Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study.

BACKGROUND: Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir. METHODS: We enrolled patients with chronic HCV genotype 1 infections who had previously not responded to pegylated interferon (peginterferon) and ribavirin or were treatment naive. Patients were randomly assigned in a 2:1:2:1 ratio to receive 150 mg simeprevir and 400 mg sofosbuvir daily for 24 weeks with (group 1) or without (group 2) ribavirin or for 12 weeks with (group 3) or without (group 4) ribavirin, in two cohorts: previous non-responders with METAVIR scores F0-F2 (cohort 1) and previous non-responders and treatment-naive patients with METAVIR scores F3-F4 (cohort 2). The primary endpoint was sustained virological response 12 weeks after stopping treatment (SVR12). Analysis was done by intention to treat. Safety data from cohorts 1 and 2 were pooled for analysis. This study is registered with ClinicalTrials.gov, number NCT01466790. FINDINGS: 168 patients were enrolled and randomised, and 167 started treatment (n=80 in cohort 1 and n=87 in cohort 2). SVR12 was achieved in 154 (92%) patients (n=72 [90%, 95% CI 81-96] in cohort 1 and n=82 [94%, 87-98] in cohort 2). The most common adverse events in the pooled groups were fatigue (n=52 [31%]), headache (n=33 [20%]), and nausea (n=26 [16%]). Grade 4 adverse events were seen in one (2%) of 54 patients in each of groups 1 and 3 and in three (10%) of 31 patients in group 2, whereas grade 3-4 events were reported in less than 5% of all patients, except increased blood amylase concentration. Serious adverse events were seen in four (2%) patients, all in groups 1 and 2. Four (2%) patients discontinued all study treatment because of adverse events, three before week 12. INTERPRETATION: Combined simeprevir and sofosbuvir was efficacious and well tolerated. FUNDING: Janssen.

Patient-reported outcomes in chronic hepatitis C patients with cirrhosis treated with sofosbuvir-containing regimens.

UNLABELLED: Whether the presence of cirrhosis influences patient-reported outcomes (PROs), including health-related quality of life, during treatment with newly available anti-HCV (hepatitis C virus) regimens is unclear. Our aim was to assess the association of cirrhosis with PROs in patients treated with sofosbuvir (SOF)-containing regimens. Four PRO questionnaires (Short Form-36 [SF-36], Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F], Chronic Liver Disease Questionnaire-HCV (CLDQ-HCV), and the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem [WPAI-SHP]) were administered to subjects receiving SOF and ribavirin (RBV; FUSION trial, N=201, 34% cirrhosis; VALENCE trial: N=333, 21% cirrhosis) and SOF, RBV, and pegylated interferon (Peg-IFN; NEUTRINO trial: N=327, 17% cirrhosis). HCV patients with cirrhosis showed significant impairment of PROs before initiation of treatment. During treatment, patients with cirrhosis treated with the IFN-free regimen experienced moderate decline in their PRO scores (0.6%-5.2% on a normalized scale of the summary scores; all P>0.02). In contrast, patients with cirrhosis treated with IFN-containing regimen showed decline in PRO scores that ranged from 3.4% to 16.0% (all P<0.005). Nevertheless, by follow-up week 12, no PRO decrement from baseline was observed in patients with cirrhosis regardless of the treatment regimen. Furthermore, in patients with cirrhosis with HCV who achieved sustained virological response at 12 weeks (SVR-12), some improvement in PROs from baseline was observed. During treatment, changes in PRO scores were similar between patients with and without cirrhosis for both treatment regimens (all P>0.05). Independent predictors of lower PROs in patients with cirrhosis included baseline depression, anxiety, fatigue, high HCV viral load, female gender, and receiving IFN-containing treatment. CONCLUSIONS: Treatment with SOF+RBV with or without Peg-IFN is tolerated by HCV patients with and without cirrhosis in terms of their PRO scores. After achieving SVR-12 with the IFN-free regimen, patients with cirrhosis showed improvement in some aspects of their PROs.

Impact of interferon free regimens on clinical and cost outcomes for chronic hepatitis C genotype 1 patients.

BACKGROUND & AIMS: Hepatitis C (HCV) is a common cause of chronic liver disease worldwide. Current standard treatment for genotype-1 patients uses a triple combination of pegylated-interferon alpha (IFN), ribavirin (RBV) and a direct-acting antiviral agent (DAA) with 75-80% sustained virologic response (SVR) rates. The aim is to determine cost-effectiveness of staging-guided vs. treat all HCV genotype-1 patients with interferon-based vs. interferon-free regimens. METHODS: A decision analytic Markov model simulating patients until death compared four strategies for treating HCV genotype-1: Triple therapy (IFN, RBV, DAA) with staging-guidance or treat all, and oral IFN-free regimen with staging-guidance or treat all. Strategies with staging initiated treatment at fibrosis stages F2-F4, with staging repeated every 5 years until age 70. The reference case was a treatment-naïve 50-year-old. Analysis was repeated for 50% increase in cost of oral therapy. Effectiveness was measured in quality-adjusted life years (QALYs). RESULTS: Treatment of all patients with oral IFN-free regimen was the most cost-effective strategy, with an ICER of $15,709/QALY at baseline cost of oral therapy. The ICER remained below $50,000/QALY in sensitivity analyses for baseline and +50% cost of oral therapy scenarios. The treat all strategy was also the most effective strategy; associated with the lowest risk of developing advanced liver disease. CONCLUSIONS: Treating all HCV patients with oral IFN-free regimen reduced the number of patients developing advanced liver disease and increased life expectancy. Additionally, IFN-free regimen without staging may be the most cost-effective approach for treating HCV genotype-1 patients. The efficacy and safety of these regimens must be confirmed using randomized clinical trials.

Minimal impact of sofosbuvir and ribavirin on health related quality of life in chronic hepatitis C (CH-C).

BACKGROUND & AIMS: Treatment for CH-C contains interferon with substantial associated side effects and health-related quality of life (HRQL) impairment. Currently, there is no published data assessing the impact of interferon-free regimens on HRQL. The aim is to report the HRQL of patients who participated in clinical trials of sofosbuvir (SOF) for CH-C. METHODS: CH-C patients were treated with sofosbuvir (SOF), pegylated interferon (PegIFN), ribavirin (RBV), or placebo in different combinations and duration (POSITRON, FISSION, FUSION, and NEUTRINO phase III trials). HRQL was assessed using SF-36 at baseline, during treatment, at the end of treatment, and at follow-up, and compared between treatment arms. RESULTS: HRQL scores decreased over the course of treatment for all treatment arms in all studies; however, patients returned to their baseline score by the end of follow-up. Compared to placebo, SOF and RBV was not associated with HRQL impairment (POSITRON). Compared to SOF and RBV, HRQL was significantly more impaired in the PegIFN and RBV arm (FISSION). For those treated with SOF and RBV, there was no difference in HRQL between 12 weeks or 16 weeks of treatment (FUSION). Multivariate analysis demonstrated that depression, fatigue, and insomnia were important predictors of patients' HRQL prior, during or after treatment. Additionally, anemia and receiving interferon were predictors of HRQL impairment during treatment. Achieving sustained virologic response after 12 weeks of follow-up (SVR-12) with SOF and RBV was associated with improvement in HRQL scores from baseline. CONCLUSIONS: Treatment-related HRQL impairment during SOF and RBV regimen is mild, and does not increase with longer treatment duration. Achieving SVR-12 with SOF and RBV is associated with an improvement in HRQL.

The impact of IL28B genotype on the gene expression profile of patients with chronic hepatitis C treated with pegylated interferon alpha and ribavirin.

BACKGROUND: Recent studies of CH-C patients have demonstrated a strong association between IL28B CC genotype and sustained virologic response (SVR) after PEG-IFN/RBV treatment. We aimed to assess whether IL28B alleles rs12979860 genotype influences gene expression in response to PEG-IFN/RBV in CH-C patients. METHODS: Clinical data and gene expression data were available for 56 patients treated with PEG-IFN/RBV. Whole blood was used to determine IL28B genotypes. Differential expression of 153 human genes was assessed for each treatment time point (Days: 0, 1, 7, 28, 56) and was correlated with IL28B genotype (IL28B C/C or non-C/C) over the course of the PEG-IFN/RBV treatment. Genes with statistically significant changes in their expression at each time point were used as an input for pathway analysis using KEGG Pathway Painter (KPP). Pathways were ranked based on number of gene involved separately per each study cohort. RESULTS: The most striking difference between the response patterns of patients with IL28B C/C and T* genotypes during treatment, across all pathways, is a sustained pattern of treatment-induced gene expression in patients carrying IL28B C/C. In the case of IL28B T* genotype, pre-activation of genes, the lack of sustained pattern of gene expression or a combination of both were observed. This observation could potentially provide an explanation for the lower rate of SVR observed in these patients. Additionally, when the lists of IL28B genotype-specific genes which were differentially expressed in patients without SVR were compared at their baseline, IRF2 and SOCS1 genes were down-regulated regardless of patients' IL28B genotype. Furthermore, our data suggest that CH-C patients who do not have the SOCS1 gene silenced have a better chance of achieving SVR. Our observations suggest that the action of SOCS1 is independent of IL28B genotype. CONCLUSIONS: IL28B CC genotype patients with CH-C show a sustained treatment-induced gene expression profile which is not seen in non-CC genotype patients. Silencing of SOCS1 is a negative and independent predictor of SVR. These data may provide some mechanistic explanation for higher rate of SVR in IL28B CC patients who are treated with PEG-IFN/RBV.

Insurance status and treatment candidacy of hepatitis C patients: analysis of population-based data from the United States.

UNLABELLED: Successful treatment with antiviral therapy could potentially reduce morbidity and mortality in patients with hepatitis C virus (HCV) infection. However, at the population level, these benefits may be offset by a limited number of patients who have access to antiviral treatment. Using data from the National Health and Nutrition Examination Survey conducted in 2005-2008, we analyzed the health insurance status and treatment candidacy of HCV-positive (HCV+) individuals. A total of 10,582 subjects were examined; of those, 1.16% had detectable HCV RNA and were defined as HCV+. The HCV+ patients were less likely to be insured than HCV-negative individuals (61.2% versus 81.2%; P = 0.004). Among those with health insurance, HCV+ patients were less likely to have private insurance, whereas the coverage by Medicare/Medicaid and other government-sponsored plans was similar to the rest of the population. In multivariate analysis, HCV infection was an independent predictor of being uninsured even after adjustment for demographic disparity of the HCV+ cohort (odds ratio, 0.43; 95% confidence interval, 0.24-0.78). Of all HCV+ patients, 66.7% were eligible for anti-HCV treatment. However, only 54.3% of HCV+ treatment candidates had any type of insurance coverage. Finally, only 36.3% of HCV+ patients were potentially eligible for treatment and had health insurance. CONCLUSION: A high proportion of HCV+ patients are currently uninsured, and many have publicly funded health insurance. Among those who could be candidates for treatment, the rate of insurance coverage is even lower. These findings can have important implications for health insurance coverage of these patients under the new health care reform legislation in the United States.

Protein pathway activation associated with sustained virologic response in patients with chronic hepatitis C treated with pegylated interferon (PEG-IFN) and ribavirin (RBV).

Only half of chronic hepatitis C (CH-C) patients treated with pegylated interferon and ribavirin (PEG-IFN+RBV) achieve sustained virologic response) SVR. In addition to known factors, we postulated that activation of key protein signaling networks in the peripheral blood mononuclear cells (PBMCs) may contribute to SVR due to inherent patient-specific basal immune cell signaling architecture. In this study, we included 92 patients with CH-C. PBMCs were collected while patients were not receiving treatment and used for phosphoprotein-based network profiling. Patients received a full course of PEG-IFN+RBV with overall SVR of 55%. From PBMC, protein lysates were extracted and then used for Reverse Phase Protein Microarray (RPMA) analysis, which quantitatively measured the levels of cytokines and activation levels of 25 key protein signaling molecules involved in immune cell regulation and interferon alpha signaling. Regression models for predicting SVR were generated by stepwise bidirectional selection. Both clinical-laboratory and RPMA parameters were used as predictor variables. Model accuracies were estimated using 10-fold cross-validation. Our results show that by comparing patients who achieved SVR to those who did not, phosphorylation levels of 6 proteins [AKT(T308), JAK1(Y1022/1023), p70 S6 Kinase (S371), PKC zeta/lambda(T410/403), TYK2(Y1054/1055), ZAP-70(Y319)/Syk(Y352)] and overall levels of 6 unmodified proteins [IL2, IL10, IL4, IL5, TNF-alpha, CD5L] were significantly different (P < 0.05). For SVR, the model based on a combination of clinical and proteome parameters was developed, with an AUC = 0.914, sensitivity of 92.16%, and specificity of 85.0%. This model included the following parameters: viral genotype, previous treatment status, BMI, phosphorylated states of STAT2, AKT, LCK, and TYK2 kinases as well as steady state levels of IL4, IL5, and TNF-alpha. In conclusion, SVR could be predicted by a combination of clinical, cytokine, and protein signaling activation profiles. Signaling events elucidated in the study may shed some light into molecular mechanisms of response to anti-HCV treatment.

Early gene expression profiles of patients with chronic hepatitis C treated with pegylated interferon-alfa and ribavirin.

UNLABELLED: Responsiveness to hepatitis C virus (HCV) therapy depends on viral and host factors. Our aim was to assess sustained virologic response (SVR)-associated early gene expression in patients with HCV receiving pegylated interferon-alpha2a (PEG-IFN-alpha2a) or PEG-IFN-alpha2b and ribavirin with the duration based on genotypes. Blood samples were collected into PAXgene tubes prior to treatment as well as 1, 7, 28, and 56 days after treatment. From the peripheral blood cells, total RNA was extracted, quantified, and used for one-step reverse transcription polymerase chain reaction to profile 154 messenger RNAs. Expression levels of messenger RNAs were normalized with six "housekeeping" genes and a reference RNA. Multiple regression and stepwise selection were performed to assess differences in gene expression at different time points, and predictive performance was evaluated for each model. A total of 68 patients were enrolled in the study and treated with combination therapy. The results of gene expression showed that SVR could be predicted by the gene expression of signal transducer and activator of transcription-6 (STAT-6) and suppressor of cytokine signaling-1 in the pretreatment samples. After 24 hours, SVR was predicted by the expression of interferon-dependent genes, and this dependence continued to be prominent throughout the treatment. CONCLUSION: Early gene expression during anti-HCV therapy may elucidate important molecular pathways that may be influencing the probability of achieving virologic response.

Managing the hematologic side effects of antiviral therapy for chronic hepatitis C: anemia, neutropenia, and thrombocytopenia.

Hematologic abnormalities such as anemia, neutropenia, and thrombocytopenia are common during combination therapy with pegylated (or standard) interferon and ribavirin for chronic hepatitis C. Ribavirin-induced hemolytic anemia is a common cause of dose reduction or discontinuation. Bone marrow suppression also contributes to the anemia and is the predominant mechanism for interferon-induced neutropenia and thrombocytopenia. Although dose reduction or discontinuation of combination therapy can reverse these abnormalities, they may reduce virologic response. Hematopoietic growth factors may provide a useful alternative for managing these hematologic side effects without reducing the optimal dose of the combination antiviral regimen. Treatment of anemia also may improve patients' health-related quality of life and their adherence to combination antiviral therapy. The impact of growth factors on sustained virologic response and their cost-effectiveness in patients with chronic hepatitis C need further assessment.

Anger experiences among hepatitis C patients: relationship to depressive symptoms and health-related quality of life.

The authors examined anger among hepatitis C (HCV) patients and its relationship to health-related quality of life (HRQL) and depression. Eighty-seven HCV patients who received pegylated interferon-alpha(2b) and ribavirin were included. Patients' mean age was 48 years; 42% were women, and 60% were white. Patients experienced moderate anger while undergoing HCV treatment. Angry feelings increased during treatment in some domains, specifically, Control Over Anger and Angry Reaction. Greater anger was associated with more depression and poorer HRQL. Findings point to the importance for physicians to screen for a wide range of neuropsychiatric side effects of interferon, including anger.

Depression, anemia and health-related quality of life in chronic hepatitis C.

BACKGROUND/AIMS: Hepatitis C (HCV) infected patients have significant health-related quality of life (HRQL) impairment which worsens during anti-viral therapy. Our aim was to examine the association of HRQL with treatment-induced depression and anemia. METHODS: Two hundred and seventy-one HCV patients who received pegylated interferon alfa 2b and ribavirin were included. Data on HRQL, depressive symptoms, laboratory values and socio-demographic characteristics were collected. RESULTS: Mean age was 47.1+/-6.5, 69% were male, and 73% were White. HCV patients' HRQL declined during anti-viral therapy but returned to or exceeded baseline levels within 24 weeks of completion. Anemia and depression were both associated with HRQL impairment. The effects of depression on HRQL were strong; once depression scores were included other factors were no longer significant. Patients' depressive symptoms tended to increase during the initial half of treatment regimen. Those with higher body mass index (BMI), cirrhosis, and women reported more HRQL impairments. HRQL scales were generally not associated with alcohol abuse, age, race, ALT and HCV RNA levels. CONCLUSIONS: Anti-viral therapy for HCV is associated with diminished HRQL. Although anemia and depression were associated with this impairment, depression was the most consistent predictor. Future studies are needed to see whether proactive management of these side effects can improve patients' HRQL and the efficacy of antiviral therapy for hepatitis C.

The use of growth factors to manage the hematologic side effects of PEG-interferon alfa and ribavirin.

Hematologic side effects (anemia, neutropenia, and thrombocytopenia) of combination therapy with pegylated (PEG)-interferon alfa and ribavirin are commonly encountered during antiviral therapy for chronic hepatitis C (HCV). An important consequence of these side effects is dose modification of PEG-interferon alfa, ribavirin, or both. Dose modification (including discontinuation) diminishes the efficacy of optimal treatment regimen for HCV and may have a negative impact on sustained virologic response. Additionally, fatigue associated with anemia may impair patients' quality of life. The clinical implications of neutropenia or thrombocytopenia are less clear than for anemia; nevertheless, severe infection and bleeding are uncommon. Dose adjustments effectively treat these hematologic side effects, but the resulting suboptimal dosing and potential impact on virologic response are major concerns. Recent attempts to maximize adherence to the optimal treatment regimen have used hematopoietic growth factors rather than dose adjustment to treat side effects. Research on growth factor support has focused on anemia and neutropenia. Epoetin alfa and darbepoetin alfa are erythropoietic growth factors that effectively increase hemoglobin while maintaining the optimal ribavirin dose and improving patients' quality of life. Preliminary work suggests that filgrastim, granulocyte colony stimulating factors, may be an effective treatment of interferon-induced neutropenia. Although this early work shows tremendous promise for managing hematologic side effects of combination therapy for HCV, and potentially enhancing adherence, further research is needed to clarify the efficacy, safety, and cost-effectiveness of growth factors in the management of patients with chronic HCV.

Erythropoietic growth factors for treatment-induced anemia in hepatitis C: a cost-effectiveness analysis.

BACKGROUND & AIMS: Treatment-induced anemia undermines the efficacy of antiviral therapy in hepatitis C by mandating ribavirin dose reduction and diminishing adherence to therapy. Erythropoietic growth factors (EGFs) may correct treatment-induced anemia, facilitate maintenance of full-dose therapy, and improve rates of sustained virologic response (SVR). We sought to determine the cost effectiveness of adjunctive treatment with an EGF vs standard care in the treatment of hepatitis C. METHODS: We used a decision analysis to calculate the cost effectiveness of 2 treatment strategies for a patient cohort with chronic hepatitis C, increased transaminase levels, and no cirrhosis who were receiving pegylated-interferon and ribavirin (RBV): (1) RBV dose-reduction for anemia, followed by discontinuation of therapy if anemia persisted (standard care strategy), (2) adjunctive treatment with EGF therapy for anemia, with RBV dose reduction reserved for persistent anemia despite EGF therapy (EGF strategy). We conducted cost-effectiveness and cost-utility analyses to compare short- and long-term outcomes between the strategies. RESULTS: The percentage achieving SVR was 52.3% in the standard care strategy and 59.5% in the EGF strategy. Compared with standard care, the EGF strategy cost an incremental $36,568 per unadjusted life-year gained and $16,443 per quality-adjusted life-year gained. In a sensitivity analysis, if a third-party payer was willing to pay $50,000 per quality-adjusted life-year gained for the use of an EGF, then 86.1% of patients would be within the budget. CONCLUSIONS: Compared with standard care, adjunctive therapy with an EGF for the management of treatment-induced anemia may increase the probability of achieving SVR, increase unadjusted lifespan, and increase quality-adjusted lifespan at an acceptable cost.

Pegylated interferon alpha-2b, ribavirin and amantadine for chronic hepatitis C.

In an attempt to improve the efficacy of antiviral therapy for chronic hepatitis C, a three-drug combination of pegylated interferon alpha-2b, ribavirin, and amantadine has been suggested. Despite the initial enthusiasm, the role of amantadine in the treatment of chronic hepatitis C remains controversial. In a multi-center, open-label clinical trial, the potential efficacy and safety of this triple combination regimen were assessed. In this open-label pilot study, two separate patient populations with chronic hepatitis C and viremia were enrolled: treatment-naive and those who had failed a previous course of treatment. Patients were started on pegylated interferon alpha-2b at a dose of 1.5 microg/kg weekly with ribavirin, 1000-1200 mg/day, and amantadine, 200 mg/day, for 4 weeks, followed by pegylated interferon alpha-2b, 0.5 microg/kg weekly, ribavirin, 1000-1200 mg/day, and amantadine, 200 mg/day, for another 20 weeks. Patients with undetectable HCV RNA at week 24 continued this regimen for a total of 48 weeks and were followed for another 24 weeks. Patients with undetectable virus (<50 IU/mL) after 24 weeks of follow-up were considered to have SVR. Health-related quality of life and safety data were also collected. Sixty-nine treatment-naive and 99 nonresponder patients with chronic hepatitis C were enrolled in the study. Of all patients enrolled, 74% were male, aged 47.27+/-5.76 years; their body mass index (BMI) was 28.87+/-5.05 kg/m2, 79.4% were white, 85% had HCV genotypes 1 and 4, and 36% had cirrhosis. Their baseline HCV RNA was 689,242+/-698,030 IU/mL, with a baseline ALT of 107.25+/-79.08. Of the entire cohort, 35 (21%) discontinued early due to side effects or loss to follow-up. Significant anemia (hemoglobin, < 10 g/dL) occurred in 11% (19/168), while severe anemia (hemoglobin, <8.5 g/dL) occurred in 0.6% (1/168). In the treatment-naive group, sustained virologic response (SVR) was 34.3%, versus 19.4% for the group who had previously failed to respond to a course of treatment (P = 0.01). For both groups combined, virologic response after 24 weeks of therapy was 40.5%, with an end-of-treatment virologic response of 35.7% and a SVR of 26.2%. Patients with genotypes 1 and 4 had lower response rates than those with genotypes 2 and 3 (SVR, 21 vs. 46%; P = 0.001). Patients with advanced fibrosis (Metavir stages 3 and 4) tended to have lower response rates than those with minimal or mild fibrosis (Metavir stages 0-2) (SVR, 10 vs. 30%; P = 0.08). African-American patients with HCV had lower response rates than Caucasians or other ethnic groups (SVR, 4 vs. 29 vs. 20%; P = 0.04). Age, gender, and BMI did not affect SVR. The addition of amantadine to pegylated interferon alpha-2b and ribavirin does not seem to increase the efficicacy of this regimen.