the QoL in patients with liver disease related to health, with particular attention to hepatitis C virus (HCV) positivity. This increased interest is justified by the significant spread of HCV in the world's population. In fact, the WHO estimated that worldwide there are about 140 million people affected by HCV, which corresponds to 2.2% of the global population. In Italy, about 2% of the general population is infected with HCV with a gradient that increases from north to south and the islands and with age (60% of patients with hepatitis) [2].

Even in the absence of overt liver disease, chronic HCV compromises HRQoL, with a negative impact on both mental health and physical well-being of the patient [3,4]. In fact, the vast majority of HCV patients present with nonspecific symptoms, such as fatigue, irritability, general malaise, abdominal pain, joint pain and headache [5]. In most cases, medical intervention is not required, however, physical and emotional health of the patient is affected. This in turn leads to inferior HRQoL for HCV patients [6]. Even if the patient is not aware of the seriousness of the disease, his psychological state is altered [7].

QoL in Patients with Liver Disease

Several studies seem to confirm a direct adverse effect of chronic HCV on HRQoL. Some recent reviews illustrate actual prospects of research in the field of QoL in patients with chronic liver disease. In a study from Britain, 72 unselected, consecutive patients with chronic HCV were compared with 30 consecutive patients with chronic hepatitis B infection and HBsAg positivity [4]. Patients with evidence of cirrhosis were excluded. SF-36 scores were markedly reduced in patients with chronic HCV infection, indicating that these patients perceived themselves as unwell and they reported a significant reduction in their QoL. Other researchers have shown that a significant percentage of HCV patients suffer from fatigue [8,9,10,11]. In one of the largest studies from France, Poynard et al. [12] reported that among 1,614 patients with HCV, 53% reported fatigue at their initial visit and the fatigue was severe in 17% of these patients. This study also found that fatigue was independently associated with female gender, age >50 years, cirrhosis, depression and purpura. In another study, HCV patients unaware of their HCV serostatus scored significantly worse in 3 parameters of general health, vitality and mental health [13]. Those aware of their serostatus did not differ demographically, clinically, virologically or serologically from those who were unaware, nor was there a link between QoL scores and objective measures of ill health. Numerous observations suggest that HCV may exert a direct effect on HRQoL through unknown mechanisms [14,15,16]. One possibility is that HCV may act within the central nervous system, since replicating viruses have been found within the nervous system tissue. Moreover, neuropsychiatric symptoms like fatigue, malaise, depression and cognitive impairment are among the most common complaints of patients with chronic hepatitis C and occur independently of liver disease or treatment status.

Importance of the Gender Variable

Over the past 30 years, medicine has reached incredible goals, including the description of the human genome, the ability to intervene at the beginning and end of life, the application of newest technologies for betterment of the patients, to name only a few. The achievements in many fields of medicine are based on evidence connected with guidelines. However, female gender has been inadequately represented in many of the epidemiological studies, which limits meaningful statistical analysis in many disorders.

The ‘woman question' emerged in 1991 when Bernadine Healy, the first female director of the National Institute of American Public Health, wrote a famous editorial in the New England Journal of Medicine [17]. She coined the term ‘Yentl syndrome' to highlight the gender-based disparities in the treatment and outcome of coronary artery disease in the intensive care unit (Yentl was a heroine of a Jewish story where a girl shaved her hair and disguised herself as a boy to enter religious training). Women in the intensive care unit were subjected to less diagnostic and therapeutic procedures than men and fewer invasive procedures such as cardiac catheterization and coronary artery bypass surgery [18,19]. Moreover, large prevention trials in patients with myocardial infarction did not include women at all. A clear discrimination by the cardiologists against the female patient was aptly emphasized. This editorial stirred basic researchers and clinicians around the world and was followed by a series of publications and studies designed to examine gender differences in various aspects of cardiovascular disease.

Another cornerstone of gender medicine was the Fourth World Conference on Women held in Peking in 1995, where the conviction to apply the principle of gender equality in all activities, including those for health, was considered a basic human right.

In 2002, the WHO established the Department for Gender and Women's Health to recognize the differences in disease burden and treatment between men and women. In 1999, the Italian Ministry for Equal Opportunities formally established a new group with the aim of working on gender disparities in medicine through a project entitled ‘A measure of health to a woman'. In 2001, a report on women's health was presented to the parliament and in 2003 a ‘Guide to women's health' was published. In Italy, the attention to the gender variable is now supported by the National Center for Health and Gender Medicine. The Center aims to gather information, impart training and encourage research in all fields of medicine. It also aims to network all Italian centers interested in these issues.

With regard to QoL in patients with chronic liver disease, the gender variable is not systematically studied so far. The aim of the present study is to assess the effect of the gender variable on the subjective evaluation of QoL in patients with chronic HCV infection.

Patients and Methods

SF-36 Questionnaire

SF-36 is the best-known, patient-oriented questionnaire for the assessment of one's general health condition. This test is the short form of the Medical Outcome Study questionnaire, which was developed by John Ware (the principal investigator) and his colleagues in the 1980s and was subject to successive modifications by researchers from various medical specialties [20]. The SF-36 is a generic instrument that proposes to evaluate the QoL from the patient's point of view. It is made up of 36 items divided into 8 scales (table 1) whose purpose is to evaluate the various aspects related to the patient's health and thereby furnish a global assessment of the patient's mental and physical well-being. To each question, a rough score is assigned; this initial score is further elaborated to furnish a final ranking only after evaluation of all answers given. The final response is given and the relationship between specific answers is evaluated to determine the score on each scale. Scoring on each scale is from 1 to 100, with higher values being indicative of a better-perceived QoL relative to one's health status (fig. 1). Scoring and standard deviations will vary from scale to scale and are also dependent on age. Its validity is recognized by the international community.

Patients

This study included a total of 52 patients (26 men and 26 women) who completed a 1-year follow-up after liver transplantation. The HRQoL was assessed using the SF-36 questionnaire. The scores in the various domains of the questionnaire were compared using Student's t test. Analyses were performed using the statistical software SPSS 11.0.

Results

Male subjects have significantly higher scores on physical role functioning (daily activities or work is less impaired by physical health than in females), bodily pain (minor limitations due to pain) and physical activity (fewer constraints on the execution of physical activity in general) compared with females. On the other hand, females have a better QoL compared to males with regard to emotional role functioning (less impaired at emotional level) and mental health (self-satisfied and better mood stability).

Discussion

The way to deal with a disease and recovery will vary from person to person but there are gender differences that are often overlooked or incorrectly addressed. The significant difference between males and females with respect to ‘bodily pain' may be explained by the effects of various hormones on the body. Current research shows that estrogen would increase nervous system activity; this effect manifests itself in the increased transmission of pain stimuli and pain sensitivity of women. Conversely, testosterone has an analgesic effect and can reduce pain sensitivity in men [21]. Many previous studies dealing with behavioral responses evoked by nociceptive stimuli have demonstrated an increased sensitivity of females [22].

In our study, male patients scored higher in the category of ‘physical functioning' and ‘physical role functioning', which are the parameters related to physical activity and perceived limitations. The female patients scored less in both parameters, suggesting impaired QoL. This may partly be explained by the effect of ‘fatigue' in the posttransplant period. In an elegant cross-sectional study, van den Berg-Emons et al. [23] investigated the incidence, etiology, severity and factors of influence of fatigue in liver transplant recipients and concluded that the female gender perceives fatigue with greater severity.

In addition, sociocultural factors have to be considered. In fact, recent studies highlight the issue of gender difference in pain perception. It has been observed that for the same objective disease women report more pain than men [24]. These observations emphasize the fact that QoL assessment in liver transplant patients should not only include the clinical and biological condition of the patient but also psychosocial and cultural aspects. In this regard, it is also interesting to note that although female patients score less in the parameters ‘physical functioning' and ‘physical role functioning', they score better in the parameters of ‘emotional role functioning' and ‘mental health'. This highlights a better ability of females to manage stress and psychoemotional demands in the posttransplant setting. This could indicate differences in the ability of coping with stress between males and females of the study population.

Studies in the experience of pain in patriarchal ideology have highlighted ‘the central role of etiologic and coping strategies (‘being a good mother' to the female gender), suggesting that the patient needs pain to give meaning to their symptoms. It also helps to avoid negative feelings of despair and isolation. In this study, both males and females reported the common belief that a woman is better able to cope with painful events. This belief is also supported by the importance of the maternal role in women (experience of childbirth, breastfeeding, primary involvement in child rearing and emotional aspects of children) and explanations relating to the increased use of emotional expressiveness and the likelihood of seeking help and support of females. Recent studies have demonstrated sex differences in response to painful situations in teenagers and adolescents. It has been observed that males would mostly use distracting behavior while females make greater use of social support and positive self statements [25].

Studies on coping styles in the course of chronic diseases have shown that being active, thinking positively and expressing emotions positively correlated with significantly higher levels of functioning, with more positive scores in the clinical measures of disease and higher levels of psychological adjustment. The ability to adequately manage the transplant event and its consequences may foster greater satisfaction and improve QoL and HRQoL. In this sense, the gender differences in the QoL questionnaire identified in this study can help to direct attention to the most problematic and often neglected aspect for a patient undergoing a liver transplant by directing care and interventions in the posttransplant period in relation to an important variable such as gender.

Conclusion

HCV confers an inferior QoL to the patients. This effect is perceived by males and females in different ways.

References

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Hepatitis C: How might the new AASLD/IDSA recommendation impact the category?

Provided by Zitter Health

Lee Goldberg, Director, Syndicated Research, Zitter Health Insights

FEBRUARY 5, 2014

The HCV category is certainly dynamic enough, with numerous agents poised for approval in the next 18 to 24 months. Still, the release last Wednesday of the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis Cadded another variable for payers and manufacturers to consider before determining their strategies. The recommendations were both confirmatory and surprising and it remains to be seen how payers will ultimately integrate them into management.

The Recommendations fully endorse new oral agents as the standard of care, advocating sofosbuvir first among treatment-naïve, genotype 1 patients who are eligible for interferon, followed by a simeprevir-based regimen as an alternative. The panel made a comparable recommendation for genotype 4 patients, then endorsed sofosbuvir for treatment of patients with genotypes 2 and 3, per label. Endorsements for telaprevir and boceprevir-based regimens were withdrawn as being “markedly inferior to the preferred and alternative regimens.”

However, not all endorsements followed the obvious path, namely those for patients intolerant to interferon. Labeling for sofosbuvir permits usage “in combination with ribavirin for 24 weeks . . . for CHC patients with genotype 1 infection who are interferon ineligible.” Nonetheless, the AASLD/IDSA made its primary treatment an off-label regimen of sofosbuvir plus simeprevir in combination for treatment-naïve, interferon-ineligible genotype 1 patients. It’s a safe assumption the panelists were impressed with the 90%-plus SVR rates achieved in the ongoing phase 2 COSMOS study, but it’s less clear payers will hold the same opinion.

Early research from the Hepatitis C Impact Monitor, a multi-stakeholder view of this rapidly changing area, published by Zitter Health Insights, indicates a majority of payers (52%) hold the guidelines as meaningfully or significantly influential on their determination of utilization management of the HCV category.  By itself that finding would indicate positive coverage of the sofosbuvir/simeprevir pairing.  But an even larger majority of the same payer sample, this time 80%, indicated they’re more unlikely than likely to cover those drugs in combination.  But that was before the guidelines were released.

To begin developing an understanding of how payers and doctors expect to change their behavior as events occur, we asked four pharmacy directors from national payers (in aggregate representing approximately 25 million commercial lives) how they anticipate their organizations will react.  While it’s still early for many to have determined final policies, reactions were evenly split.  One participant commented, “We try to support evidence based guidelines, but, the evidence is not there to support use at phase 2.  We’ll need more evidence development.” However, another pharmacy director was more resigned, commenting, “We won’t have a choice.  There’s no way to combat the recommendation.”
Combat may be a strong word, but may not be far from an accurate description because physicians appear on board. Prior to publication nearly a majority (47%) of specialists were more likely than unlikely to prescribe the combination. We expect those figures to increase because seventy-three percent of them grant the guidelines meaningful or significant influence in their prescribing decisions.

Perhaps beneficially for pharmacy directors, the conundrum about off-label sofosbuvir/simeprevir coverage comes with an expiration date. The AASLD/IDSA includes the caveat that “This regimen should be considered only in those patients who require immediate treatment, because it is anticipated that safer and more effective IFN-free regimens will be available by 2015.”  Which means payers will have new guidelines to digest upon the approval of Gilead’s sofosbuvir/ledipasvir, or of AbbVie’s triple therapy, or of Boehringer’s faldaprevir/deleobuvir. In the interim, payers will weigh the nature of Phase 2 results against the imprimatur of the AASLD.  Each of the four pharmacy directors we spoke with on Monday indicated their organization is currently reviewing the Recommendations document but hadn’t yet made a final policy determination.  Zitter’s Hepatitis C Impact Monitor will continue to examine the changing HCV landscape, providing timely, deep insights into non-clinical factors that influence agent access and adoption.

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