Direct costs of first‐generation protease inhibitors for the treatment of genotype 1 chronic hepatitis C viral infection

To evaluate the cost‐effectiveness of Hepatitis C therapy, robust real‐world data are needed to understand the costs and benefits of treatment alternatives. The objective of this study was to evaluate the true direct cost of treatment in an unselected sequential population of patients treated at a tertiary care centre for hepatitis C virus genotype 1. A total of 200 consecutive patients were treated with interferon, ribavirin and a first‐generation direct‐acting antiviral agent (DAA) between 2011 and 2013. A total of 41% had cirrhosis, 31% were prior relapsers, and 41% were prior partial or null responders. Costs used were wholesale acquisition cost prices for medications, average hospital costs per day for each diagnosis code based on US inpatient hospital charges. All costs were adjusted to 2013 dollars. Sustained virologic response (SVR) was achieved in 97 patients (48.5%). A total of 14% experienced relapse, 19% breakthrough or nonresponse, and 18.5% discontinued secondary to side effects. Twenty per cent of patients had at least one hospitalization attributable to a complication of therapy. Thirty‐seven per cent of patients required erythropoietin‐stimulating agents, 16% received filgastrim, and 15% needed a red blood cell transfusion. The mean overall cost of treatment was $83 851 per patient. The cost per SVR was $172 889; $266 670 for patients with cirrhosis. The costs per SVR after treatment with first‐generation DAAs are dependent on the stage of disease and therapy side effects. These real‐world costs significantly exceed those described in prior cost‐effectiveness assessments and should be used instead for future studies.     

Hepatitis C: viral and host factors associated with non‐response to pegylated interferon plus ribavirin

Treatment for chronic hepatitis C virus (HCV) infection has evolved considerably in the last years. The standard of care (SOC) for HCV infection consists in the combination of pegylated interferon (PEG‐IFN) plus ribavirin. However, it only induces a sustained virological response (SVR) in half of genotype 1‐infected patients. Several viral and host factors have been associated with non‐response: steatosis, obesity, insulin resistance, age, male sex, ethnicity and genotypes. Many studies have demonstrated that in non‐responders, some interferon‐stimulated genes were upregulated before treatment. Those findings associated to clinical, biochemical and histological data may help detect responders before starting any treatment. This is a very important issue because the standard treatment is physically and economically demanding. The future of HCV treatment would probably consist in the addition of specifically targeted antiviral therapy for HCV such as protease and/or polymerase inhibitors to the SOC. In genotype 1 patients, very promising results have been reported when the protease inhibitor telaprevir or boceprevir is added to the SOC. It increases the SVR rates from approximately 50% (PEG‐IFN plus ribavirin) to 70% (for patients treated with a combination of PEG‐IFN plus ribavirin plus telaprevir). Different elements are associated with non‐response: (i) viral factors, (ii) host factors and (iii) molecular mechanisms induced by HCV proteins to inhibit the IFN signalling pathway. The goal of this review is to present the mechanisms of non‐response, to overcome it and to identify factors that can help to predict the response to anti‐HCV therapy.     

Accumulation of refractory factors for pegylated interferon plus ribavirin therapy in older female patients with chronic hepatitis C

Aim: Several host and viral factors have been reported to influence the effectiveness of pegylated interferon plus ribavirin combination therapy for chronic hepatitis C. In Japan, where the age of treated patients is comparatively high, recent studies have reported poor response to treatment in older female patients, but little is known about the relationship between advanced age in women and previously reported factors. Methods: Using a database of 1167 patients chronically infected with hepatitis C virus (HCV) genotype 1b, we analyzed the amino acid sequences of the HCV core protein and interferon sensitivity determining region (ISDR) and examined the relationships among predictive factors. Results: The proportion of patients with substitutions at core 70, which is associated with poor response to pegylated interferon plus ribavirin therapy, increased with age only in female patients. A similar trend was observed for ISDR wild type (wt). We also found that core 70 wt is associated with core 91 wt (P = 5.4 × 10^?9) as well as ISDR wt (P = 0.025). HCV RNA levels were higher in patients with core and ISDR wt (P < 0.001). Furthermore, core amino acid mutations were associated with advanced fibrosis and higher inflammatory activity (P = 0.028 and 0.048, respectively) as well as higher gamma‐glutamyltranspeptidase, alanine aminotransferase and low‐density lipoprotein cholesterol levels (P < 0.001, 0.006 and 0.001, respectively). Conclusion: A combination of factors account for poor response rate in older female patients in Japan. Elucidating the relationship between amino acid substitutions and metabolic alteration is an important step in understanding the mechanism of HCV interferon resistance.     

Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-alpha therapy.

BACKGROUND: The efficacy of consensus interferon (CIFN), a synthetic IFN with optimised in vitro activity, was assessed in chronic hepatitis C virus (HCV) patients who had failed the pretreatment with interferon-alpha (IFNalpha) and ribavirin. METHODS: One hundred and three patients after non-response (n=69) or relapse (n=34) to IFNalpha+/-ribavirin were randomly assigned to high-dose induction (CIFN 27-->9 microg daily for 24 weeks, 9 microg t.i.w. for 24 weeks) or low-dose treatment (CIFN 18 microg t.i.w. for 12 weeks, 9 microg t.i.w. for 36 weeks); each with ribavirin 800 mg/day. Follow-up was 24 weeks. RESULTS: Non-responder patients treated with high-dose induction had higher early virological response rates (63% vs. 39%, P<0.05). This initial positive effect was lost during the last 24 weeks of treatment yielding sustained virological response (SVR) rates of 26% in both groups. Relapse patients revealed SVR in 70% and 38% in groups A and B (NS). Treatment was well tolerated with side effect-related preterm discontinuations in 8% and 5%. CONCLUSIONS: CIFN and ribavirin treatment induced considerable SVR rates in patients with non-response or relapse to IFNalpha+/-ribavirin. Viral elimination rates might be further increased by continuous daily administration of CIFN and weight-adjusted ribavirin dosing.     

Serum chemokine levels are associated with the outcome of pegylated interferon and ribavirin therapy in patients with chronic hepatitis C

Aim: Serum chemokine levels and amino acid substitutions in the interferon‐sensitivity determining region (ISDR) and core region have been associated with treatment outcome of pegylated interferon and ribavirin therapy in genotype 1 hepatitis C virus (HCV)‐infected patients. The present study was conducted to clarify the association between serum chemokines and treatment outcome in patients with chronic HCV‐1 infection in a Japanese cohort. Methods: A total of six serum chemokines were quantified before, during and after pegylated interferon and ribavirin treatment in 79 genotype 1 chronic HCV patients using a multiple bead array system. Viral ISDR and core region variants were determined by direct sequencing. Results: The baseline serum levels of eotaxin, IP‐10 and RANTES were significantly higher in chronic HCV patients than in controls. High levels of eotaxin and macrophage inflammatory protein (MIP)‐1β before therapy and more than two mutations in the ISDR were associated with a sustained virological response, and patients with more than two mutations in the ISDR also had significantly higher MIP‐1β levels. Receiver–operator curve analysis showed a 77% sensitivity and 73% specificity for predicting an SVR using MIP‐1β values. Conclusion: Serum MIP‐1β levels may predict the response to HCV treatment with pegylated interferon and ribavirin and are associated with amino acid substitutions in the ISDR.     

Disparity of basal and therapeutically activated interferon signalling in constraining hepatitis E virus infection

Hepatitis E virus (HEV) represents one of the foremost causes of acute hepatitis globally. Although there is no proven medication for hepatitis E, pegylated interferon‐α (IFN‐α) has been used as off‐label drug for treating HEV. However, the efficacy and molecular mechanisms of how IFN signalling interacts with HEV remain undefined. As IFN‐α has been approved for treating chronic hepatitis C (HCV) for decades and the role of interferon signalling has been well studied in HCV infection, this study aimed to comprehensively investigate virus–host interactions in HEV infection with focusing on the IFN signalling, in comparison with HCV infection. A comprehensive screen of human cytokines and chemokines revealed that IFN‐α was the sole humoral factor inhibiting HEV replication. IFN‐α treatment exerted a rapid and potent antiviral activity against HCV, whereas it had moderate and delayed anti‐HEV effects in vitro and in patients. Surprisingly, blocking the basal IFN pathway by inhibiting JAK1 to phosphorylate STAT1 has resulted in drastic facilitation of HEV, but not HCV infection. Gene silencing of the key components of JAK‐STAT cascade of the IFN signalling, including JAK1, STAT1 and interferon regulatory factor 9 (IRF9), stimulated HEV infection. In conclusion, compared to HCV, HEV is less sensitive to IFN treatment. In contrast, the basal IFN cascade could effectively restrict HEV infection. This bears significant implications in management of HEV patients and future therapeutic development.     

Ribavirin rather than PEG-interferon pharmacodynamics predict nonresponse to antiviral therapy in naive chronic hepatitis C patients

Twenty to fifty per cent of patients with chronic hepatitis C (CHC) experience nonresponse to current antiviral therapy, which may relate in part to ribavirin or PEG-interferon pharmacodynamics. We evaluated potential relevance of various factors for nonresponse. Two hundred forty-two naive CHC patients who received in a previous trial at least 24 weeks of antiviral therapy, including PEG-interferon alfa-2b and ribavirin, were analysed. Of them, 53% were infected with hepatitis C virus (HCV) genotype 1-4, 71% exhibited high viral load and 32% had severe fibrosis/cirrhosis. After 24 weeks of treatment, 39 patients (16%) were nonresponders. In multivariate analysis, lower serum ribavirin concentrations, HCV genotype 1-4 and higher baseline γ-GT predicted nonresponse. Week-24 ribavirin concentrations (2.2 vs 2.8 mg/L, P < 0.001), average ribavirin doses (14.5 vs 15.2 mg/kg per day, P = 0.03) and week-24 haemoglobin decreases (1.7 vs 2.0 mm, P = 0.02) were lower in nonresponders. Nonresponse rates increased progressively at decreasing ribavirin concentrations: 4%, 11%, 13% and 36% in case of serum ribavirin concentrations ≥4, 3-4, 2-3 and ≤2 mg/L, respectively (P = 0.001). Ribavirin concentrations correlated with both week-24 haemoglobin decreases (r = 0.42, P < 0.001) and ribavirin doses (r = 0.17, P = 0.01). Subgroup analysis in HCV genotype 1-4 patients revealed essentially the same results. Nonresponse was exceptional in HCV genotype 2-3 patients and associated with ribavirin concentrations <2 mg/L. Presumed interferon-related factors (average PEG-interferon doses and decreases in leucocytes, granulocytes, platelets and body weight) did not differ between nonresponders and responders. In conclusion, ribavirin- rather than PEG-interferon-related factors are independent and potentially modifiable predictors of nonresponse in treatment-naive CHC patients.     

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

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

In vivo interferon system assessed by 2′‐5′ oligoadenylate synthetase activity in chronic hepatitis C virus patients treated with pegylated interferon and ribavirin

Aim: 2′,5′ oligoadenylate synthetase (2‐5AS), an enzyme induced by interferon, is an accurate indicator of the antiviral effect of interferon. We measured it during pegylated interferon based therapies in patients with chronic hepatitis C virus (HCV) in order to determine the dynamics of antiviral status in vivo and the relationship between the response to exogenous interferon and the outcome of therapy. Methods: A total of 160 patients with chronic HCV were treated with pegylated interferon alfa 2a or 2b or non‐pegylated interferon, with or without ribavirin. Serum 2‐5AS activity was measured by radioimmunoassay assay kits every 2 weeks. Results: In 60 patients treated with pegylated interferon alfa 2a or 2b, 2‐5AS levels increased to 7–40 times (average 235 pmol/dL) above the pretreatment levels (30 pmol/dL), which were significantly higher than the levels during non‐pegylated interferon therapy. Ribavirin did not enhance 2‐5AS levels. 2‐5AS levels between sustained virological response (SVR) and non‐SVR, including null responders to pegylated interferon plus ribavirin therapy were not significantly different. Conclusion: 2‐5AS levels were significantly higher in patients treated with pegylated interferon than in those treated with non‐pegylated interferon, suggesting that pegylated interferon is more potent at inducing interferon response genes resulting in an improved antiviral effect. Ribavirin did not appear to be related to interferon response gene induction.     

Long-term follow-up of sustained responders to interferon therapy, in patients with chronic hepatitis C

Interferon (IFN) therapy has been proven to induce the normalization of serum alanine aminotransferase (ALT) levels and to eradicate the hepatitis C virus (HCV) in some patients with chronic hepatitis C, and these patients are usually defined as 'sustained responders'. However, there have been some reports of hepatocellular carcinoma (HCC) in these patients, and the development of HCC remains life-threatening in patients who clear HCV. We analysed the long-term prognoses of patients with chronic hepatitis C in whom HCV was eradicated with IFN. We investigated 392 sustained responders to IFN therapy, from 1,277 patients with chronic HCV infection who received IFN treatment at one of our institutions between April 1989 and March 1999. We analysed the medical records and looked for the development of HCC. About 30% of the sustained responders had been lost to follow-up 3 years after the end of IFN therapy, and the follow-up rate of sustained responders was significantly lower than that of non-sustained responders (P < 0.0001). HCC were found in eight patients: in seven patients HCC developed within 5 years after completion of IFN therapy; but in one patient, a single HCC less than 3 cm in diameter was detected between 7 and 8 years after completion of IFN. Of the five patients who had regular medical follow-up, the HCC was solitary, and the patients survived without any evidence of recurrence. Of the three patients who had not been followed-up, two died from HCC and HCC recurred in the third. These results suggest that HCC can develop in sustained responders and that sustained responders should be followed-up closely after completion of IFN so that HCC may be detected at an early stage. The optimal duration of the follow-up period of the sustained responders remains unclear. Additional prospective studies are required in order to establish an appropriate follow-up protocol for sustained responders to IFN.     

HCV RNA levels during therapy with amantadine in addition to interferon and ribavirin in chronic hepatitis C patients with previous nonresponse or response/relapse to interferon and ribavirin

Interferon (IFN) alpha in combination with ribavirin (RIB) is standard therapy for patients with chronic hepatitis C virus (HCV) infection. However, many patients do not respond with sustained HCV clearance to this therapy. At present, no accepted treatment strategy exists for these patients. Recent preliminary data have suggested that amantadine (AMA) is effective against HCV infection. In a pilot study, we treated 13 nonresponders and 10 response/ relapsers to previous IFN/RIB therapy with AMA 200 mg per day in combination with IFN 3 MU thrice weekly, and RIB 1000 mg per day for 24 weeks, with a 24-week follow-up period after end-of-treatment. At the end-of-treatment, 1 previous nonresponder and 5 previous response/relapsers were HCV RNA negative. At the end of follow-up, only 1 previous response/relapser remained HCV RNA negative and had a sustained response. During therapy, serum HCV RNA became undetectable in 4 previous nonresponders, of whom 3 had a breakthrough at week 24. Twenty-one patients continued therapy without dose reductions. One patient discontinued therapy prematurely due to sleeping disturbances, and another patient was withdrawn from therapy due to heavy alcohol intake. We conclude that the addition of AMA to IFN and RIB was well tolerated but had little, if any, impact on HCV RNA eradication in nonresponders or response/relapsers to previous IFN/RIB combination therapy.     

Efficacy of interferon monotherapy in young adult patients with chronic hepatitis C virus infection

Background Suppression of the progression to cirrhosis and hepatocellular carcinoma is important, especially for young hepatitis C virus (HCV)-infected patients. The aim of this study was to analyze the response to interferon (IFN) monotherapy in young HCV patients. Methods Between 1989 and 2002, 1021 anti-HCV-positive patients hospitalized at Toranomon Hospital received IFN monotherapy. Among these patients, 144 were ≤35 years of age, while the remaining 877 were 36–73 years old. We retrospectively identified 209 patients with known dates of blood transfusion (i.e., start of HCV infection) among the 1021 patients. IFN treatment lasted 6 months. Results HCV RNA level (P < 0.001), HCV genotype (P < 0.001), age (P < 0.001), and liver histology (P = 0.01) were identified as determinants of the response to IFN monotherapy in 1021 patients. Moreover, in patients with high viral load and genotype 1b, the sustained virological response (SVR) rate was significantly higher in those aged ≤35 years than in older patients (P < 0.001). In patients with genotype 1b with known date of blood transfusion, a longer duration of infection negatively influenced the SVR rate. In the 209 patients, multivariate analysis identified HCV RNA level (P < 0.001), age (P = 0.002), and duration of infection (P = 0.049) as determinants of SVR. Conclusions The response of IFN monotherapy is better in patients aged ≤35 years than in older patients, probably because of mild stage histology, the effect of host-related factors, and shorter period of infection. Long-term IFN monotherapy may be suitable for young women who desire to become pregnant or those with anemia.