All Journal Entries Journals
Sort By:  

EASL 2014:  Final Phase II data from Interferon-free COSMOS Study

Apr 14, 2014 - 0 comments
Tags:

EASL 2014

,

simeprevir

,

Sofosbuvir

,

HCV genotype 1

,

Cosmos Study



Below please find data from Phase II of the Interferon-free Cosmos study presented at EASL 2014 in London this week.  93% of prior null responders and treatment naive patients with HCV G1, including patients with advanced liver fibrosis (F3 & F4) achieved SVR12 after 12 weeks of treatment with Simeprevir in combination with Sofosbuvir.
The link to the article is found at the bottom.
Advocate1955

EASL - Final data phase II COSMOS study with Simeprevir in combination with Sofosbuvir
Final data from the phase II COSMOS study with Simeprevir in combination with Sofosbuvir presented at EASL

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announces that positive new simeprevir data were presented at The International Liver Congress™ 2014 of the European Association for the Study of the Liver (EASL) in London.

The data presented included;
Final phase II data from the interferon-free COSMOS study
Phase III efficacy data in patients with genotype 4 hepatitis C
Subgroup analyses of patients from phase III studies QUEST-1, QUEST-2 and PROMISE

Final phase II data from the interferon-free COSMOS study

Cohort 2
Final results from cohort 2 of the phase II COSMOS study demonstrated that 93 percent of prior null responder and treatment-naïve patients with genotype 1 HCV and advanced liver fibrosis (METAVIR scores F3 and F4) who were treated with simeprevir and sofosbuvir for 12 weeks achieved sustained virologic response 12 weeks after the end of treatment (SVR12). The addition of ribavirin did not improve SVR rates and consistent responses for both treatment arms were seen across HCV genotype subgroups after 12 weeks.
Click to Enlarge



*Excluding non-virologic failures.

The most common adverse events reported during the study were fatigue, headache, nausea, anemia, pruritus, dizziness, rash and photosensitivity. One patient discontinued treatment due to adverse events.

Cohort 1
Previously presented data from cohort 1 at AASLD in November 2013, demonstrated that 96 percent and 93 percent of prior null responder patients with METAVIR F0-F2 scores treated with simeprevir and sofosbuvir without or with ribavirin, respectively, for 12 weeks achieved SVR12.

Click To Enlarge



*Excluding non-virologic failures.

In genotype 1a patients with the Q80K polymorphism at baseline, 83 percent and 89 percent achieved SVR12 after 12 weeks of treatment without and with ribavirin, respectively. The most common adverse events reported during the study were fatigue, headache, nausea and insomnia. Two patients discontinued treatment due to adverse events.

Phase III efficacy data in patients with genotype 4 hepatitis C

Results from the Phase III RESTORE trial of simeprevir in combination with pegylated interferon and ribavirin in HCV genotype 4 treatment-naïve and treatment-experienced patients demonstrated that overall 65 percent of patients achieved SVR12, including 83 percent of treatment-naïve patients, 86 percent of prior relapsers, 60 percent of prior partial responders, and 40 percent of prior null responders. Among patients with more severe liver fibrosis characterized by a METAVIR score of F3 or F4, 67 percent and 47 percent achieved SVR12, respectively. Among patients with genotype 4a and 4d HCV, 69 percent and 52 percent achieved SVR12, respectively. The most frequent adverse events included influenza-like illness, asthenia (weakness) and fatigue.

Genotype 4 HCV is considered particularly difficult to cure and currently only limited treatment options are available.

Subgroup analyses of patients from phase III studies of Simeprevir

Analyses of pooled efficacy data from the QUEST-1 and QUEST-2 studies found 87 percent of European patients treated with simeprevir in combination with pegylated interferon and ribavirin achieved SVR12, compared to 80 in the overall study population. In an analysis from the PROMISE study, 88 percent of European patients treated with simeprevir in combination with pegylated interferon and ribavirin achieved SVR12 compared to 79 percent in the overall study population.

The efficacy of simeprevir in combination with pegylated interferon and ribavirin was also observed among European patients with baseline characteristics typically considered more difficult to cure. In QUEST-1 and QUEST-2, 71 percent of patients with METAVIR F4 scores, 86 percent of patients with the IL28B CT genotype, 69 percent of patients with the IL28B TT genotype and 64 percent of genotype 1a patients with the Q80K polymorphism at baseline achieved SVR12 in the simeprevir arm, compared to 25 percent, 44 percent, 31 percent and 50 percent of patients in the active placebo arm, respectively. In PROMISE, 85 percent of patients with METAVIR F4 scores, 88 percent of patients with the IL28B CT genotype, 77 percent of patients with the IL28B TT genotype and 75 percent of genotype 1a patients with the Q80K polymorphism at baseline achieved SVR12 in the simeprevir arm, compared to 30 percent, 41 percent, 18 percent and 57 percent of patients treated in the active placebo arm, respectively.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR, mobile: +46 708 537 292

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 17.15 CET on 12 April 2014.

About Simeprevir
Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated for the treatment chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 and 4 infected patients with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB retains marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved for the treatment of chronic hepatitis C infection as part of an antiviral treatment regimen in combination with pegylated interferon and ribavirin in genotype 1 infected adults with compensated liver disease, including cirrhosis in September 2013 in Japan, in November 2013 in Canada and the U.S. and in March 2014 in Russia. A Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) in April 2013 by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C and the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending Marketing Authorisation in the European Union for the use of simeprevir in combination with other medicinal products for the treatment of chronic HCV. This application is under review by the EMA.


http://hepatitiscnewdrugs.blogspot.com/2014/04/easl-final-data-phase-ii-cosmos-study.html



Ledipasvir-Sofosbuvir, 94-99% SVR rate for HCV G1 previous non responders

Apr 12, 2014 - 0 comments
Tags:

Ledipasvir

,

Sofosbuvir

,

Hepatitis C Genotype 1



Below is an article that came out on 4/12/14 in the New England Journal of Medicine summarizing results of a randomized open label trial of Ledipasvir-Sofosbuvir fixed dose once daily.  94-99% of people with HCV G1, previous non responders, attained SVR after 12 weeks of treatment with this combination.
The link to the article is at the bottom.
Advocate1955

Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1 Infection

Nezam Afdhal, M.D., K. Rajender Reddy, M.D., David R. Nelson, M.D., Eric Lawitz, M.D., Stuart C. Gordon, M.D., Eugene Schiff, M.D., Ronald Nahass, M.D., Reem Ghalib, M.D., Norman Gitlin, M.D., Robert Herring, M.D., Jacob Lalezari, M.D., Ziad H. Younes, M.D., Paul J. Pockros, M.D., Adrian M. Di Bisceglie, M.D., Sanjeev Arora, M.D., G. Mani Subramanian, M.D., Ph.D., Yanni Zhu, Ph.D., Hadas Dvory-Sobol, Ph.D., Jenny C. Yang, Pharm.D., Phillip S. Pang, M.D., Ph.D., William T. Symonds, Pharm.D., John G. McHutchison, M.D., Andrew J. Muir, M.D., Mark Sulkowski, M.D., and Paul Kwo, M.D. for the ION-2 Investigators

April 12, 2014DOI: 10.1056/NEJMoa1316366

Among the estimated 170 million people in the world who have chronic hepatitis C virus (HCV) infection, approximately 60% have the genotype 1 strain of the virus. 1The treatment of patients infected with HCV genotype 1 is evolving rapidly.2-6 At the end of 2013, the Food and Drug Administration (FDA) approved two new direct-acting antiviral agents for the treatment of HCV infection: the nucleotide polymerase inhibitor sofosbuvir (Gilead Sciences) and the protease inhibitor simeprevir (Janssen Therapeutics).

Among the regimens that have been approved by the FDA for patients with HCV genotype 1 infection who have not had a sustained virologic response to prior interferon-based therapy — historically, the population hardest to cure — are 12 weeks of sofosbuvir with peginterferon and ribavirin or 24 to 48 weeks of simeprevir with peginterferon and ribavirin. The only interferon-free option currently approved for HCV genotype 1 infection is 24 weeks of sofosbuvir and ribavirin for patients who are ineligible to receive interferon because of absolute or relative contraindications. A guideline recently issued by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recommends 12 weeks of sofosbuvir and simeprevir, with or without ribavirin, for previously treated patients with HCV genotype 1 infection (on the basis of limited data from phase 2 trials).

Ledipasvir (Gilead Sciences) is a new HCV NS5A inhibitor with potent antiviral activity against HCV genotypes 1a and 1b.11 In phase 2 trials, the combination of ledipasvir and sofosbuvir, with and without ribavirin, resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had received prior treatment with interferon-based regimens, including patients who had received a protease-inhibitor regimen and those with compensated cirrhosis.12,13 To simplify the regimen and improve adherence to therapy, ledipasvir and sofosbuvir have been combined in a single fixed-dose tablet for use once daily (ledipasvir–sofosbuvir). We conducted a phase 3 trial of 12 or 24 weeks of treatment with ledipasvir–sofosbuvir, with and without ribavirin (Ribasphere, Kadmon Pharmaceuticals), in patients with HCV genotype 1 infection who did not have a sustained virologic response after treatment with either peginterferon, ribavirin, and a protease inhibitor or peginterferon and ribavirin; the trial included patients with cirrhosis.

Methods
Patients
From January 3, 2013, to February 26, 2013, at 64 sites in the United States, we enrolled patients 18 years of age or older who had chronic HCV genotype 1 infection. Eligible patients were those who had not had a sustained virologic response with either peginterferon and ribavirin or an NS3/4A protease inhibitor combined with peginterferon and ribavirin. Patients who had discontinued prior treatment owing to an adverse event were not eligible. All the patients provided written informed consent.

Approximately 20% of the enrolled patients had evidence of cirrhosis, defined by a liver-biopsy specimen showing evidence of cirrhosis (Metavir stage 4 [on a scale from 0 to 4, with higher stages indicating a greater degree of fibrosis] or Ishak score of 5 or 6 [on a scale from 0 to 6, with higher scores indicating a greater degree of fibrosis]) or a FibroTest score of more than 0.75 (on a scale of 0 to 1, with higher scores indicating more severe fibrosis) and an aspartate aminotransferase:platelet ratio index of more than 2 (with higher scores indicating a greater likelihood of extensive fibrosis). There were no upper limits on age or body-mass index. All the eligibility criteria are listed in the study protocol (available with the full text of this article at NEJM.org).

Study Design
In this randomized, open-label trial, all the patients received a fixed-dose combination tablet containing 90 mg of ledipasvir and 400 mg of sofosbuvir, administered orally once daily. Ribavirin was administered orally twice daily, with the dose determined according to body weight (1000 mg daily in patients with a body weight of <75 kg, and 1200 mg daily in patients with a body weight ≥75 kg).

Patients were randomly assigned in a 1:1:1:1 ratio to one of four treatment groups: ledipasvir–sofosbuvir for 12 weeks, ledipasvir–sofosbuvir plus ribavirin for 12 weeks, ledipasvir–sofosbuvir for 24 weeks, or ledipasvir–sofosbuvir plus ribavirin for 24 weeks. Randomization was stratified according to genotype (1a vs. 1b), presence or absence of cirrhosis, and response to prior therapy (relapse or virologic breakthrough vs. no response). See the Supplementary Appendix, available at NEJM.org, for definitions of all types of response to prior therapy.

Study Oversight
This study was approved by the institutional review board or independent ethics committee at each participating site and was conducted in compliance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulatory requirements. The study was designed and conducted according to the protocol by the sponsor (Gilead Sciences) in collaboration with the academic investigators. The sponsor collected the data, monitored the study conduct, and performed the statistical analyses. An independent data and safety monitoring committee reviewed the progress of the study.

The investigators, participating institutions, and sponsor agreed to maintain confidentiality of the data. All the authors had access to the data and assume responsibility for the integrity and completeness of the data and analyses reported. The first draft of the manuscript was prepared by a professional writer who is an employee of Gilead Sciences, an author who is also an employee of Gilead Sciences, and the first author, with input from all the authors.

Study Assessments
In addition to laboratory and clinical tests, the screening assessments included serum HCV RNA genotyping, measurement of the HCV RNA level, and IL28B genotyping. The serum HCV RNA level was measured with the COBAS TaqMan HCV Test, version 2.0, for use with the High Pure System (Roche Molecular Systems), which has a lower limit of quantification of 25 IU per milliliter. See the Supplementary Appendix for more information on study assessments.

End Points
The primary efficacy end point was the rate of sustained virologic response, defined as the absence of quantifiable HCV RNA in serum (<25 IU per milliliter), at 12 weeks after the end of therapy among all patients who underwent randomization and were treated. Secondary end points included the rate of sustained virologic response at 24 weeks after the end of treatment.

Statistical Analysis
The primary statistical hypotheses of the study were that the rate of sustained virologic response in each of the four treatment groups would be higher than an adjusted historical rate of 25%, which was based on the expected response rate for this patient population (see the Supplementary Appendix). We calculated that a sample of 100 patients in each treatment group would provide the study with more than 99% power to detect an improvement of at least 45 percentage points in the rate of response over the historical null rate of 25%, with the use of a two-sided, exact one-sample binomial test and a significance level of 0.0125 on the basis of a Bonferroni correction. An exact logistic-regression analysis was performed to identify baseline factors associated with sustained virologic response; the Kruskal–Wallis test was used to test for the overall difference across treatment groups for continuous variables, and the Cochran–Mantel–Haenszel test was used for categorical variables. See the Supplementary Appendix for methods used in the regression analyses.

Results
Baseline Characteristics
Of the 551 patients who underwent initial screening, 441 underwent randomization and 440 began treatment (Table S1 and Figure S2 in the Supplementary Appendix). The demographic and baseline clinical characteristics of the patients were generally balanced among the four treatment groups (Table 1Table 1 Demographic and Clinical Characteristics of the Patients at Baseline.). As expected in a population of patients who had not had a sustained virologic response to interferon-based therapy, most patients (88%) had the non-CC IL28B genotype. A total of 20% of the patients in each of the four treatment groups had cirrhosis. Overall, 52% of the enrolled patients had received prior treatment with a protease-inhibitor regimen.

Efficacy
In all four treatment groups, the rate of sustained virologic response was superior to the adjusted historical response rate of 25% (P<0.001 for all comparisons). The rates of sustained virologic response at 12 weeks after the end of treatment were as follows: among 109 patients who received 12 weeks of ledipasvir–sofosbuvir, 102 had a sustained virologic response (94%; 95% confidence interval [CI], 87 to 97); among 111 who received 12 weeks of ledipasvir–sofosbuvir plus ribavirin, 107 had a sustained virologic response (96%; 95% CI, 91 to 99); among 109 who received 24 weeks of ledipasvir–sofosbuvir, 108 had a sustained virologic response (99%; 95% CI, 95 to 100); and among 111 who received 24 weeks of ledipasvir–sofosbuvir plus ribavirin, 110 had a sustained virologic response (99%; 95% CI, 95 to 100) (Table 2Table 2

Response during and after Treatment.). Across treatment groups, 85 to 91% of the patients with an elevated serum level of alanine aminotransferase at baseline had a reduction to a level that was within the limits of the normal range by week 2 of treatment (Table S4 in the Supplementary Appendix).

Overall, 11 of the 440 patients (2%) had a virologic relapse after the end of treatment: 7 of 109 patients (6%) in the group that received 12 weeks of ledipasvir–sofosbuvir and 4 of 111 (4%) in the group that received 12 weeks of ledipasvir–sofosbuvir plus ribavirin. A total of 10 of these 11 patients had a relapse by week 4 after the end of treatment; 1 patient had a relapse between post-treatment weeks 4 and 12. The characteristics of the patients who had a relapse are shown in Table S5 in the Supplementary Appendix.

No patient in a group that received 24 weeks of treatment had a virologic relapse. Only two patients who received 24 weeks of treatment did not have a sustained virologic response: one patient who received ledipasvir–sofosbuvir withdrew consent after post-treatment week 4 (HCV RNA level at post-treatment week 4, <25 IU per milliliter), and one who received ledipasvir–sofosbuvir plus ribavirin had virologic rebound during treatment. This patient had low-to-undetectable plasma concentrations of ledipasvir and GS-331007 (the major circulating metabolite of sofosbuvir) at weeks 2, 4, and 6, which suggested nonadherence to the study-drug regimen.

All 427 patients who had a sustained virologic response at 12 weeks after the end of treatment also had a sustained virologic response at 24 weeks after the end of treatment. No patient had a relapse after post-treatment week 12.

The rates of sustained virologic response in various patient subgroups are shown in Figure 1Figure 1 Rates of Sustained Virologic Response According to Subgroup. and in Table S3 in the Supplementary Appendix. In all the groups, the response rates were similar among patients with HCV genotype 1a infection and those with HCV genotype 1b infection, among patients who had previously received peginterferon and ribavirin and those who had received a protease-inhibitor regimen, and among patients with no response to prior treatment and those with prior virologic breakthrough or relapse. Ribavirin had no effect on response rates, regardless of treatment duration.
Among patients with cirrhosis who were assigned to 12 weeks of treatment, the rates of sustained virologic response were 86% for those who received ledipasvir–sofosbuvir and 82% for those who received ledipasvir–sofosbuvir plus ribavirin; the respective rates among patients without cirrhosis were 95% and 100%. Among patients assigned to receive 24 weeks of treatment, the response rates were similar for patients with cirrhosis and those without cirrhosis. The difference between the rates of response among patients with cirrhosis who received 12 weeks of treatment and the rates among patients with cirrhosis who received 24 weeks of treatment was significant (P=0.007 by the stratified Cochran–Mantel–Haenszel test).

The multivariate exact logistic-regression analysis identified the absence of cirrhosis as the only baseline factor associated with a significant increase in the rate of response (Tables S6 and S7 in the Supplementary Appendix). Overall, the rate of sustained virologic response was 98% (95% CI, 96 to 99) among patients without cirrhosis and 92% (95% CI, 84 to 97) among those with cirrhosis. We explored whether differences in the kinetics of virologic suppression during early treatment among patients with cirrhosis and those without cirrhosis could predict the differences in response rates. Viral kinetics during the first 2 weeks of treatment did not predict the treatment outcome with ledipasvir–sofosbuvir, regardless of cirrhosis status (Tables S9 and S10 in the Supplementary Appendix). No baseline factors predictive of relapse in patients with cirrhosis were identified.

Virologic Resistance Testing
At baseline, variants associated with resistance to NS5A inhibitors were detected by means of deep sequencing in 62 of the 439 patients (14%) for whom data were available; 55 of the 62 patients (89%) had a sustained virologic response. Variants associated with resistance to NS3/4A protease inhibitors were detected at baseline in 163 of the 228 patients (71%) who underwent successful sequencing and had received prior treatment with a protease-inhibitor regimen; 159 of the 163 patients (98%) had a sustained virologic response.

Of the 7 patients who received 12 weeks of ledipasvir–sofosbuvir and had a relapse, 4 (57%) had NS5A-resistant variants at baseline. Of the 4 patients who received 12 weeks of ledipasvir–sofosbuvir plus ribavirin and had a relapse, 2 (50%) had NS5A-resistant variants at baseline. All 11 patients who had a relapse had detectable NS5A-resistant variants at the time of the relapse. Patients with NS5A-resistant variants at baseline and those without NS5A-resistant variants at baseline had similar viral kinetics during early treatment (Figure S3 and S4 in the Supplementary Appendix). The NS5B-resistant variant S282T was not detected in any patient at baseline or at any time thereafter.

Safety
The majority of patients in each treatment group (67 to 90%) had adverse events, most of which were mild to moderate in severity. None of the 440 patients in the study discontinued treatment prematurely owing to adverse events. No patient in either 12-week group had a serious adverse event. Among the patients assigned to a 24-week regimen, the rate of serious adverse events was 6% among those who received ledipasvir–sofosbuvir and 3% among those who received ledipasvir–sofosbuvir plus ribavirin (P=0.36). Table 3Table 3 Treatment Discontinuations, Adverse Events, and Hematologic Abnormalities. lists all the serious adverse events.

Among patients who received ledipasvir–sofosbuvir alone, the incidence of adverse events was higher in the 24-week group than in the 12-week group (81% vs. 67%). Among those who received ledipasvir–sofosbuvir plus ribavirin, the incidence of adverse events was similar in the 12-week group and the 24-week group (86% and 90%, respectively). Patients in the groups that received ribavirin had higher rates of events that are known to be associated with ribavirin therapy14 — fatigue, nausea, insomnia, arthralgia, cough, rash, irritability, dyspnea, and anemia — than did the patients who received ledipasvir–sofosbuvir alone (Table 3).

The mean change in the hemoglobin level from baseline to week 12 was −0.5 g per deciliter and −0.6 g per deciliter in patients who received 12 weeks and 24 weeks, respectively, of ledipasvir–sofosbuvir, as compared with −2.5 g per deciliter and −2.4 g per deciliter in patients who received 12 weeks and 24 weeks, respectively, of ledipasvir–sofosbuvir plus ribavirin. Mild-to-moderate (grade 1 or 2) hyperbilirubinemia developed in more patients who received ledipasvir–sofosbuvir plus ribavirin (in 32% of patients who received 12 weeks of therapy and 41% of those who received 24 weeks of therapy) than in those who received only ledipasvir–sofosbuvir (1% and 7%, respectively). Two patients who received ledipasvir–sofosbuvir plus ribavirin had grade 3 hyperbilirubinemia. The rates of laboratory abnormalities were otherwise similar among the four treatment groups. Platelet counts and albumin levels during treatment are shown in Tables S11 and S12 in the Supplementary Appendix.

Discussion
In this study, treatment with the once-daily, single-tablet regimen of ledipasvir–sofosbuvir resulted in a sustained virologic response in 94 to 99% of patients with HCV genotype 1 infection who had not had a sustained virologic response after prior interferon-based treatment, including protease-inhibitor regimens. These rates of response are among the highest reported to date for HCV genotype 1 infection. The rates of sustained virologic response were similar, with widely overlapping confidence intervals, among patients who received 12 weeks of treatment and among those who received 24 weeks of treatment, and also among those who received ledipasvir–sofosbuvir alone and among those who received ledipasvir–sofosbuvir plus ribavirin. However, this study was not powered to compare responses to regimens with and without ribavirin or to 12 weeks and 24 weeks of treatment.

Ledipasvir–sofosbuvir was not associated with any new or characteristic adverse events, although the patients who received ledipasvir–sofosbuvir plus ribavirin had higher rates of fatigue, nausea, insomnia, arthralgia, cough, rash, irritability, dyspnea, and anemia — events that are consistent with the known side effects of ribavirin — than did those who received ledipasvir–sofosbuvir alone.14 Overall, the rate of adverse events was substantially lower in the group that received 12 weeks of ledipasvir–sofosbuvir alone (67%) than in the other three treatment groups (81 to 90%).

The study population included substantial numbers of patients with characteristics historically associated with a poor response to treatment.15 In particular, 84 to 91% of the patients had a non-CC IL28B genotype, 41 to 46% had a documented prior nonresponse to interferon-based therapy, and 52% had previously been treated with a protease-inhibitor regimen and were therefore without treatment options. This treatment was effective in patients who had not had a sustained virologic response with a protease-inhibitor regimen — a population that accounts for a substantial proportion of patients with diagnosed HCV infection. The rates of sustained virologic response in all these difficult-to-treat subgroups ranged from 92% to 100%.

In the 12-week treatment groups, patients with cirrhosis had modestly lower rates of response (86% with ledipasvir–sofosbuvir and 82% with ledipasvir–sofosbuvir plus ribavirin) than did those without cirrhosis (95 and 100%, respectively), whereas in the 24-week treatment groups, the rates of response were similar in patients with cirrhosis (99% with both regimens) and those without cirrhosis (100% with both regimens). However, this observation is preliminary, since the study was not powered for intergroup comparisons. We explored the usefulness of virologic suppression during early treatment in predicting sustained virologic response in patients with cirrhosis. Among patients with cirrhosis who received 12 weeks of ledipasvir–sofosbuvir alone, 80% of those who had a detectable HCV RNA level at week 2 had a sustained virologic response (Table S10 in the Supplementary Appendix), indicating that virologic response during early treatment does not accurately identify the small subset of patients who might benefit from 24 weeks of treatment. We were unable to identify any baseline characteristics that might predict which patients with cirrhosis were most likely to have a relapse after 12 weeks of treatment.

The NS5B S282T variant, which reduces susceptibility to sofosbuvir, was not observed in this study, confirming the high genetic barrier to the development of resistance that has been observed in previous studies of sofosbuvir. Treatment failure with inhibitors of the HCV NS5A protein is often associated with the presence at baseline of NS5A variants that are resistant to treatment and also with the rapid development of resistant variants during treatment. Although no virologic relapse was observed in patients who received 24 weeks of treatment, 11 of those who received 12 weeks of treatment had a relapse. Of the 11 patients who had a relapse after treatment, 6 had NS5A-resistant variants at baseline. All the patients who had a relapse had detectable NS5A-resistant variants at the time of virologic failure. Early reductions in the HCV RNA level were similar in patients without resistant variants at baseline and in those with resistant variants at baseline, including those who had a relapse.
The study also characterizes the burden of adverse events associated with ribavirin. Higher rates of constitutional and neuropsychiatric side effects were observed in the two groups that received the ribavirin-containing regimen than in the two groups that received ledipasvir–sofosbuvir alone. Decreases in the hemoglobin level and increases in the bilirubin level were seen in the two groups that received the ribavirin-containing regimen — findings consistent with ribavirin-mediated hemolysis — but not in the two groups that received ledipasvir–sofosbuvir alone. The exclusion of patients who had discontinued prior therapy owing to adverse events, which was intended to restrict the study population to patients who had not had a response to prior therapy, may have inadvertently selected for patients who were more likely to have a low rate of adverse events.

In conclusion, treatment with a single-tablet regimen containing ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a response to prior interferon-based treatment.

http://www.nejm.org/doi/full/10.1056/NEJMoa1316366?query=featured_home#t=article




Recommendations for Testing, Managing, and Treating Hepatitis C from AASLD and IDSA

Feb 09, 2014 - 1 comments
Tags:

hepatitis c treatment

,

Retreatment of Hepatitis C

,

Hep C prior treatment failed



Below are two sections from the recently released AASLD and IDSA recommendations for testing, managing, and treating Hepatitis C, specifically retreatment of persons in whom prior therapy has failed.  Links are posted below each section.
Advocate1955

Recommendations for Testing, Managing, and Treating Hepatitis C

RETREATMENT OF PERSONS IN WHOM PRIOR THERAPY HAS FAILED

A summary of recommendations for retreatment

This section provides guidance on the retreatment of a person with chronic HCV infection in whom prior therapy has failed. In general, treatment responses of patients achieving an undetectable level of virus during a prior treatment course who relapse following cessation of therapy (relapser) are similar to those of treatment-naive persons. Treatment responses are generally lower in prior non-responders, which includes null responders (those in whom serum HCV RNA levels declined less than 2 log10 IU/mL by week 12 during a prior treatment course) and partial responders (those with a > 2 log10 IU/mL response whose virus remained detectable up to 24 weeks or the end of treatment). This section assumes that a decision to treat has been made and advises on the optimal treatment. In many instances, however, it may be advisable to delay treatment for some patients with documented early fibrosis stage (F 0-2), because waiting for future highly effective, pangenotypic, combinations in IFN-free regimens may be prudent. Potential advantages of waiting to begin to treatment will be provided in a future update to this guidance.

The level of the evidence supporting the best treatment for each patient and the corresponding confidence in the recommendation varies as does the strength of the recommendation, and is graded in the same manner as the section on initial treatment of treatment-naive patients. In addition, when treatment differs for a particular group (eg, those infected with various genotypes) specific recommendations are given. Regimens are classified as "Recommended" when it is favored for most patients or "Alternative" when it might be optimal in a particular subset of patients in that category. When a treatment is clearly inferior or should not be used, it is classified as "Not Recommended."

As always, patients receiving antiviral therapy require careful pretreatment assessment for comborbidities that may influence treatment response. All patients should have careful monitoring during treatment, particularly for anemia if ribavirin is included in the regimen.

I. Genotype 1

Recommended regimen for HCV genotype 1 PEG/RBV (without an HCV protease inhibitor) nonresponder patients:
Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weight-based RBV (1000 mg [75 kg]) for 12 weeks is recommended for retreatment of HCV genotype 1 infection, regardless of subtype or IFN eligibility

Rating: Class IIa, Level B

COSMOS is a phase 2a randomized trial in which participants received sofosbuvir (400 mg once daily) plus simeprevir (150 mg once daily) with or without weight-based RBV (1000 mg to 1200 mg daily) for 12 or 24 weeks (Jacobson, 2013b). Of the 80 null responders with a Metavir fibrosis stage of 2 or less included in this trial, 79% to 96% achieved SVR (79%-96% in RBV-containing arms and 93% in both RBV-free arms). Among those null responders with a Metavir fibrosis stage of 3 or 4 (n=47) who received 12 weeks of sofosbuvir and simeprevir, SVR4 was observed in 14 (93%) of 15 patients in the ribavirin-containing arm and 100% (all 7 participants) in the RBV-free arm. Although benefit from RBV is not apparent from these preliminary results, it cannot be excluded before availability of SVR12 data. Post-treatment results are not yet available for the 24-week arms. Excluding nonvirologic failures, patients with HCV genotype 1a with Q80K mutations had slightly lower numeric response rates (fibrosis stage 0-2: SVR12=89% [n=27]; fibrosis stage 3 or 4: SVR4=91% [n=11]) than genotype 1a patients without Q80K and genotype 1b (fibrosis stage 2: SVR12 100%, n=47; fibrosis stage 3 or 4: SVR4=100% [n=29]). However, because the study was not powered to assess this comparison, insufficient evidence exists on the role of testing for the Q80K mutation at this time. These regimens were well tolerated, although adverse events (eg, anemia and hyperbilirubinemia) were seen more often in patients on RBV-containing regimens. (Jacobson, 2013b)
The safety and efficacy of simeprevir have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). The uncertain impact of cholestasis and the occasional association of SMV with elevated transaminases create potential for drug accumulation or impaired hepatic function during SMV use. Clinical trials with SMV have been limited to patients with compensated disease who have CTP class A, total bilirubin of 1.5 x ULN or lower, and transaminases 10 x ULN or lower. For these reasons, simeprevir use should be limited to patients with compensated liver disease. Use of simeprevir is not recommended in patients with moderate to severe hepatic impairment. The combination of PEG/RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C).

Alternative regimen for PEG/RBV (with or without an HCV protease inhibitor) nonresponder patients with HCV genotype 1 who are eligible to receive IFN.

Daily sofosbuvir (400 mg) for 12 weeks and weight-based RBV (1000 mg [75 kg]) plus weekly PEG for 12 to 24 weeks is an alternative for retreatment of IFN-eligible persons with HCV genotype 1 infection, regardless of subtype.

Rating: Class IIb, Level C

NEUTRINO is an open-label, single-arm trial that evaluated 12 weeks of sofosbuvir plus PEG/RBV in treatment-naive subjects with HCV genotypes 1, 4, 5, or 6; 89% had HCV genotype 1, and 17% had cirrhosis. The SVR was 89% (261 of 292) and was somewhat lower in patients with genotype 1b than 1a (82% and 92%, respectively) and those with cirrhosis versus those without (80% versus 92%, respectively). (Lawitz, 2013a) Although treatment-experienced subjects were not included in this study, FDA estimates that the response rate in such patients would approximate the observed response rate in those NEUTRINO subjects with baseline factors traditionally associated with a lower response to IFN-based treatment. (US FDA, 2013a) In the NEUTRINO trial, SVR rate was 71% among participants with HCV genotype 1 with IL28B non-C/C alleles, high HCV RNA levels, and METAVIR 1 fibrosis stage F3 or F4 (37 of 52 patients). (Gilead Sciences, 2013; Solvadi package insert)

Alternative regimen for PEG/RBV (without an HCV protease inhibitor) nonresponder patients with HCV genotype 1 who are eligible to receive IFN.

Daily simeprevir (150 mg) for 12 weeks plus weight-based RBV (1000 mg [75 kg]) and weekly PEG for 48 weeks is an alternative for IFN-eligible persons with HCV genotype 1 infection. (All patients with cirrhosis who are receiving simeprevir should have well compensated liver disease.)

Rating: Class IIa, Level A

Simeprevir was combined with PEG/RBV in patients who had previously failed to respond to PEG/RBV dual therapy in the Phase 2b ASPIRE trial. (Zeuzem, 2013a); (Janssen Therapeutics, 2013) (www.fda.gov; package insert). SVR24 after 48 weeks of triple therapy in the simeprevir 150 mg/day arm was 65% in patients with a previous partial response (n=23) and 53% in patients with a prior null response (n=17). Patients with HCV genotype 1a infection had inferior response rates compared with those with genotype 1b (SVR24: 47% vs 77% in patients with a partial response and 41% vs 47% in patients with a null response, respectively). Despite lower SVR in patients with HCV genotype 1a infection, SVR rates were similar with and without the presence of the Q80K mutations at baseline. SVR rates in patients with advanced fibrosis (METAVIR stage F3 or F4) treated with simeprevir (150 mg daily) plus PEG/RBV for 48 weeks were 59% in patients with a partial response (n=33) and 35% in patients with a null response (n=34). Safety in patients exposed to simeprevir was similar to that of persons in the placebo arms; however, there was a higher incidence of hyperbilirubinemia (8%) and photosensitivity/rash (5%). (Zeuzem, 2013a)

The safety and efficacy of simeprevir have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). The uncertain impact of cholestasis and the occasional association of simeprevir with elevated transaminases pose potential for impaired hepatic function during simeprevir use. Clinical trials with simeprevir have been limited to patients with compensated disease who have CTP class A, total bilirubin level of 1.5 x ULN or lower, and transaminase level of 10 x ULN or lower. For these reasons, simeprevir use should be limited to patients with compensated liver disease. Use of simeprevir is not recommended in patients with moderate to severe hepatic impairment. Use of the drug in this population is not recommended at this time. The combination of PEG/RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C).

The following regimens are NOT recommended for PEG/RBV (with or without an HCV protease inhibitor) nonresponder patients with HCV genotype 1:

PEG/RBV with or without telaprevir or boceprevir
Rating: Class IIb, Level A

Monotherapy with PEG, RBV, or a DAA
Rating: Class III, Level A

For nonresponder patients with genotype 1 and a history of decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C), treatment is not indicated because of the risks of PEG and boceprevir and telaprevir in this population.

Triple therapy with boceprevir plus PEG/RBV for 48 weeks may result in SVR for up to 52% of PEG/RBV partial responders (RESPOND 2; (Bacon, 2011)) and 38% of null responders (PROVIDE; (Di Bisceglie, 2013)). Similarly, telaprevir plus PEG/RBV resulted in SVR24 of 54% to 59% among partial responders and an SVR24 of 29% to 33% among null responders (REALIZE;  (Zeuzem, 2011)). Due to the relatively poor efficacy, prolonged duration of therapy (48 weeks), and poor tolerability, these regimens are no longer recommended.

Monotherapy with PEG, RBV, or any of the available DAAs is ineffective; further, DAA monotherapy leads to rapid selection of resistant variants.

Patients with advanced liver disease are at increased risk for sepsis, worsening decompensation, and death when treated with dual or triple IFN-based therapy. (Crippin, 2002); (Coilly, 2014) Simeprevir is primarily metabolized by the liver and should not be used in patients with advanced cirrhosis (CTP B or C), as the AUC is increased 2.4- to 5.2-fold. (Janssen Therapeutics, 2013) (Olysio package insert, Janssen).

http://hcvguidelines.org/full-report/retreatment-persons-whom-prior-therapy-has-failed


++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Retreatment Box. Recommendations for Patients in Whom Previous PEG/RBV Treatment Has Failed

Genotype Recommended Alternative NOT Recommended

Patients in whom previous PEG/RBV has failed*

1 SOF + SMV ± RBV x 12 weeks SOF x 12 weeks + PEG/RBV 12 weeks
SMV x 12 weeks + PEG/RBV x 24 weeks** PEG/RBV ± telaprevir or boceprevir Monotherapy with PEG, RBV, or a DAA
Do not treat decompensated cirrhosis with PEG or SMV

2 SOF + RBV x 12 weeks SOF + PEG/RBV x 12 weeks PEG/RBV ± telaprevir or boceprevir
Monotherapy with PEG, RBV, or a direct-acting antiviral agent
Do not treat decompensated cirrhosis with PEG

3 SOF + RBV x 24 weeks SOF + PEG/RBV x 12 weeks PEG/RBV ± any current protease inhibitor
Monotherapy with PEG, RBV, or a DAA
Do not treat decompensated cirrhosis with PEG

4 SOF x 12 weeks + PEG/RBV 12 weeks
SOF + RBV x 24 weeks SMV x 12 weeks + PEG/RBV x 24-48 weeks PEG/RBV ± any current HCV protease inhibitor
Monotherapy with PEG, RBV, or a DAA
Do not treat decompensated cirrhosis with PEG

5 or 6 SOF x 12 weeks + PEG/RBV 12 weeks SOF + RBV x 24 weeks PEG/RBV ± any current HCV protease inhibitor
Monotherapy with PEG, RBV, or a DAA
Do not treat decompensated cirrhosis with PEG

Patients in whom previous treatment with PEG/RBV plus either telaprevir or boceprevir*** has failed †† †††
1a SOF x 12 weeks + PEG/RBV x 24 weeks SOF + RBV x 24 weeks PEG/RBV ± telaprevir or boceprevir or SMV
Monotherapy with PEG, RBV, or a DAA
Do not treat decompensated cirrhosis with PEG or SMV

1b SOF x 12 weeks + PEG/RBV x 12-24 weeks SOF + RBV x 24 weeks
*Non-responder is defined as partial or null response to treatment with PEG/RBV. Relapse to prior therapy should be treated the same as treatment-naive

**For genotype 1a, baseline resistance testing for Q80K should be performed and alternative treatments considered if this mutation is present

*** Non-responder is defined as partial or null response to treatment with PEG/RBV plus telaprevir or boceprevir. Relapse to prior therapy should be treated the same as treatment naive
† Consideration should be given to postponing treatment, pending release of new drugs for patients with limited (F 0-2) hepatic fibrosis

†† A recommendation for simeprevir use for patients with previous telaprevir or boceprevir exposure not provided due to potential risk of preexistant resistance to protease inhibitor treatment.

††† Given the lack of prior approval PI therapy for genotypes 2, 3, 4, 5, 6 and the lack of sufficient data, no recommendations are given for these genotype at this time

http://hcvguidelines.org/full-report/retreatment-box-recommendations-patients-whom-previous-pegrbv-treatment-has-failed


Appointment with Hepatologist on 12/5/13

Dec 26, 2013 - 13 comments

My husband saw his hepatologist for a routine follow up (labs, imaging, check up) earlier this month on 12/5/13.  His Ultrasound results were stable (no change, normal size, benign cyst unchanged, no sign of ascites, no sign of liver cancer).  Kidney function is good.  White count is good.  INR=1, Alb=3.6, Bili is good.  She gave him a MELD score of 6, which is about where it's been for the past five years.  Since he has Hep C and Cirrhosis, and has previously treated and failed 3 times (2007=Interferon and Ribavirin; 2010=Consensus Interferon and 1400 mg Ribavirin; 2012=Triple Tx with Incivek), the newly approved treatment meds are not for him.  She discussed the possibility of treating him with sofosbuvir, ribavirin, and interferon "off label", but with his recent diagnosis of serous retinopathy, there could be risk to treat with interferon again.  She also discussed the possibility of combining simeprevir and sofosbuvir, which would again be an "off label" treatment and would require special consideration for prior treatment failures with higher risk factors.  She seemed to feel that the best option might be to wait for sofosbuvir and ledipasvir combined with ribavirin, which she hopes will be approved about December, 2014.  In the meantime, his liver is still well compensated.  she will see him again in June, 2014, for another ultrasound, lab work, and ultrasound.  He is still on the UW's study radar to be called if any appropriate clinical studies come up in our area.  In the meantime, she is in communication with his retina specialist to see if he would advise or advise against another interferon based treatment (e.g. sofosbuvir, ribavirin, and interferon "off label") given his retinopathy.  If he advises against, then I think she plans to request special permission to consider treating with simeprevir and sofosbuvir "off label", but if she doesn't feel that will benefit him, if I'm understanding correctly, she will wait until sofosbuvir combined with ledipasvir is approved end of 2014.
Advocate1955