How to Optimize Treatment of Hepatitis C : Editorial

Journal of Viral Hepatitis

Special Issue: How to Optimize Treatment of Hepatitis C

Volume 19, Issue Supplement s1, pages 1–2, January 2012

Massimo Colombo

Article first published online: 10 JAN 2012

DOI: 10.1111/j.1365-2893.2011.01520.x

© 2012 Blackwell Publishing Ltd

Editorial

Chronic carriers of the hepatitis C virus (HCV) constitute a huge reservoir of cirrhosis and hepatocellular carcinoma which, ultimately, are a growing cause of liver-related mortality worldwide [1]. Treatment with pegylated interferon (PegIFN) combined with ribavirin (Rbv) is the only option for preventing HCV-related end stage liver disease. Currently, sustained virological response (SVR) rates, the surrogate definition of a cure of the disease, of up to 90% are achievable in patients infected with HCV genotypes 2 and 3, but the SVR rate is about 50% for patients infected with HCV genotype 1, the most common form [2]. Therefore, patients infected with HCV genotypes 1 and 4 who fail to respond to IFN-based therapies represent a very important unmet clinical need in the HCV arena, as highlighted also by the unsatisfactory success rate of re-treatment with Peg IFN/Rbv [3,4]. Therefore, it was with understandably great anticipation that hepatologists awaited the final reports on triple therapy with the orally bio-available protease inhibitors (PI) telaprevir and boceprevir, known to improve SVR rates to 75% in this difficult-to-cure population [5,6]. Even more welcomed were the final reports of the Prove 3 (telaprevir) and Respond 2 (boceprevir) studies, which demonstrated that re-treatment of relapsing or nonresponding HCV genotype 1 infections with standard therapy plus a PI significantly increases the likelihood of HCV eradication [7,8]. Now that we have confirmation that the new direct-acting antiviral agents will provide a major breakthrough in the treatment of patients with HCV genotype 1 infections, although at the cost of increased treatment-related side effects and discontinuation rates, we must adopt new therapeutic algorithms based on careful pretreatment patient stratification. This purpose might be served by the recent description of a set of polymorphisms in the interleukin 28B (IL28B) gene region, which encodes interferon λ3 and is associated with response to Peg IFN/Rbv therapy in HCV patients [9,10]. In fact, the link between IL28B genotype and treatment outcome might allow for pretreatment stratification aimed at refining not only decisions regarding the initiation of current therapy, but also the design of clinical trials with new direct antiviral agents. Indeed, it is worthwhile to test both a strategy restricting dual therapy to patients with the favourable IL28B genotype (CC), while administering triple therapy to those with unfavourable genotypes (TT or CT), and also a strategy in which patients are stratified by IL28B genotype for dosing and duration of antiviral therapy. This strategy might be even more cost-effective once ‘second wave’ direct antiviral agents, endowed with higher genetic barriers and broader antiviral activity against different HCV genotypes, become available. Indeed, we should acknowledge that the applicability of first generation antivirals is jeopardized by a very high risk of generating resistant HCV mutants with variable degrees of replicative fitness and by low tolerability, which could translate into higher rates of treatment discontinuation compared to dual therapy with PegIFN/Rbv alone [11]. Cutaneous rash, pruritus and anaemia following telaprevir versus anaemia and disgeusia following boceprevir were more common in the triple regimen than in the standard of care groups. Undoubtedly, the management and treatment of patients with chronic HCV infection will become more complicated, requiring increased scientific and clinical expertise to meet the new challenges that this first generation of direct-acting antivirals will provide. Although the development of viral resistance to PIs occurs in a minority of patients receiving the triple therapy regimens, it is important to outline that those mutant strains will likely preclude or delay our patients from receiving other class-specific direct antiviral agents [12]. Because alternative anti-HCV agents such as nucleoside or nonnucleoside NS5B polymerase inhibitors are in the early stages of development, patients with resistant disease will be left waiting for future drugs to enter the market before an effective anti-HCV regimen can be started. Thus, when a patient is considered for treatment with PIs, a careful risk/benefit evaluation must be conducted at the individual level; careful patient selection for triple therapy is mandatory. This is even more important when re-treating patients with genotype-1 infections, where breakthrough rates are higher among nonresponders (particularly those with < 1 log decline of HCV-RNA at week 4 of treatment) than among relapsers and among patients infected with subtype 1a compared with subtype 1b. The clinical implication of these observations is clear: PIs require some degree of viral response to PegIFN and Rbv to maximize their antiviral activity, therefore suggesting that treatment be prioritized in relapsing patients and in those primary nonresponders experiencing a ≥1 log decline in HCV-RNA at week 4 of lead in treatment with PegIFN+Rbv. In addition, an updating of HCV genotype definition is mandatory to avoid false positive diagnosis of 1b using tests based on sequence analysis or reverse hybridization of only the 5′ noncoding region of HCV, a risk that can be avoided using a second generation reverse hybridization assay that targets both the 5′ noncoding and the core-coding region of HCV [13]. Last but not least, the landscape of therapeutic effectiveness needs to be reshaped in terms of reducing HCV-related mortality at the population level. Given that HCV-related mortality in the general population can only be reduced by increasing the number of HCV patients on treatment (only 1% in Italy) and that most of the infected patients are unaware of their liver disease because of its symptomless course, more effort should be made to identify infected patients to be treated. Although the implementation of screening of persons at risk for HCV is an important step in this direction, we must realize that in many European countries including Italy, more than half of the patients with chronic hepatitis C lack a history of exposure to known risk factors and, therefore, will escape identification based on such a case-finding strategy [14]. As it is estimated that the health burden of HCV-related complications will continue to grow in most countries, in May 2010 the World Health Organization declared hepatitis a global and urgent health issue to be combated through prevention campaigns and widespread treatment of patients with the aim of avoiding progression to cirrhosis in individuals already infected. To offer anti-HCV therapy to every eligible patient, efforts should be geared toward improving the currently available screening programs for HCV infection, such as in individuals born between 1950 and 1960, as was recently suggested by the American Association for the Study of the Liver. A Markov model analysis clearly shows that increasing the number of patients currently treated with dual therapy by 50% would prevent 30% of liver-related deaths because of HCV by 2030 [15]. The advent of a rapid point-of-care test for HCV exposure that can be performed without phlebotomy needs to be recognized as a major breakthrough in this field [16]. Obviously, an agreement between local health authorities and big pharma to significantly decrease drug costs is necessary to make an expanded HCV therapy program affordable.

Acknowledgement

Declaration of personal interests: Massimo Colombo received grants and research support from Merck, Roche, BMS, Gilead Science and participated in Advisory Committees organized by Merck, Roche, Novartis, Bayer, BMS, Gilead Science, Tibotec, Vertex and moreover acted as a speaker and as a teacher for Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex.

References

Source

Ribavirin Rather than PEG-interferon Pharmacodynamics Predict Nonresponse to Antiviral Therapy in Naive Chronic Hepatitis C Patients

From Journal of Viral Hepatitis

L. G. van Vlerken; E. J. Huisman; H. van Soest; G. J. Boland; J. P. H. Drenth; P. D. Siersema; D. M. Burger; K. J. van Erpecum

Posted: 01/30/2012; J Viral Hepat. 2012;19(1):39-46. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

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.

Introduction

Current treatment for chronic hepatitis C (CHC), consisting of PEG-interferon and ribavirin, is not effective in 20–50% of cases.^[1,2] Several baseline patient and viral characteristics have been described as predictive factors for nonresponse to PEG-interferon and ribavirin treatment in previous studies, such as hepatitis C virus (HCV) genotype, viral load, patient weight, presence of cirrhosis and African American race.^[3] It is important to explore which modifiable on-treatment factors affect nonresponse rates, in order to develop effective strategies to improve outcome of antiviral treatment. Adherence to at least 80% of the prescribed (PEG) interferon and ribavirin doses has been associated with better response rates, especially in HCV genotype 1 patients.^[4] Inter-individual variability in plasma concentrations of ribavirin during treatment is high,^[5,6] and low plasma concentrations of ribavirin could be important predictors of nonresponse.^[5,7–10] Interferon-related factors could also be relevant: in a recent post hoc analysis of the HALT-C trial in previous nonresponders with advanced fibrosis or cirrhosis undergoing PEG-interferon and ribavirin re-treatment, presumed interferon-related factors (less pronounced reductions in body weight, leucocytes or platelets) were significantly associated with null response (≤1 log decrease in HCV RNA at week 24) in multivariate analysis.^[11] The underlying mechanism could be systemic interferon resistance. The aim of the current study was therefore to evaluate the influence of various baseline and on-treatment factors, including serum ribavirin concentrations, on nonresponse in treatment-naive CHC patients.

Patients and Methods

Patients

In this study, we analysed a subgroup of patients who participated in a multicentre, double-blind randomized placebo-controlled trial on potential benefit of adding amantadine to PEG-interferon alfa-2b and ribavirin combination therapy in 297 treatment-naive hepatitis C patients: the CIRA trial. Details of this study have been published previously.^[12] Of the 297 patients included in this trial, 242 patients received therapy for at least 24 weeks and are included in the current analysis. All patients received induction therapy (from day 1 combined with ribavirin), consisting of interferon alfa-2b (Schering Plough B.V., Maarssen, the Netherlands) 10 MIU/day subcutaneously during the first 6 days, followed by 5 MIU/day for the next 6 days, followed by PEG-interferon alfa-2b (Schering Plough B.V.) 1.5 μg/kg per week subcutaneously up to 26 weeks and 1.0 μg/kg per week from week 26 to 52, regardless of HCV genotype. Oral ribavirin (Schering Plough B.V.) was given from day 1 during the entire 52-week treatment period in two different doses: 1000 mg/day for body weight <75 kg and 1200 mg/day for body weight ≥75 kg. There were no differences in the amantadine and placebo groups regarding virological response. Therefore, data of both groups are combined in the following analyses.

Methods

Follow-up occurred at 0, 1, 2 and 4 weeks and monthly thereafter during 1 year of treatment and at 3-month intervals during 1 year after the end of treatment. During each visit, laboratory tests, including haemoglobin, leucocytes, granulocytes and platelet counts, were performed. Body weights and doses of ribavirin and PEG-interferon alfa-2b were also recorded at each visit. Average ribavirin and PEG-interferon alfa-2b doses during the first 24 weeks of therapy were calculated for each individual patient. Baseline creatinine clearance was calculated according to the Cockcroft–Gault equation.^[13] Quantitative serum HCV RNA testing (Cobas Amplicor HCV Monitor Test, version 2.0, detection limit 615 IU/mL; Roche Diagnostics, Almere, the Netherlands) and genotyping [sequence analysis of the 5' untranslated region of the HCV genome by TrueGene Hepatitis C Assay (Visible Genetic, Suwanee, GA, USA)] were performed before inclusion by the central study laboratory. Baseline HCV RNA values >800 000 IU/mL were considered high viral loads. Baseline liver biopsies were performed in 215 patients (89%) and assessed according to the METAVIR scoring system.^[14] Qualitative serum HCV RNA testing was performed at weeks 24, 52 and 104 (Cobas Amplicor HCV test, version 2.0; detection limit 50 IU/mL; Roche Diagnostics) by the central study laboratory. Treatment was terminated if qualitative HCV RNA test was positive after 24 weeks of treatment. Detailed information concerning dose reduction policy and definitions of virological response has been published previously.^[12]

Fifty-five of 297 patients discontinued treatment before week 24 because of patient preference (n = 13), noncompliance (n = 2), loss to follow-up (n = 9) or WHO grade 4 or persistent/recurrent grade 3 toxicity [n = 31: decompensated cirrhosis (n = 1), death because of drug overdose (n = 1), leucopenia or granulocytopenia (n = 16), anaemia (n = 2), psychiatric side effects (n = 7), miscellaneous (n = 4)].

Ribavirin Measurements

Serum samples of all patients were prospectively collected and stored at −80 °C. For the current analysis, all available week-24 samples (98% of all patients) were thawed, mixed and tested for ribavirin concentrations simultaneously using high-pressure liquid chromatography with UV detection (4.6 × 150 mm Atlantis T3 5 μm reverse-phase C18 column, autosampler column oven 35 °C: mobile phase 20 mm phosphate buffer pH 3.23 with flow rate 1.0 mL/min, λ 235 nm). Accuracy values were 104.6%, 105.2%, 101.5%, 100.9% and 100.8% at 0.300, 1.00, 4.00, 10.0 and 12.0 mg/L, respectively. At the same concentrations, the precision values (within and between days, coefficient of variation) were all below 6.0%. The calibration curve was linear over a concentration range of 0.3–12.0 mg/L. One hundred six possible co-medications were tested on this assay, none interfered with ribavirin.

Statistics

SPSS for Windows, version 15.0.1 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. We analysed patients according to per-protocol principle: for analysis of nonresponse, only patients who were treated for at least 24 weeks were included, and for analysis of final outcome, only patients who reached a primary study endpoint (i.e. completion until end of follow-up or detectable HCV RNA after 24 or 52 weeks of treatment) were included. Values are expressed as means ± SD for data with Gaussian distribution; otherwise medians with range are used. Differences in potential predictors for virological response were tested for statistical significance with the Student's t-test, Mann–Whitney U-test, Pearson's chi-square test and Fisher's exact test, as appropriate. Differences between patients with nonresponse, relapse and sustained viral response (SVR) were tested with ANOVA with post hoc LSD test. Baseline and week-24 factors that were associated with nonresponse/SVR in univariate analysis at the 0.1 level were entered in a multivariate logistic regression model with stepwise backward selection to identify independent predicting factors for these two outcomes of interest. A two-sided P-value <0.05 was considered statistically significant.

Results

Patient and Treatment Characteristics

Baseline patient characteristics of the 242 patients who received antiviral therapy during at least 24 weeks are given in Table 1. Fifty-three per cent of patients were infected with HCV genotype 1–4, 71% had high viral loads (>800 000 IU/mL), 32% exhibited severe fibrosis or cirrhosis on liver biopsy and 54% had elevated γ-GT levels at baseline. Dose reductions of ribavirin were applied in 18 patients (7%: five patients WHO grade 3 toxicity of haemoglobin, 13 patients other reasons). Dose reductions of PEG-interferon were applied in 49 patients (20%: 30 patients WHO grade 3 toxicity of granulocytes and/or leucocytes, two patients WHO grade 3 platelet toxicity, 17 patients other reasons).

Ribavirin Concentrations

Average ribavirin dose during 24 weeks of treatment was [median (range)] 1033 mg/day (467–1200 mg/day). Median week-24 serum ribavirin concentration was 2.7 mg/L (range 0.2–7.4 mg/L). Serum ribavirin concentrations were higher in female than male patients (median 2.9 vs 2.6 mg/L, P = 0.045). Serum ribavirin concentrations were not affected by HCV genotype, baseline viral load, fibrosis severity or baseline body weight. By multivariate linear regression analysis with backward stepwise selection, only higher average ribavirin dose during the first 24 weeks of therapy (in mg/kg per day) was identified as an independent predictive factor for higher week-24 serum ribavirin concentrations (coefficient 0.07, 95% CI 0.02–0.13, P = 0.01) However, only 3% (r² = 0.029) of variability in serum ribavirin concentrations could be ascribed to differences in ribavirin doses. Week-24 serum ribavirin concentrations tended to negatively correlate with baseline creatinine clearance (r = −0.12, P = 0.07) and baseline haemoglobin (r = −0.12, P = 0.06). Furthermore, a significant correlation of serum ribavirin concentrations with week-24 haemoglobin decreases (r = 0.42, P ≤ 0.001) was found. In contrast, average ribavirin doses did not correlate with week-24 haemoglobin decreases (r = −0.05, P = 0.40).

Factors Associated with Nonresponse

After 24 weeks of therapy, 203 of 242 patients (84%) exhibited negative qualitative serum HCV RNA (responders). HCV RNA was positive in the remaining 39 patients (16%; nonresponders). Of the 128 patients with HCV genotype 1–4, 36 had a nonresponse (28%). In contrast, only three of the 113 patients (3%) infected with HCV genotype 2–3 were nonresponders.

Results of univariate analysis of baseline and on-treatment factors associated with nonresponse in the total group are summarized in Table 2. Baseline factors significantly associated with nonresponse were male gender, HCV genotype 1–4 infection and higher gamma-glutamyl transpeptidase (γ-GT) levels. Week-24 serum ribavirin concentrations, average ribavirin doses during 24 weeks of therapy and week-24 haemoglobin decrease were significantly lower in nonresponders than responders.

Nonresponse rates increased progressively at decreasing serum 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). Figure 1 shows the nonresponse rates as a function of serum ribavirin concentrations, according to HCV genotype. Interestingly, all HCV genotype 2 or 3 nonresponder patients exhibited week-24 serum ribavirin concentrations <2 mg/L.

Figure 1. Nonresponse rates in naive chronic hepatitis C patients after 24 weeks of antiviral therapy as a function of week-24 serum ribavirin concentrations. Bars represent the percentage of patients with nonresponse after 24 weeks of antiviral treatment: grey bars represent patients with hepatitis C virus (HCV) genotype 1–4, white bars represent patients with HCV genotype 2–3.

Multivariate logistic regression analysis identified infection with HCV genotype 1–4, higher pretreatment levels of γ-GT and lower week-24 serum ribavirin concentrations as independent predicting variables for nonresponse at 24 weeks of therapy (Table 3). Uni- and multivariate analysis in the subgroup of HCV genotype 1–4 patients revealed essentially the same results as in the total group, again with lower serum ribavirin concentrations, lower ribavirin doses and higher baseline γ-GT levels as independent risk factors for nonresponse (Tables S1 and S2). As in the total population, week-24 serum ribavirin concentrations in the subgroup of HCV genotype 1–4-infected patients significantly correlated with week-24 haemoglobin decreases (r = 0.50, P < 0.001). In contrast, no significant correlation between serum ribavirin concentrations and average ribavirin doses (in mg/kg per day) was found (r = 0.15, P = 0.11). In HCV genotype 2–3 patients, serum ribavirin concentrations correlated with both week-24 haemoglobin decreases (r = 0.32, P = 0.001) and average ribavirin doses (r = 0.20, P = 0.03).

PEG-interferon-related Factors

Presumed interferon-related factors (leucocytes, granulocytes, platelets and body weight) did not differ significantly between nonresponders and responders, nor did PEG-interferon doses (Table 2). In the subgroup of HCV genotype 1–4 patients, also no significant differences in interferon-related factors were found between responders and nonresponders (Table S1).

Factors Associated With Null or Partial Virological Response After 24 Weeks of Therapy

Quantitative HCV RNA at week 24 in the nonresponders revealed <1 log₁₀ decrease of viral load (null response) in six cases, ≥1 log₁₀ decrease (partial response) in 30 cases and could not be determined in three cases because of absence of serum samples. Decreases from pretreatment levels of leucocytes (2.1 vs 3.7 × 10⁹/L, P = 0.09), granulocytes (0.8 vs 2.2 × 10⁹/L, P = 0.22), platelets (4 vs 48 × 10⁹/L, P = 0.08) and body weight (3.3 vs 5.0 kg, P = 0.11) and serum ribavirin concentrations (1.6 vs 2.3 mg/L, P = 0.18) tended to be less in null responders. Week-24 haemoglobin decreases and average ribavirin or PEG-interferon alfa-2b doses during antiviral therapy were not significantly different between the null and partial responders (data not shown).

Final Treatment Outcome

Of the 203 patients with negative qualitative HCV RNA at week 24, 145 patients (71%) reached SVR, 13 patients (6%) relapsed, 10 patients (5%) exhibited viral breakthrough and 35 patients (17%) were dropouts at later stages for various reasons. Characteristics for a more favourable treatment outcome generally increased progressively in the order: nonresponse, relapse and SVR groups, including week-24 serum ribavirin concentrations (2.2, 2.6 and 2.9 mg/L: Table S3). SVR rates increased progressively at increasing serum ribavirin concentrations: 47%, 69%, 76% and 95% in case of serum ribavirin concentrations ≤2, 2–3, 3–4 and ≥4 mg/L, respectively (P = 0.001, Fig. 2). By multivariate analysis, HCV genotype 2–3, lower baseline γ-GT levels and higher serum ribavirin concentrations were identified as independent predictors of SVR (Table S4). Highly similar findings were found in the subgroup of HCV genotype 1–4 patients (Tables S5 and S6).

Figure 2. Sustained viral response (SVR) rates in naive chronic hepatitis C patients as a function of week-24 serum ribavirin concentrations (per-protocol analysis). Bars represent the percentage of patients with SVR: grey bars represent patients with hepatitis C virus (HCV) genotype 1–4, white bars represent patients with HCV genotype 2–3.

Discussion

In this study, we explored the potential influence of various baseline and on-treatment factors, including serum ribavirin concentrations, on nonresponse to PEG-interferon alfa-2b and ribavirin in treatment-naive CHC patients. Our main finding is that lower week-24 serum ribavirin concentrations are an independent risk factor for nonresponse.

This finding indicates the importance of adequate exposure to ribavirin, especially in HCV genotype 1–4 patients. Only 3% of patients with HCV genotype 2–3 were nonresponders, but all had a serum ribavirin concentration below 2 mg/L. Although one could speculate that a certain threshold in serum ribavirin concentrations has to been reached to exclude an unfavourable outcome in patients with HCV genotype 2–3, the low numbers of genotype 2–3 patients with nonresponse preclude any conclusion in this respect.

Inter-patient variability in serum ribavirin concentrations is known to be high.^[5,6] Body weight, renal function, gender and age are associated with ribavirin clearance at various time points but can only explain a small part of the variability.^[5,15,16] In our study, only higher average ribavirin doses (in mg/kg per day) were an independent predictor of higher serum ribavirin concentrations (r² = 0.029). Determinants not studied in the current analysis such as nonadherence^[17] and factors influencing absorption, transport and intracellular metabolism of ribavirin could contribute to the high variability.

Ribavirin has a narrow therapeutic index: while low ribavirin concentrations increase the risk of nonresponse, high ribavirin concentrations increase the risk of toxicity, especially haemolytic anaemia.^{[5,7,8,18,19]} In line with these data, week-24 haemoglobin decreases in the current study were significantly correlated with week-24 ribavirin concentrations (r = 0.42, P < 0.001).

A potential bias in our analysis is that only patients who completed 24 weeks of treatment were included. However, only two patients stopped therapy before week 24 because of anaemia. We were interested in week-24 serum ribavirin concentrations, because we aimed at identifying factors determining risk of nonresponse rather than to adapt ribavirin dose at an early point during antiviral therapy. However, according to previous literature, steady state concentrations are already reached after 4–8 weeks.^[20] Another possible limitation of this study is that we did not measure serum PEG-interferon concentrations. It should also be noted that some aspects of the study protocol differ from current practice, because the design of the CIRA study dated from 1999–2000.^[12] Patients received high-dose induction therapy with interferon, which is currently not advised. PEG-interferon alfa-2b dose was decreased in the second half of the treatment period from 1.5 to 1.0 μg/kg per week. However, PEG-interferon doses 1.0 μg/kg per week appear not to compromise SVR rates.^[21,22] Also, in our series of 236 patients with ribavirin determinations, there was one outlier, with ribavirin concentration of 7.4 mg/L. Although we cannot exclude some haemolysis associated with antiviral therapy in this patient, all available clinical data would suggest that ribavirin exposure was considerable: the patient received a high ribavirin dose (17.5 mg/kg per day), with corresponding drop in haemoglobin (3.6 mm at week 24 compared to basal). Finally, patients were not checked after 12 weeks of treatment for early viral response,^[23] and patients with HCV genotype 2–3 were treated for 1 year.

Apart from lower serum ribavirin concentrations, infection with HCV genotype 1–4 and higher baseline γ-GT levels were identified as independent risk factors for nonresponse. HCV genotype 1 has extensively been described as the predominant risk factor for nonresponse to combination therapy for CHC. In our study, HCV genotype 1–4 was the predominant predictor for nonresponse. In contrast, elevated γ-GT levels have not been described as an independent predictive factor for nonresponse in patients with hepatitis C before. However, low or normal γ-GT levels have been associated with SVR,^[24–26] and our findings suggest that lower nonresponse rates under these circumstances could be the explanation of this finding. Elevated γ-GT levels are associated with more severe hepatic fibrosis or cirrhosis.^[27,28] In the current analysis, 54% of patients exhibited elevated γ-GT levels, similar to other reports,^{[25,26,29,30]} and γ-GT levels were significantly correlated with severe fibrosis or cirrhosis (median of γ-GT level 70 (range 16–700) in case of severe fibrosis or cirrhosis vs 48 (5–575) in case of less severe fibrosis scores, P = 0.004). Severe fibrosis or cirrhosis could not be identified as a predictive factor for nonresponse, and one may speculate that γ-GT is a more sensitive marker for fibrosis than classification according to the METAVIR scoring system.

We also compared various on-treatment factors suggested to be different on re-treatment between patients with partial response and null response in the HALT-C trial^[11] to evaluate whether similar differences could be found in treatment-naive patients. The predictive value of less reduction in body weight, leucocytes and platelets for nonresponse was not confirmed in our treatment-naive patients. Nevertheless, when comparing partial responders with null responders, a trend towards less reduction in body weight, leucocytes, granulocytes and platelets was observed, suggesting type II error. Alternatively, interferon-related factors may predict null response, especially during re-treatment of previous nonresponder patients and/or patients with severe fibrosis/cirrhosis. No other relevant studies on this topic have been published.

In conclusion, our results indicate that ribavirin rather than PEG-interferon pharmacodynamics determine in part the chance of nonresponse in treatment-naive CHC patients. This is especially the case in patients with HCV genotype 1–4, although HCV genotype 2–3 patients with serum ribavirin concentrations below a threshold of 2.0 mg/L may also experience nonresponse.

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22. McHutchison JG, Lawitz EJ, Shiffman ML et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580–593.
23. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003; 38: 645–652.
24. Berg T, Sarrazin C, Herrmann E et al. Prediction of treatment outcome in patients with chronic hepatitis C: significance of baseline parameters and viral dynamics during therapy. Hepatology 2003; 37: 600–609.
25. Berg T, von Wagner M, Nasser S et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 2006; 130: 1086–1097.
26. von Wagner M, Huber M, Berg T et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005; 129: 522–527.
27. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 2001; 357: 1069–1075.
28. Parise ER, Oliveira AC, Figueiredo-Mendes C et al. Noninvasive serum markers in the diagnosis of structural liver damage in chronic hepatitis C virus infection. Liver Int 2006; 26: 1095–1099.
29. Silva IS, Ferraz ML, Perez RM, Lanzoni VP, Figueiredo VM, Silva AE. Role of gamma-glutamyl transferase activity in patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol 2004; 19: 314–318.
30. Villela-Nogueira CA, Perez RM, de Segadas Soares JA, Coelho HS. Gamma-glutamyl transferase (GGT) as an independent predictive factor of sustained virologic response in patients with hepatitis C treated with interferon-alpha and ribavirin. J Clin Gastroenterol 2005; 39: 728–730.

Source

New developments in HCV therapy

Journal of Viral Hepatitis

Special Issue: How to Optimize Treatment of Hepatitis C

Volume 19, Issue Supplement s1, pages 48–51, January 2012

B. Kronenberger, S. Zeuzem

Article first published online: 10 JAN 2012

DOI: 10.1111/j.1365-2893.2011.01526.x

© 2012 Blackwell Publishing Ltd

Abstract

Summary. About half of the patients with chronic hepatitis C are still not cured by treatment with the current standard of care, peginterferon α/ribavirin. Direct antiviral drugs may overcome the limitations of standard antiviral therapy. The most promising new agents are inhibitors of the NS3/4A protease, the NS5B polymerase and the NS5A protein. Several compounds against these targets have entered clinical evaluation. Early clinical trials have emphasized the high potential for selecting resistant Hepatitis C virus variants. Furthermore, development of several new direct antivirals was stopped because of concerns over tolerability and safety. Then, in 2010, two phase III trials with the NS3/4A protease inhibitors boceprevir (SPRINT-2) and telaprevir (ADVANCE) showed that the combination of these compounds with standard care increases sustained virologic response rates in treatment-naïve genotype 1 patients from 38–44% to 66–75%. Future goals of therapy with direct antiviral agents are to improve tolerability, shorten the duration of therapy and overcome the issue of resistance. Several studies have been initiated that combine different novel therapies, with and without interferon α/ribavirin.

Introduction

Despite numerous attempts to optimize peginterferon α/ribavirin therapy, more than half of all patients with chronic Hepatitis C virus (HCV) genotype 1 cannot be cured with this treatment. The limitations of antiviral therapy with peginterferon α/ribavirin may be overcome by direct antiviral agents (DAA), which specifically target hepatitis C viral proteins.

Among all approaches for direct antiviral treatment of patients with chronic hepatitis C, two NS3/4A protease inhibitors have progressed into phase III development (telaprevir and boceprevir). Both compounds show a good safety profile and high antiviral efficacy. Assuming approval by regulatory agencies these drugs, in combination with peginterferon α and ribavirin, will become the new standard treatment for patients with HCV genotype 1 infections.

Phase III Trials with Protease Inhibitors

Telaprevir

Treatment-naïve patients

The ADVANCE trial is a randomized placebo-controlled phase III study to investigate the efficacy and safety of telaprevir in combination with peginterferon α-2a and ribavirin [1,2]. Treatment-naïve HCV genotype 1–infected patients (n = 1095) were randomized into two telaprevir arms and one control arm. Telaprevir was administered for either 8 or 12 weeks in combination with peginterferon α-2a/ribavirin for 24 weeks. Patients without extended rapid virologic response (eRVR; undetectable HCV RNA at week 4 and 12) continued peginterferon α-2a/ribavirin up to week 48. Patients in the control arm received peginterferon α-2a/ribavirin for 48 weeks.

The sustained virologic response (SVR) rates in both telaprevir arms were superior to standard therapy, with the highest rate achieved in the 12-week telaprevir arm (75%) compared to 69% in the 8-week telaprevir arm and 44% in the peginterferon α-2a/ribavirin arm [1,2].

The ILLUMINATE trial was supplementary to ADVANCE and had the aim of investigating the effect of treatment duration on SVR rates [3]. In this trial, treatment-naïve patients with HCV genotype 1 were treated with telaprevir, peginterferon α-2a and ribavirin. Patients who achieved an eRVR (undetectable HCV RNA at weeks 4 and 12) were randomized at week 20 to continue receiving peginterferon α-2a/ribavirin for a total of 24 or 48 weeks of treatment. Patients not achieving an eRVR were assigned to 48 weeks of treatment. The overall SVR rate after response-guided therapy was 71.9%. Among patients who achieved an eRVR, a 24-week telaprevir-based therapy was noninferior to 48-week telaprevir-based treatment (92% SVR compared to 87.5%). The study supports response-guided therapy for telaprevir-based treatment regimens.

Retreatment of nonresponders to SOC therapy

The REALIZE trial evaluated telaprevir-based triple therapy in patients with prior treatment failure to SOC [4]. Telaprevir was administered for 12 weeks, while pegylated interferon α-2a/ribavirin combination therapy was given for 48 weeks. Telaprevir was either started simultaneously with peginterferon α-2a/ribavirin or delayed until after a 4-week lead-in (LI) phase with peginterferon α-2a/ribavirin. Overall, SVR rates following telaprevir-based retreatment in the simultaneous and delayed arm were superior to retreatment with standard therapy (64% and 66% vs 17%). The highest SVR rates were observed in patients with prior relapse after standard therapy (simultaneous/delayed/control: 83/88/24%), followed by partial responders (59/54/15%) and finally by nonresponders (29/33/5%).

Boceprevir

Treatment-naïve patients

SPRINT-2 is a randomized placebo-controlled phase III study to investigate the efficacy and safety of boceprevir in combination with peginterferon α-2b and ribavirin in treatment-naïve patients with chronic HCV genotype 1 infection [5,6].

The study compared a 4-week lead-in (LI) treatment period with peginterferon α-2b/ribavirin (PR), followed by (i) response-guided therapy: boceprevir plus peginterferon α-2b/ribavirin (BPR) for 24 weeks with an additional 20 weeks of PR only if HCV RNA was detectable during weeks 8–24 (LI + 24 BPR ± 20 PR) or (ii) Boceprevir plus PR for 44 weeks (LI + 44 BPR) or (iii) PR plus placebo for 44 weeks (48 PR).

In the HCV SPRINT-2 study, 1097 treatment-naïve patients were enrolled. The overall SVR rates were superior in the boceprevir arms (66% for LI + 44 BPR and 63% for LI + 24 BPR ± 20 PR), compared with the control arm (38%, 48 PR). The SVR rates were further distinguished according to ethnicity, with 159 patients being African American/Black and 938 patients non-African American/Black. SVR rates among the non-African American/Black patients were higher than SVR rates in African American/Black patients (68%, 67% and 40% vs 53%, 42% and 23% for patients in the LI + 44 BPR, the response-guided therapy LI + 24 BPR ± 20 PR and control 48 PR arms, respectively).

Retreatment of nonresponders to SOC therapy

The HCV RESPOND-2 study was conducted in 403 patients with chronic HCV genotype 1 infections who had failed prior standard therapy [7]. HCV genotype 1 partial responders (decrease in HCV RNA of at least 2 log₁₀ but with detectable HCV RNA throughout therapy) or relapsers to prior peginterferon α/ribavirin treatment were randomized into three arms. Each patient received a 4-week LI with PR. Patients in the control arm then received PR for 44 weeks. Patients in experimental arm 1 received boceprevir and PR for 32 weeks, and those with detectable HCV RNA at week 8 received an additional 12 weeks of PR. Patients in experimental arm 2 received BPR for 44 weeks. The SVR rates were 59% in the boceprevir response-guided arm, 66% in the 44-week boceprevir treatment arm and 21% in the control group.

Relevance of viral and host factors for direct antiviral agents treatment

Genotype

Both protease inhibitors telaprevir and boceprevir were developed for treatment of HCV genotype 1–infected patients. Telaprevir is less active against HCV genotype 2 and markedly so against HCV genotypes 3 and 4, compared with HCV genotype 1 [8,9]. Also, boceprevir was reported to have lower antiviral activity against HCV genotypes 2 and 3 [10]. HCV genotype will therefore remain an important factor for individualized therapy. New NS3/4A protease inhibitors such as ACH-2684 and MK-5172 currently in preclinical or early clinical development are active against genotypes 1–6 and genotypes 1 and 3, respectively, and may overcome this restriction [11,12]. Nuc polymerase inhibitors that target the active centre of the NS5B polymerase have the highest potential for direct antiviral therapy of nongenotype 1 HCV. A recent phase I study shows that NS5A inhibitors such as PPI-461 also have the potential for pan-genotype activity [13].

IL28B genotype

Genome-wide association studies have recently identified single-nucleotide polymorphisms at the IL28B gene locus that are strongly associated with treatment response to SOC in patients infected with HCV genotype 1 [14–17]. The more responsive C/C variant was associated with a twofold increase in cure rate. Allele frequencies differ between ethnic groups, largely explaining the observed differences in response rates between Caucasians, African Americans and Asians.

The IL28B C/C genotype is associated with improved early antiviral kinetics and a greater likelihood of rapid and complete early virologic response in patients with HCV genotype 1 [17]. An ongoing phase II trial revealed that the non-nuc polymerase inhibitor ANA598 was able to improve RVR and EVR rates in patients with the less favourable IL28B C/T and T/T alleles, where SOC alone is less efficacious (RVR 31% vs 10% and EVR 69% vs 50% for ANA598 plus SOC vs SOC alone) [18]. The study shows that the IL28B genotype distribution may also be important for DAA treatment. Furthermore, knowledge of the IL28B genotype may be relevant for designing early phase clinical trials with small patient numbers (stratification according to IL28B genotype) [19].

Future of Treatment

Combination therapy without interferon

Triple therapy of protease inhibitors with peginterferon α and ribavirin continues to be unsatisfactory for two reasons: (i) anti-HCV therapy still depends on peginterferon α and ribavirin, and therefore, SOC null responders are less likely to achieve SVR; (ii) triple therapy is associated with more adverse events than previous SOC. Therefore, the next goal of anti-HCV therapy will be to develop an interferon-free regimen with better tolerability. This goal may be achievable with a combination of two or more direct antivirals that have nonoverlapping resistance profiles.

Combination of NS3/4A inhibitor plus NS5B polymerase inhibitor

The INFORM-1 trial was the first study that investigated an interferon-free approach for treatment of chronic hepatitis C. The nuc polymerase inhibitor RG7128 and the protease inhibitor RG7227 were administered to treatment-naïve and treatment-experienced HCV genotype 1–infected patients for 2 weeks. All patients who received combination therapy achieved profound reduction in HCV RNA without evidence of treatment emergent resistance (HCV drop after 2 weeks −4.8, −4.0 and −4.9 log₁₀ IU/mL in treatment naïve, relapsed and nonresponders to SOC) [20].

Another phase I trial also investigated an interferon-free combination of the NS3/4A protease inhibitor BI201335 and the NS5B polymerase inhibitor BI207127 plus ribavirin for 4 weeks in treatment-naïve HCV genotype 1–infected patients [21]. This combination yielded a rapid sharp drop in HCV RNA followed by a second declining phase in most patients. A majority of patients (11/15) in the BI207127 low-dose (400 mg TID) and all patients (17/17) in the high-dose (600 mg TID) arms had an HCV RNA level lower than 25 IU/mL at week 4. This combination will be investigated in a phase II trial testing different dose regimens and longer treatment using SVR as the primary endpoint.

GS-9256 is a NS3/4A protease inhibitor and GS-9190 a non-nucleoside NS5B inhibitor, which are each active against genotype 1 HCV as monotherapy. Mutations associated with resistance to GS-9256 or GS-9190 were introduced into HCV 1b replicons, and antiviral susceptibility was tested in transient replication assays. GS-9256 maintained antiviral activity in replicons bearing mutations associated with lower susceptibility to GS-9190 and vice versa, and GS-9190 maintained antiviral activity in replicons bearing mutations associated with lower susceptibility to GS-9256. The combination is now in active clinical development [22].

Combination of an NS3/4A inhibitor plus an NS5A inhibitor

A phase II study investigated the efficacy and safety of the NS5A inhibitor BMS-790052 in combination with the NS3/4A inhibitor BMS-650032, with and without peginterferon α-2a/ribavirin in HCV genotype 1 patients not responding to prior SOC [23]. An interim analysis revealed RVR rates of 63% and 60% in the arms with and without interferon/ribavirin, respectively. However, between week 4 and 12, 6 of 11 patients in the interferon-free arm had viral breakthroughs, while all patients in the interferon/ribavirin-containing arm maintained viral suppression.

Summary

Peginterferon α/ribavirin has been the standard treatment for HCV for almost a decade. The most promising and clinically advanced direct anti-HCV compounds are inhibitors of the NS3/4A protease and the NS5B polymerase. Because of the risk of selecting for resistant strains, the current protease inhibitors telaprevir and boceprevir must be administered in combination with peginterferon α/ribavirin. Two phase III trials with boceprevir (SPRINT-2) and telaprevir (ADVANCE) in combination with SOC have shown SVR rates in the order of 66-75% in patients with genotype 1 HCV infections. The future of anti-HCV therapy will focus on the development of interferon-free treatment regimens with better tolerability and shorter treatment duration compared with SOC.

Acknowledgements and Disclosures

Bernd Kronenberger has served as a speaker or an advisory board member for Roche, Human Genome Sciences, Novartis, Gilead, Bristol-Myers Squibb, Schering Plough. Stefan Zeuzem has served as a speaker, a consultant or an advisory board member for Abbott, Achillion, Anadys, BMS, Gilead, Itherx, Merck, Novartis, Pfizer, Pharmasset, Roche, Santaris, Tibotec, Vertex; member of speaker’s bureau: BMS, Gilead, Merck, Novartis, Roche.

References

Source

Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C

Journal of Viral Hepatitis

Volume 19, Issue 2, pages e134–e142, February 2012

N. Hayashi¹, T. Okanoue², H. Tsubouchi³, J. Toyota⁴, K. Chayama⁵, H. Kumada⁶

Article first published online: 8 NOV 2011

DOI: 10.1111/j.1365-2893.2011.01528.x

© 2011 Blackwell Publishing Ltd

Abstract

Summary. The aims of this phase III study were to assess the efficacy and safety of telaprevir in combination with peginterferon alfa-2b (PEG-IFN) and ribavirin (RBV) for difficult-to-treat patients who had not achieved sustained virological response (SVR) to prior regimens in Japan. The subjects were 109 relapsers (median age of 57.0 years) and 32 nonresponders (median age of 57.5 years) with hepatitis C virus genotype 1. Patients received telaprevir (750 mg every 8 h) for 12 weeks and PEG-IFN/RBV for 24 weeks. The SVR rates for relapsers and nonresponders were 88.1% (96/109) and 34.4% (11/32), respectively. Specified dose modifications of RBV that differed from that for the standard of care were introduced to alleviate anaemia. RBV dose reductions were used for 139 of the 141 patients. The SVR rates for relapsers did not depend on RBV dose reduction for 20–100% of the planned dose (SVR rates 87.5–100%, P < 0.05). Skin disorders were observed in 82.3% (116/141). Most of the skin disorders were controllable by anti-histamine and/or steroid ointments. The ratios of discontinuation of telaprevir only or of all the study drugs because of adverse events were 21.3% (30/141) and 16.3% (23/141), respectively. A frequent adverse event leading to discontinuation was anaemia. Telaprevir in combination with PEG-IFN/RBV led to a high SVR rate for relapsers and may offer a potential new therapy for nonresponders even with a shorter treatment period.

Introduction

Hepatitis C virus (HCV) affects approximately 170 million people worldwide [1]; patients with chronic hepatitis C (CHC) eventually develop cirrhosis and hepatocellular carcinoma (HCC) [2,3]. The standard of care (SOC) with peginterferon plus ribavirin (RBV) for 48 weeks is most effective for eradicating HCV genotype 1 [4], which is a dominant genotype for CHC [1]. However, the sustained virological response (SVR) rate of SOC for the treatment of naïve patients with genotype 1 is approximately <50% [5,6]. The retreatment regimen for patients who do not achieve SVR is limited to exposure to peginterferon plus RBV with modification of dose and treatment duration. Some studies have been conducted to estimate the effectiveness of peginterferon plus RBV for 48 weeks for nonresponders to prior interferon-based combination therapy, and the SVR rates in most studies did not exceed 20% [7–9]. A large randomized study of patients who had not responded to previous treatment with peginterferon alfa-2b (PEG-IFN) plus RBV gave SVR rates for peginterferon alfa-2a 180 μg/kg plus RBV for 72 weeks that were not as high as those for 48 weeks (14%, 9%) [10]. HCV patients who had failed to achieve SVR with the combination therapy displayed high risk rates of decompensated cirrhosis, HCC and liver-related mortality [11]. Therefore, it is very important to establish new regimens to increase the SVR rate and shorten the treatment period for patients who do not achieve SVR with prior treatments.

Telaprevir, classified as a direct-acting antiviral agent, is a reversible, selective, orally bioavailable inhibitor of the nonstructural NS3/4A HCV serine protease [12]. Two phase II studies (PROVE 1 and PROVE 2) on the treatment of naïve patients with genotype 1 were conducted to assess the efficacy of telaprevir for 12 weeks in combination with peginterferon and RBV for 24 weeks [13,14]. These studies demonstrated that the SVR rates of the telaprevir regimen were significantly higher compared with SOC (PROVE 1: 61%vs 41%, P = 0.02, PROVE 2: 69%vs 46%, P = 0.004). A subsequent phase II study (PROVE 3) for treatment-failure patients with genotype 1 gave SVR rates for nonresponders, relapsers and breakthroughs in the telaprevir regimen of 39%, 69% and 57%, respectively [9].

In Japan, a phase III study was conducted for the treatment of naïve patients with genotype 1 to compare the efficacy and safety between the telaprevir regimen and SOC. It has demonstrated that the SVR rate for the telaprevir regimen was significantly higher than that for SOC (73.0%vs 49.2%, P = 0.0020) [15]. We decided to conduct a phase III study to assess the efficacy and safety of telaprevir in combination with PEG-IFN and RBV in relapsers and nonresponders who had not achieved SVR to a previously administered IFN-based regimen in Japan.

Patients and methods

Study patients

Relapsers and nonresponders were enrolled in Study 1 (ClinicalTrials.gov Identifier: NCT00780910) and Study 2 (ClinicalTrials.gov Identifier: NCT00781274), respectively. Relapsers were defined as patients who had been previously treated for CHC and had undetectable HCV RNA during interferon or peginterferon therapy (including combination with RBV). Nonresponders were defined as patients who were previously treated for CHC and had never had undetectable HCV RNA for more than 24 weeks with interferon or peginterferon therapy (including combination with RBV).

The patients were enrolled from 17 sites in Japan. Patients considered eligible were of 20–65 years of age, had CHC because of HCV genotype 1 (defined by NS5B sequence) [16] and ≥5.0 log₁₀ IU/mL HCV RNA level at the screening test, had been previously treated for CHC with interferon or peginterferon therapy (including combination with RBV), had a body weight of 40 kg or more and below 120 kg, could be hospitalized for at least 2 weeks after the first administration, were not pregnant and agreed to contraception from the screening period to 24 weeks after the last dosing of the study drug. The patients were excluded if they had a haemoglobin level of <12 g/dL, neutrophil count of <1500/mm³, platelet count of <100 000/mm³, were positive for HBs antigen and HIV antibodies at the screening test, had chronic renal failure or creatinine clearance of ≤50 mL/min, depression, schizophrenia or its history, history of suicide attempt, decompensated cirrhosis, previous or current HCC or other malignancies, autoimmune hepatitis, alcoholic liver disease or haemochromatosis.

All patients provided written informed consent before participating in the study. These studies were approved by each site’s institutional review board and conducted in accordance with good clinical practice and the Declaration of Helsinki.

Study design

All patients received PEG-IFN (PegIntron^®; MSD, Tokyo, Japan) at a dose of 1.5 μg/kg per week subcutaneously, RBV (Rebetol^®; MSD) at a dose of 600 mg per day (for body weight ≤60 kg), 800 mg per day (for body weight >60 to ≤80 kg) or 1000 mg per day (for body weight >80 kg) and telaprevir (MP-424; Mitsubishi Tanabe Pharma, Osaka, Japan) at a dose of 750 mg every 8 h after food. The patients were treated with telaprevir, PEG-IFN and RBV for 12 weeks, followed by PEG-IFN and RBV (PEG-IFN/RBV) for 12 weeks. All patients had a 24-week follow-up period after the last dosing of study drugs to assess SVR.

Dose modification of study drugs

Specified dose modification of RBV that differed from the dose for SOC was introduced to alleviate anaemia. The initial dose of RBV was reduced by 200 mg per day in case of a haemoglobin level <13 g/dL at baseline. The RBV dose was reduced by 200 mg per day in patients receiving 600 or 800 mg per day (by 400 mg per day in those receiving 1000 mg) when the haemoglobin level was <12 g/dL and was reduced by an additional 200 mg per day when the haemoglobin level was <10 g/dL. The RBV dose was also reduced by 200 mg per day if the haemoglobin level dropped ≥1 g/dL within 1 week, and this level was <13 g/dL. Telaprevir was withdrawn when the haemoglobin level was <8.5 g/dL. PEG-IFN/RBV were withdrawn or interrupted when the haemoglobin level was <8.5 g/dL. The dose modifications of PEG-IFN were followed by SOC. Dose modification and interruption of telaprevir were not allowed. Telaprevir was withdrawn if serious adverse events appeared. The use of erythropoietin was not allowed for elevating the haemoglobin level.

Stopping rules

Patients could be discontinued from the study at any time if the investigator or sponsor determined that it was not in the interest of the patient to continue the study or the patient wished to withdraw from the study. The study drugs were discontinued if the patients had a haemoglobin level of <8.5 g/dL, white blood cell count of <1000/mm³, neutrophil count of <500/mm³ or platelet count of <50 000/mm³.

In case of the following criteria for serum HCV RNA viral kinetics measured during the treatment period, discontinuation of the study drugs was decided at the investigator’s discretion. (i) When the following criteria applied twice consecutively: (a) the amount of change from the lowest value for HCV RNA level exceeded 2.0 log₁₀ IU/mL and (b) HCV RNA level exceeded 2.0 log₁₀ IU/mL after it had been confirmed to be <1.2 log₁₀ IU/mL. (ii) When the serum HCV RNA level at 13 weeks after administration of study drugs did not decrease by >2.0 log₁₀ IU/mL from the baseline level.

Efficacy assessments

Serum HCV RNA levels were measured using the COBAS TaqMan HCV test (Roche Diagnostics Co. Ltd., Tokyo, Japan). The linear dynamic range was 1.2–7.8 log₁₀ IU/mL. Samples with undetectable HCV RNA were reported as ‘<1.2 log₁₀ IU/mL (no detectable HCV RNA)’. Measurements were obtained at week 4 before day 1 of the screening period: at days 1 (predose), 2 and 3; weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24 of the treatment period; and weeks 2, 4, 8, 12, 16, 20 and 24 of the follow-up period.

The primary endpoint was a SVR defined as an undetectable HCV RNA level 24 weeks after the end of treatment. Relapse, breakthrough, and nonresponse were defined based on AASLD Guidelines as follows [4]: ‘relapse’ was a state of undetectable serum HCV RNA at the end of treatment and reappearance of serum HCV RNA during the follow-up period; ‘breakthrough’ was a state of undetectable serum HCV RNA and reappearance of serum HCV RNA during the treatment period; and ‘nonresponse’ was a state of continuously detectable serum HCV RNA during the treatment period.

Safety assessments

All adverse events were recorded up to the last visit and coded using MedDRA/J version 13.0. (MedDRA Japanese Maintenance Organization, Tokyo, Japan) Measurements for chemical laboratory data were obtained at week 4 before day 1 of the screening period: at day 1 (predose); weeks 1, 2, 4, 8, 10, 12, 14, 16, 18, 20 and 24 of the treatment period; and weeks 2, 4, 8, 12 and 24 of the follow-up period. Electrocardiogram (ECG) and fundus examinations were performed once during the screening period. Adverse events, haematological and chemical laboratory data, and vital signs were assessed and summarized. The severity of rash was categorized into three grades.

Statistical analysis

Sustained virological response rates were evaluated for the full analysis set. Categorical variables were compared by Fisher’s exact test. Statistical analyses were performed using the statistical software SAS Version 9.1 (SAS Institute Inc., Cary, NC, USA), and a P value < 0.05 was considered significant.

Results

Study patients

From November 2008 to August 2009, a total of 168 patients [Study 1 (N = 135) and Study 2 (N = 33)] were screened, and 141 patients [Study 1 (N = 109) and Study 2 (N = 32)] received at least one dose of a study drug. The baseline characteristics of the study patients are shown in Table 1. Patients previously treated with PEG-IFN (with or without RBV) and IFN (with or without RBV) in Study 1 and Study 2 accounted for 75.2% (82 of 109) and 24.7% (27 of 109) and 90.6% (29 of 32) and 9.4% (3 of 32), respectively. The median of age, weight, haemoglobin level, platelet count and HCV RNA level for Study 1 and Study 2 were 57.0 and 57.5 years, 62.5 and 61.3 kg, 14.7 and 14.5 g/dL, 17.8 and 17.85 × 10⁴/mm³, and 6.75 and 6.78 log₁₀ IU/mL, respectively. Patients over 50 years of age accounted for 81.7% (89 of 109) and 81.3% (26 of 32), respectively.

Efficacy in study 1 (relapsers)

Figure 1 shows the change in the undetectable HCV RNA rates at each measurement point. The rapid viral response (RVR) rate and the end of treatment response (ETR) rate were 87.2% (95/109) and 94.5% (103/109), respectively. The SVR rate, nonresponse, breakthrough and relapse were 88.1% (96/109), 0.9% (1/109), 0.9% (1/109) and 7.3% (8/109), respectively (Fig. 2).

Figure 1. Undetectable hepatitis C virus RNA rates at each measurement point. SVR, sustained virological response; ETR, end-of-treatment response.

Figure 2. Response rates of patients with virological response. *Number of patients who achieved SVR in each subgroup/N (%). SVR, sustained virological response; RVR, rapid viral response; ETR, end-of-treatment response.

Factors influencing the SVR rate are compared in Table 2. The SVR rate in the patients who achieved undetectable HCV RNA at ≤week 4 was significantly higher than that in the patients who achieved undetectable HCV RNA at >week 4 (91.8%vs 66.7%, P = 0.0487). Also, the SVR rate for men was significantly higher than that for women (93.9%vs 79.1%, P = 0.0316). The SVR rate with discontinuation of all the study drugs was significantly lower than that with discontinuation of only telaprevir or no discontinuation of the study drugs (all the study drugs: 60.0%, only telaprevir: 95.0% and no discontinuation: 94.2%, P = 0.0007). In contrast, there was no difference in the SVR rate in relation to HCV RNA level and prior therapy for CHC. SVR rates by the ratio of the actual total RBV dose to the anticipated total RBV dose were evaluated (Fig. 3). The SVR rates did not depend on RBV dose reduction for 20–100% of the planned dose (87.5–100%, P < 0.05).

Figure 3. Sustained virological response rates according to adherence to the ribavirin dose.

Efficacy in study 2 (nonresponders)

The RVR and ETR rates were 71.9% (23/32) and 59.4% (19/32), respectively (Fig. 1). The SVR rate, nonresponse, breakthrough and relapse were 34.4% (11/32), 6.3% (2/32), 18.8% (6/32) and 40.6% (13/32), respectively (Fig. 2). There was no difference in the SVR rate in relation to baseline characteristics, HCV RNA level and prior treatment for CHC. The SVR rates for the patients who received 40–80% RBV dose reduction were over 30% (Fig. 3).

Safety

Adverse events were observed in all the patients in Study 1 and Study 2. Adverse events observed in at least 15% of the patients in each clinical study are listed in Table 3. Adverse events were similar between Study 1 and Study 2. Most of the adverse events were mild and moderate. Serious adverse events in Study 1 and Study 2 were reported in 11.9% (13/109) and 9.4% (3/32) of the patients, respectively. The ratios of discontinuation of all the study drugs because of adverse events in Study 1 and Study 2 were 17.4% (19/109) and 12.5% (4/32), respectively. A frequent adverse event leading to discontinuation was anaemia. Discontinuation rates of all the study drugs because of anaemia in Study 1 and Study 2 were 10.1% (11/109) and 9.4% (3/32), respectively. One death was reported in Study 1. One patient in Study 1 died of pulmonary embolism. Causality of PEG-IFN and RBV was classified as ‘probably related’ and that of telaprevir was classified as ‘possibly related’.

Adverse events related to skin disorders were observed in 82.3% (116/141) of the patients. Skin disorders reported in over 10% of the patients were rash in 39.0% (55/141), drug eruption in 24.1% (34/141), injection site reaction in 12.8% (18/141) and injection site erythema in 12.8% (18/141) of the patients. Most of the skin disorders were controllable by anti-histamine and/or steroid ointments. Grade 3 (severe) skin disorders in Study 1 and Study 2 were reported in 6.4% (7/109) and 6.3% (2/32) of the patients, respectively. Discontinuation of all the study drugs because of skin disorders in Study 1 amounted to 3.7% (4/109). No discontinuation because of skin disorders occurred in Study 2.

Figure 4 shows the changes in haemoglobin levels, platelet counts and neutrophil counts during the treatment and follow-up periods. Changes in the haematological parameters were similar between Study 1 and Study 2. The platelet count and neutrophil count decreased sharply within 4 weeks and then gradually decreased. Despite the modification of RBV, the median haemoglobin levels in Study 1 and Study 2 decreased to 10.6 and 10.4 g/dL at week 12, respectively. No patient discontinued all the study drugs because of neutrophil decrease. The haematological parameters recovered to the baseline level at the end of the follow-up period.

Figure 4. Changes in hematology parameters. Median haemoglobin levels (a), median platelet counts (b) and median neutrophil counts (c) were plotted during treatment and follow-up periods.

Discussion

This phase III study was planned and conducted to assess the efficacy and safety of telaprevir in combination with PEG-IFN/RBV for relapsers and nonresponders. Most of the patients who participated in this study had received a prior PEG-IFN/RBV regimen. Despite a shorter treatment period, the SVR rates for relapsers and nonresponders were 88.1% and 34.4%, respectively. The result indicates that the HCV RNA response to previous treatment history should be one of the diagnostic factors for predicting SVR.

The SVR rate for men was significantly higher than that for women in the relapser group (93.9%vs 79.1%, P = 0.0316). There was no significant difference in other characteristics of the patients in that group. Once the relapsers had achieved undetectable HCV RNA, this condition was sustained until the end of the treatment period. The patients who achieved RVR had a higher SVR rate than the patients who had no RVR in the relapser group (91.8%vs 66.7%, P = 0.0487).

In contrast, there was no significant difference related to characteristics in the nonresponder group. The SVR rates between men and women and undetectable HCV RNA were, however, slightly different. As Study 2 for the nonresponders was of a small scale, it will be necessary to evaluate a larger number of patients. The breakthrough ratio in the nonresponders during the PEG-IFN/RBV treatment period and relapse ratio were 18.8% and 40.6%, respectively. Two patients were nonresponders with high telaprevir-resistant variants; one was subtype 1a and the only patient with this characteristic in the study.

Triple therapy for 12 weeks, followed by PEG-IFN/RBV for 12 weeks for the relapsers led to a high SVR rate. In contrast to the relapsers, all breakthroughs were observed in 18.8% of nonresponder patients after the end of telaprevir treatment, and relapse were observed in 40.6% of nonresponder patients after the end of treatment period. Continuation of telaprevir over 12 weeks and PEG-IFN/RBV over 24 weeks might be needed to achieve a higher SVR rate for nonresponders.

Dose modification of RBV that differed from that for SOC was introduced to prevent anaemia in the patients [17]. Dose reductions of RBV were observed in 98.6% of the patients, and those who had 200 mg RBV per day as a minimum dose and those who discontinued it accounted for 41.8% and 29.8%, respectively. The haemoglobin level recovered to the baseline level at the end of the follow-up period. As a result of dose modification, the change in the haemoglobin level in this study was similar to that in PROVE 3 [9]. Checking the haemoglobin level once a week during the treatment period is important. The SVR rates did not depend on RBV dose reduction among the relapsers who had over 20% of the anticipated total RBV dose (87.5–100%). Thus, it is important to monitor haemoglobin levels and continue RBV dosing appropriately to achieve SVR, even with a low RBV dose.

Adverse events related to skin disorder were reported by 82.3% of the subjects. Of the nine cases of severe skin disorders, seven occurred within 8 weeks. Telaprevir was likely to be related to the occurrence of the severe skin disorders. The mechanism of skin disorders is unknown. All the patients who discontinued treatment received immediate care from dermatologists and recovered eventually. Skin disorders should be carefully monitored by physicians in collaboration with dermatologists.

The relationship between the SVR rates and the difference in SNPs in gene IL28B or near IL28B has become clear [18,19]. With genetic variation in rs8099917, SVR rates of 83.8% and 27.6% were achieved for patients with genotype TT and non-TT who were treated with telaprevir in combination with PEG-IFN/RBV, respectively [20]. Also, genetic variations in gene ITPA related to haemoglobin decrease and reduction of RBV has been discussed for patients treated with PEG-IFN/RBV [21,22]. We did not evaluate IL28B and ITPA in this study. As anaemia was the most frequent adverse event leading to the discontinuation of the study drugs in the present study, it should become a valuable pharmacogenetic diagnostic tool to optimize the triple therapy.

In conclusion, this phase III study conducted in Japan demonstrated that telaprevir in combination with PEG-IFN/RBV had a high SVR rate for relapsers and shows promise as a potential therapy for nonresponders even with a short treatment period. Prolongation of telaprevir and PEG-IFN/RBV treatment should be a better option for achieving high SVR for nonresponders. As the data demonstrated convincingly that the benefits greatly outweigh the risks, telaprevir-based regimen is at the lead for the next generation of HCV therapies.

Disclosures

None to declare.

References

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Long-term effects of treatment and response in patients with chronic hepatitis C on quality of life

Published on: 2012-01-31

Background Hepatitis C decreases health related quality of life (HRQL) which is further diminished by antiviral therapy. HRQL improves after successful treatment.

This trial explores the course of and factors associated with HRQL in patients given individualized or standard treatment based on early treatment response (Ditto-study).Methods The Short Form (SF)-36 Health Survey was administered at baseline (n= 192) and 24 weeks after the end of therapy (n= 128).Results At baseline HRQL was influenced by age, participating center, severity of liver disease and income. Exploring the course of HRQL (scores at follow up minus baseline), only the dimension general health increased.

In this dimension patients with a relapse or sustained response differed from non-responders. Men and women differed in the dimension bodily pain.

Treatment schedule did not influence the course of HRQL.Conclusions Main determinants of HRQL were severity of liver disease, age, gender, participating center and response to treatment. Our results do not exclude a more profound negative impact of individualized treatment compared to standard, possibly caused by higher doses and extended treatment duration in the individualized group.

Antiviral therapy might have a more intense and more prolonged negative impact on females.

Author: Geert BezemerArthur R van GoolElke Verheij-HartBettina E HansenYoav LurieJuan I EstebanMartin LaggingFrancesco NegroStefan ZeuzemCarlo FerrariJean-Michel PawlotskyAvidan U NeumannSolko W SchalmRobert J de Knegt

Credits/Source: BMC Gastroenterol

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How Do Lipids Affect Liver Disease?

As Posted on The AGA Journals Blog

Posted on January 30, 2012

by Kristine Novak, PhD, Science Editor

Changes in lipid intake or metabolism can affect development of liver injury and fibrosis, according to two studies in mice published in the January issue of Gastroenterology.

The liver is an important site of energy production and lipid metabolism. However, accumulation of excess fat in the liver promotes development of fibrosis, cirrhosis and hepatocellular cancer. Not much is known about how lipids and lipid metabolism influence liver diseases. Two studies used mice to learn more.

Teratani et al. investigated the effects of a high cholesterol diet on hepatic fibrosis induced by bile duct ligation or carbon tetrachloride, which cause biliary and toxic liver injury.The diet did not affect hepatocytes, but increased levels of cholesterol in hepatic stellate cells (HSCs; liver cells that store lipid and promote fibrogenesis) and increased up-regulation of profibrogenic genes in response to transforming growth factor (TGF)-β.

Although the high-cholesterol diet did not affect expression of the receptor for TGF-β, the authors observed increased levels of the lipopolysaccharide Toll-like receptor (TLR)4, and other alterations in this hepatocyte signaling pathway. Cholesterol did not increase levels of TLR4 mRNA, so the authors to propose that cholesterol prevents degradation of TLR4 protein. This is one of the first studies to show that cholesterol affects HSCs and their fibrogenic abilities.

Moustafa et al. uncovered a unique role for hepatic lipids using a mouse model of cholestatic liver disease, caused by genetic disruption of the ATP-binding cassette sub-family B member 4 (Abcb4−/−). Abcb4 encodes a phospholipid flippase that promotes biliary secretion of phospholipid and protects the biliary epithelium from the damaging effects of bile acids. Mice deficient in Abcb4 develop hepatocellular injury, cholestasis, and liver fibrosis. ABCB4 mutations in humans cause progressive familial intrahepatic cholestasis type 3 (PFIC3).

In the in Abcb4−/− mice, 24-NorUrsodeoxycholic acid (NorUDCA, a side-chain variant of ursodeoxycholic acid that ameliorates cholestatic liver injury), loss of PPAR-α (PPAR-/-), and the high-fat diet (HFD, in figure below) reduced cholestasis, hepatic inflammation and fibrosis. The improvements coincided with reductions in activities of hepatic phospholipase and triglyceride lipase.

Factors that alter lipid metabolism, leading to liver damage.

These results were surprising because they show that hepatic lipid homeostasis in an important determinant of outcome in a liver disease not characterized by hepatic steatosis. They are also unique in that they demonstrate cholestatic liver disease, at least in Abcb4−/−mice, is improved by increasing, rather than decreasing, hepatic triglyceride levels.

In an editorial that accompanies the articles, Robert Schwab and Jacquelyn Maher ask whether this means that there is some optimal level of hepatic triglyceride—that disease develops if there is too much or too little? They say that the answer is no—instead, the development of liver disease depends on the metabolic activity of hepatic lipid. Excess fatty acids in the liver are dangerous only when they are prevented from being incorporated into triglycerides, and the findings of Moustafa et al. show that liver injury can also occur if lipid droplets are unable to hold on to their triglyceride. Schwab and Maher conclude that these findings incriminate fatty acids as hepatotoxic compounds and support the concept that triglyceride synthesis in hepatocytes is a cytoprotective mechanism.

Although Abcb4−/− mice are a model of human cholestatic liver disease, it is not clear if the lipid-related abnormalities in these mice can be compared to those of patients—even patients with PFIC3. It will be important to determine whether patients with PFIC3 have the same reduction of hepatic triglycerides and increased triglyceride hydrolysis as Abcb4−/− mice. If so, these findings could lead to a new therapeutic approach for this disease.

Read the articles online:
Teratani T, Tomita K, Suzuki T, et al. A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology 2012;152–164.e10.

Moustafa T, Fickert P, Magnes C, et al. Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology 2012; 140–151.e12

Read the accompanying editorial.
Schwabe RF, Maher JJ. Lipids in liver disease: looking beyond steatosis. Gastroenterology 2012;8–11.

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New Hep C treatment available in Australia

AAP February 01, 2012 12:20AM

A RECENTLY developed treatment for the most common form of hepatitis C has been approved for use in Australia by the Therapeutic Goods Administration (TGA).

Victrelis, also known as boceprevir, comes from a group of drugs known as a protease inhibitors.

Scientists say it is an effective way to fight hepatitis C, genotype 1.

The director of the AW Morrow Gastroenterology and Liver Centre in Sydney, Professor Geoff McCaughan, says people who suffer from this strand of hepatitis C now have their first new treatment option in a decade.

"In the last ten years there has been little development in the availability of treatments for hepatitis C and a significant proportion of patients fail to respond to current standard of care." Professor McCaughan said in a statement.

"Victrelis is an approved treatment that works directly on the hepatitis C virus and prevents it from replicating and therefore reproducing."

He said this was a big step forward in the battle against hepatitis C, genotype 1.

"Unfortunately, hepatitis C is a silent disease where there is very little awareness of the condition and patients often present late with severe complications.

"Hepatitis C is a huge burden for individuals and is still very heavily stigmatised, and having another new treatment option marks progress in the management of patients with the disease."

Hepatitis C affects more than 200,000 Australians, with 20,000 new cases reported each year.

A spokeswoman for the TGA said now that Victrelis had been approved it had been released for public use.

The Pharmaceutical Benefits Scheme Committee is to consider listing the drug at its March meeting.

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