Durability of Sustained Response Shown in Paediatric Patients With Chronic Hepatitis C Who Were Treated With Interferon Alfa-2b Plus Ribavirin

From Journal of Viral Hepatitis

D. A. Kelly; B. Haber; R. P. González-Peralta; K. F. Murray; M. M. Jonas; J. P. Molleston; M. R. Narkewicz; F. R. Sinatra; T. Lang; A. Lachaux; S. Wirth; M. Shelton; H. S. Te; H. Pollack; W. Deng; S. Noviello; J. K. Albrecht

Posted: 05/07/2012; J Viral Hepat. 2012;19(4):263-270. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Summary. Long-term studies in adults indicate that sustained virologic response (SVR) after combination treatment for chronic hepatitis C (CHC) predicts long-term clearance. Although peginterferon plus ribavirin is now standard care for children with CHC, long-term follow-up studies are not yet available. This study evaluated durability of virologic response over 5 years in children previously treated with interferon alfa-2b plus ribavirin (IFN/R). Ninety-seven of 147 children with CHC, who were treated with IFN/R and completed the 6-month follow-up in two previous clinical trials, participated in this long-term follow-up study. All were assessed annually for up to 5 years; patients with SVR were assessed for durability of virologic response. Children with SVR (n = 56) and those with detectable hepatitis C virus (HCV) RNA 24-week post-treatment (n = 41) were followed for a median of 284 weeks. Overall, 70% (68/97) of patients completed the 5-year follow-up. One patient with genotype 1a CHC had SVR and relapsed at year 1 of follow-up with the same genotype. Kaplan–Meier estimate for sustained response at 5 years was 98% (95% CI: 95%, 100%). Six patients with low-positive HCV RNA levels (n = 4) or missing HCV RNA at the 24-week follow-up visit (n = 2) in the initial treatment studies had virologic response during this long-term follow-up study. Linear growth rate was impaired during treatment with rapid increases in the immediate 6 months post-treatment. Mean height percentile at the end of the 5-year follow-up was slightly less than the mean pretreatment height percentile. Five patients experienced serious adverse events; none related to study drug exposure. SVR after IFN/R predicts long-term clearance of HCV in paediatric patients; growth normalized in the majority of children during the long-term follow-up. Similar long-term results could be expected after peginterferon alfa-2b plus ribavirin treatment.

Introduction

The World Health Organization estimates the prevalence of hepatitis C virus (HCV) infection between 1.3% and 1.7% in Europe and the Americas.^[1] Seroprevalence of HCV among children is lower than in adults, with estimated rates of 0.1–0.4% in developed countries.^[2,3] Although chronic hepatitis C (CHC) is often benign in young children, the occurrence of fibrosis increases with age and duration of the disease.^[4] Thus, effective treatment of children with CHC may reduce the progression of liver disease in young adulthood.^[5] Studies using interferon (both nonpegylated and pegylated) plus ribavirin for 48 or 52 weeks in children and adolescents with CHC have yielded sustained virologic response (SVR) rates of 46–65%.^[6–11] However, the long-term safety of interferon (both nonpegylated and pegylated) plus ribavirin and durability of the virologic response in children are unknown and are essential outcome measures.

In a long-term follow-up study of adults with CHC who attained SVR after treatment with interferon alfa-2b with or without ribavirin, 99% remained virus free during the subsequent 5-year period.^[12] Similar findings were seen in adults previously treated with peginterferon alfa-2b plus ribavirin.^[13] These findings indicate that sustained loss of serum HCV RNA for 6 months after the end of treatment is an excellent predictor of long-term viral clearance in adult patients with CHC.

The durability of response has not been formally studied in the paediatric population. Although peginterferon plus ribavirin is currently the standard of care for the treatment of paediatric patients with CHC, there are no long-term data on safety or durability of virologic response. Thus, long-term data on children treated with interferon alfa-2b plus ribavirin are uniquely relevant. This study was designed to confirm long-term safety and durability of virologic response in paediatric patients with CHC who were previously treated with interferon alfa-2b plus ribavirin for 48 weeks.^[8]

Materials and Methods

Study Design

A phase 3b, multicentre, long-term, follow-up study of paediatric patients with CHC who were previously treated with interferon alfa-2b (Intron A®; Schering-Plough Corporation, now Merck & Co., Whitehouse Station, NJ, USA) 3 MIU/m² three times per week plus ribavirin (Rebetol®; Schering-Plough Corporation, now Merck & Co.) 8, 12, or 15 mg/kg/day for 48 weeks in two international clinical trials was conducted.^[8] The initial treatment studies allowed patients who had detectable HCV RNA levels at treatment week 24 to discontinue as treatment failures at the discretion of individual investigators. Patients who completed 24 weeks of follow-up after the end of treatment in the two clinical trials were eligible for enrolment. No study medications were administered to patients during the 5-year follow-up study.

Baseline data, including gastrointestinal/liver examinations, weight and height measurements, haematology, blood chemistry, and HCV RNA, were obtained from the 24-week follow-up visit in the initial treatment studies. Annual assessments for clinical evidence of liver disease progression and safety in all patients as well as virologic relapse in those who attained SVR in the initial treatment studies were performed for up to 5 years. A patient was considered to have an enduring SVR at a given time point if serum HCV RNA [by quantitative polymerase chain reaction (PCR)] was undetectable at that time point. A patient was considered to have relapsed if a single serum sample had detectable HCV RNA.

Polymerase chain reaction testing for HCV RNA was performed by Schering-Plough Research Institute using a proprietary TaqMan reverse transcriptase–PCR assay (lower limit of detection, <125 IU/mL) and by Quest Diagnostics, Nichols Institute, using the Roche COBAS TaqMan assay (lower limit of quantitation, <50 IU/mL).

The study was conducted in accordance with Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies.

Study Population

Paediatric patients (3–16 years of age) from 24 study sites (17 in the United States and seven international) who participated in one of two clinical trials were invited to enrol in the long-term, follow-up study.^[8] Patients who completed 24 weeks of follow-up in the initial treatment studies and whose parents or legal guardians provided informed consent prior to any study-related procedures were included. Patients were excluded if they were currently participating in any other clinical trial for treatment of CHC, if they had received antiviral retreatment for CHC after completing 24 weeks of follow-up in the initial treatment studies or if the investigator determined that the patient had any condition which would make him or her unsuitable for participation in the study. Patients were discontinued from the study if antiviral retreatment for CHC was administered, if the investigator determined that it was in the best interest of the patient or if the patient wished to withdraw.

Efficacy End Point

The primary efficacy end point was the assessment of the durability of SVR in paediatric patients with CHC who were previously treated with interferon alfa-2b plus ribavirin. Durability of SVR was assessed at 1 year after the week-24 follow-up visit of the initial treatment studies and then annually for the next 4 years.

Safety Assessments

Signs of clinical disease progression and safety were assessed for patients at 1 year after the week-24 follow-up visit of the initial treatment studies and then annually for the next 4 years. To assess for clinical disease progression, investigators examined patients for ascites, hepatomegaly, splenomegaly and liver tenderness. In addition to the physical exams and laboratory evaluations, height and weight measurements were collected. Growth measurements were converted electronically to an age- and gender-specific percentile according to the method developed by the Centers for Disease Control and Prevention.^[14] Growth velocities during the different study periods were compared with age- and gender-standardized norms for the US population. Growth velocity was calculated by regressing assessed height during the period over the day of assessed height from randomization. At least two height assessments at least 90 days apart were required in any period to calculate growth velocity. Growth velocity percentiles relative to those norms were determined to assess the impact of treatment on growth.^[14,15]

Results

Patient Disposition

Of the 166 patients who received interferon alfa-2b plus ribavirin in the two initial treatment studies, 147 (78 sustained responders and 69 treatment failures) completed 24 weeks of follow-up and were eligible for enrolment in the long-term follow-up study (Fig. 1). Enrolled patients (N = 97) had been treated with interferon alfa-2b (3 MIU/m²) three times per week plus ribavirin 8 mg/kg/day (n = 11), 12 mg/kg/day (n = 10) or 15 mg/kg/day (n = 76) at 16 study centres. Owing to the timing of the initial treatment studies and long-term study enrolment, the majority of the enrolled patients (54%, 52/97) were initially treated in the second study, the phase 3 trial.^[8] Of those enrolled in this long-term follow-up study, 58% (56/97) had attained SVR and 42% (41/97) of them had not attained SVR (Table 1). Therefore, 72% of sustained responders and 59% of treatment failures from the initial treatment studies entered this long-term follow-up study. In genotype 1, infected patients were 77% (75/97) of the study population, of whom 47% (35/75) had achieved SVR.

Figure 1. Patient disposition. Study 1, a phase 1 trial, includes patients who were treated with IFN alfa-2b plus RBV 8, 12 or 15 mg/kg/day and Study 2, a phase 3 trial, includes patients treated with IFN alfa-2b plus RBV 15 mg/kg/day.⁸

Duration of Long-term Follow-up

Overall, 70% (68/97) of patients completed the 5 years of long-term follow-up (Table 2). More patients who attained SVR (75%, 42/56) than those who did not attain SVR (63%, 26/41) in the initial treatment studies completed the long-term follow-up. One patient with detectable HCV RNA at the end of the initial treatment study was subsequently retreated with peginterferon alfa-2b and ribavirin and was therefore withdrawn from the long-term follow-up study.

Efficacy Evaluation

Durability of Response Of 56 patients who attained SVR, only one had virologic relapse during long-term follow-up, with detectable serum HCV RNA level of 3.6 million copies/mL at the year-1 annual evaluation. HCV genotype was 1a at initial infection and at relapse. This patient had received interferon alfa-2b plus ribavirin (15 mg/kg/day) and completed 48 weeks of treatment without any known dose reductions. The Kaplan–Meier point estimate (95% confidence intervals) for the likelihood of maintaining SVR at 5 years after the initial treatment studies was 98% (95%, 100%).

Alanine Aminotransferase Levels The majority (98%, 51/52) of patients who attained SVR and had normal alanine aminotransferase (ALT) levels at the 24-week follow-up of the initial treatment studies maintained normal ALT levels throughout their long-term follow-up visits. The remaining patient with SVR had an elevated ALT level during long-term follow-up (67 U/L at the year-5 visit) with hepatomegaly, possibly caused by obesity (body mass index of 37.1 kg/m²). The investigator did not consider this finding to be clinically significant. In addition, three patients who attained SVR but had abnormal ALT levels at week-24 follow-up visit had normalized ALT levels at their last long-term follow-up evaluation. ALT values in the long-term follow-up period were missing for one patient.

Treatment Failures Of the 41 patients who did not respond to therapy and who had detectable HCV RNA levels at the 24-week follow-up in the initial treatment studies, 26 (63%) completed the 5-year follow-up study. Among these 41 patients with treatment failure, 33 (80%) had ALT levels <2 times their baseline ALT level throughout the study; 7 (17%) had elevated ALT levels of at least two times their baseline level within the last 3 years of long-term follow-up, despite having ALT levels <2 times their baseline level at the 24-week follow-up visit in the initial treatment studies; and one had missing ALT levels.

Six patients who enrolled in the long-term follow-up study had been treated with interferon alfa-2b (3 MIU/m²) three times/week plus ribavirin 15 mg/kg/day in the initial treatment studies and were classified as treatment failures. Four of these patients had low detectable serum HCV RNA (125–250 copies/mL) at week-24 follow-up in the initial treatment studies although they had undetectable HCV RNA levels at week 24 during treatment and three of the four patients had undetectable HCV RNA levels at week 12 as well. These patients had undetectable serum HCV RNA and normal ALT values throughout the long-term follow-up study (4–5 years after completing treatment). The two remaining patients were defined as not having responded to therapy when they entered the long-term follow-up study because, although they had undetectable serum HCV RNA at their last visit in the initial treatment protocol, they did not have HCV RNA results available for the 24-week follow-up visit. However, their serum HCV RNA remained undetectable throughout the 5 years of long-term follow-up.

Safety Evaluation

In this long-term follow-up study, 5% (5/97) of patients reported a serious adverse event, all of which were considered unlikely to be related to previous treatment with interferon alfa-2b and ribavirin. The serious adverse events included a cardiac catheterization in a patient with a history of congenital heart disease, injury with loss of consciousness after tipping an all-terrain vehicle, contrast media reaction during magnetic resonance imaging, tooth abscess and depression with self-injurious ideation and drug abuse after an alleged sexual assault. No patients died during the study. During the initial treatment studies, 23 of the 118 patients reported severe adverse events, which included mainly neutropenia as well as more significant events of suicidal ideation (n = 3), attempted suicide (n = 1) and hypothyroidism requiring treatment (n = 3); one patient with hypothyroidism also developed diabetes mellitus.^[8] Of these seven patients with more significant events, five patients were followed for up to 5 years in this long-term follow-up study without further serious adverse events reported. Mean changes in haematologic parameters (haemoglobin, platelet and white blood cell counts) during treatment returned to normal levels at the end of the 24-week follow-up period and remained stable during the long-term follow-up study. No patient showed signs of clinical progression of hepatic disease.

Body Weight and Height During the initial treatment studies, weight loss occurred during treatment with compensatory weight gain during the 24-week follow-up and long-term follow-up (Table 3). The mean weight percentile, 60th percentile, for all patients at the end of the long-term follow-up was above their mean baseline weight percentile, 54th percentile, as well as the median for the US population.^[14]

The mean height percentile, 44th percentile, for all patients at the end of the long-term follow-up was slightly below the patients' mean pretreatment baseline height percentile, 48th percentile, and below the median for the US population (Table 3). Twenty (21%) patients had >15 height percentiles decrease from baseline to their last visit in the long-term follow-up period. Of these 20 patients, 10 patients had >30 percentiles decreases. Decreases in height of >15 percentiles were most common in patients treated with interferon alfa-2b plus ribavirin during their estimated period of peak growth velocity based on age [girls 9–12 years old (6/15, 40%) vs girls 3–8 and 13–16 years old (1/31, 3%); P = 0.001 and boys 11–14 years old (9/19, 47%) vs boys 3–10 and 15–16 years old (4/32, 13%); P = 0.006]. In contrast, 15 (15%) patients (girls 4–12 years old and boys 5–16 years old) had increases in height of >15 percentiles from baseline to their last visit in the long-term follow-up study.

Mean growth velocity (2.46 ± 2.48 cm/year) and mean growth velocity percentile (11 ± 22) were at their lowest during treatment (Table 3). During the 24-week follow-up period of the initial studies, both growth velocity and growth velocity percentile increased to levels above the median for the US population. Mean growth velocity during this period was 5.40 ± 4.13 cm/year, and mean growth velocity percentile increased to 62 ± 40. During the long-term follow-up period, mean growth velocity was 3.29 ± 2.74 cm/year, and mean growth velocity percentile was 36.7 ± 37.6.

Discussion

Chronic hepatitis C is a significant cause of liver disease and a frequent indication for liver transplantation in adults.^[16] Long-term follow-up studies in adult patients with CHC have shown that attainment of SVR (defined as undetectable HCV RNA at 24 weeks after the end of therapy) following treatment with interferon (nonpegylated and pegylated) with or without ribavirin therapy is durable and predictive of long-term clinical benefit.^[12,17–26] Results of this 5-year follow-up study confirm that the long-term outcome for children who achieved SVR with interferon alfa-2b and ribavirin treatment for CHC is consistent with that observed in adults. Overall, 98% (55/56) of paediatric patients who attained SVR maintained undetectable HCV RNA levels during the long-term follow-up period. In addition to maintaining undetectable HCV RNA levels, 98% of paediatric patients who attained SVR and had normal ALT levels following treatment maintained normal ALT levels at their last long-term follow-up visit. The high percentage of patients who maintained long-term undetectable HCV RNA levels and normalization of ALT confirm the durability of virologic response in this population of paediatric patients, highlighting the success of this therapy in children.

Although nonpegylated interferon plus ribavirin is no longer the standard of care treatment for CHC in children, long-term data on safety and durability of response of any interferon in this population are not yet available. This study of long-term response in children treated with interferon alfa-2b plus ribavirin demonstrates similar durability to that reported in adults and suggests that similar outcomes are likely in children treated with peginterferon plus ribavirin. In addition, this study provides data on decreases in growth during combination therapy and recovery post-treatment, which is of value in selecting children for CHC therapy.

The initial treatment studies indicated that 8% and 20% of patients had haemoglobin level <10 g/dL and/or neutropenia (<1000 cells/L), respectively, while on treatment they recovered to pretreatment levels after therapy.^[8] No evidence of latent effects of treatment with interferon alfa-2b and ribavirin on haematologic parameters was apparent. Additionally, no delayed serious adverse events related to previous interferon alfa-2b and ribavirin treatment during the 5-year follow-up period were reported.

Treatment with interferon alfa-2b has been shown to cause a temporary slowing of growth in paediatric patients.^[27] Growth analyses of the initial and long-term follow-up studies showed that treatment with interferon alfa-2b and ribavirin slowed patients' growth during treatment and that some patients did not return to their baseline height percentile when treatment was completed. The mean height percentile observed during the 5 years of follow-up was slightly below the mean pretreatment height percentile and the median for the US population, but the mean last weight percentile was above the median for the US population and mean pretreatment weight percentile. Although the largest decreases in height percentiles were mainly seen in patients treated during their estimated peak height velocity based on age, there is much variability in the timing and rate of growth during puberty between individuals, and growth charts only capture a certain standard. In addition, a major limitation of our observations regarding growth is the absence of parental height data that would provide perspective on the patients' estimated final target heights.

Observations regarding a temporary reduction in growth velocity have also been made in paediatric patients receiving peginterferon alfa-2b plus ribavirin. Jara et al. reported a reduction in growth of 1.6 cm compared with the growth velocity 50th percentile for age and sex in 22 of 26 paediatric patients receiving peginterferon alfa-2b plus ribavirin. Despite a return to normal growth velocity after the end of treatment, the authors reported that the modest decrease in height percentile that occurred during treatment was not regained during the 6-month follow-up period.^[9] In addition, Wirth et al.^[10] reported that the mean height percentile after the 24-week post-treatment follow-up period for 107 paediatric patients treated with peginterferon alfa-2b plus ribavirin was slightly lower than the median of the US population and below the mean pretreatment height percentile. The 5-year long-term follow-up of this study is ongoing. However, Sokal et al.^[28] reported no influence of peginterferon alfa-2a plus ribavirin therapy on height in 65 paediatric patients. The trends seen in growth after interferon and ribavirin therapy are not consistent.

The risk/benefit ratio between the possible slowing of growth in paediatric patients receiving interferon products and the clinical consequences if treatment is withheld or delayed must be considered when treating a child with CHC with these agents. Much variability in growth was seen in this population, but supporting data including parental heights, nutritional status, concurrent disease status and medications were not available to firmly assess the impact of treatment on growth in this population. The long-term effect on growth is being further studied in patients who underwent treatment with peginterferon alfa-2b and ribavirin, and will be available in coming years.

Spontaneous resolution of chronic HCV infection is rare in untreated children, whereas persistent viremia after infection is almost universal.^[5] The disease course varies, but most children show at least mild or moderate hepatic inflammation and a small proportion have steatosis.^[29] Rare cases of children with hepatitis C-related bridging fibrosis, decompensated cirrhosis and hepatocellular carcinoma have been reported.^[4,30–33] Delaying therapy until early adulthood may have less impact on growth but increases the risk of liver disease progression or the need for liver transplantation in the interim, which may impede attainment of SVR in later years. In contrast, early treatment with interferon alfa-2b plus ribavirin results in an enduring clinical cure in almost half of all treated paediatric patients. The possibility of successful viral clearance needs to be weighed against the reported adverse events in children, which are largely consistent with the well-described tolerability profile among adult patients with hepatitis C receiving interferon alfa-2b (nonpegylated or pegylated) plus ribavirin.^[8] Thus, the arguments for withholding therapy from paediatric patients may be outweighed by the benefits of early viral eradication and the potential difficulties that may be incurred if treatment is delayed until the course of disease is further advanced. In addition, peginterferon alfa plus ribavirin treatment has shown improvement in therapeutic outcome among paediatric patients with CHC and is likely to demonstrate similar durability.^[10,11]

In conclusion, results of this 5-year follow-up study confirm that sustained loss of serum HCV RNA 24 weeks after the end of treatment with interferon alfa-2b plus ribavirin is predictive of long-term virologic response in paediatric patients. Most children had normalized (within 15 percentiles of pretreatment height) or improved growth during this 5-year long-term follow-up, although their mean height percentile at their last long-term follow-up visit was slightly below their mean pretreatment height. The findings of this study support the future treatment of paediatric patients with hepatitis C to prevent progression of liver disease.

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Source

Boceprevir in Chronic Hepatitis C Infection

From Therapeutic Advances in Chronic Disease

A Perspective Review

Antonio Ascione MD

Posted: 05/07/2012; Ther Adv Chronic Dis. 2012;3(3):113-121. © 2012 Sage Publications, Inc.

Abstract and Introduction

Abstract

Boceprevir (Victrelis), from the oral α-ketoamide class of slow-binding reversible hepatitis C virus (HCV)-NS3 protease inhibitors, creates a new class of drugs: direct acting antivirals (DDAs). Boceprevir is highly selective against HCV serine protease. Its use is restricted to genotype 1 HCV infection and it must not be used as monotherapy. Boceprevir is given orally, rapidly absorbed, reaching plasma peak concentration within 1–2 h and is metabolized by aldo-ketoreductase and partly by the cytochrome P450 enzyme CYP3A4/5. Administration with drugs that induce or inhibit CYP3A4/5 could decrease or increase its plasma concentration. The optimal dosage is 800 mg three times daily; capsules should be taken with food. Boceprevir was approved by the US Food and Drug Administration and the European Medicines Agency and is indicated in combination with peginterferon plus ribavirin for the treatment of patients with genotype 1 HCV who have not received previous treatment or whose condition has failed to respond to previous therapy. In the Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial (treatment-naïve patients) and RESPOND-2 trial (patients whose condition relapsed or did not respond to previous treatment), the boceprevir-containing regimen was always more effective than standard of care (SOC). Adverse events were similar in the treatment groups, but in the boceprevir treated group, anemia was more frequent, requiring erythropoietin in nearly 40% of cases. Discontinuation of therapy because of adverse events was identical in all treated groups. As for cost effectiveness, two studies showed that boceprevir plus SOC is cost effective with regard to the lifetime incidence of liver complications, quality of life years, and the incremental cost-effectiveness ratio. The management of this therapy is more complex than before for physicians and patients. The educational role of the physician is crucial for successful therapy and counseling should be carefully given, especially for adherence to the assigned treatment.

Introduction

Any new therapy for the treatment of hepatitis C virus (HCV) infection is certainly welcome [Jensen and Ascione, 2008]. There are at least two reasons for saying this: over 180 million people worldwide are affected by HCV chronic liver disease with an ominous outcome in nearly 20% after a very long, asymptomatic period lasting as long as 20–30 years [Craxi et al. 2008]; and the results of therapy in genotype 1 HCV infection in particular are not exciting. According to recently published data, the eradication of viral replication [i.e. HCV-RNA negative 24 weeks after the end of therapy, defined as a sustained virological response (SVR)] in genotype 1 naïve patients ranges from 40.9% to 55% [McHutchison et al. 2009; Rumi et al. 2010; Ascione et al. 2010], which is not very satisfactory. Moreover, if we analyze the group of patients with advanced fibrosis or cirrhosis, the SVR is even worse (30–42%). However, after more than 10 years in which peginterferon (pegINF) α-2a/2b plus ribavirin were the standard of care (SOC), two new antiviral molecules have recently been approved in the USA and Europe: boceprevir and telaprevir. With the approval of these two drugs, a new era of better results in HCV treatment will begin [Jensen, 2011]. Although treatment with these drugs is currently restricted to genotype 1 infection, the SVR in naïve patients and in those whose condition relapsed or did not respond to previous treatment is much higher compared with SOC. There are many other drugs under investigation that showed in vitro and in vivo antiviral activity, creating a new class: direct acting antivirals (DAAs). However, many of these drugs are in phase I or II studies, and a few are in phase III studies, and so there is still a long way to go before they can potentially receive approval from the regulatory authorities.

This review is restricted to boceprevir (Victrelis), from the oral α-ketoamide class of slow-binding reversible HCV-NS3 protease inhibitors, which showed no cross reactivity with other serine proteases and no major interactions with other general enzymes. This compound is highly selective against the HCV serine protease. From the beginning, this drug has shown good performance in stopping viral replication and in inhibiting the HCV life cycle in vitro and in vivo. The drug is given orally and is rapidly absorbed, reaching the plasma peak concentration within 1–2 h, with an elimination half life of between 7 and 15 h [Boceprevir, 2010; Foote et al. 2011]. Boceprevir is metabolized by aldo-ketoreductase and partly by the cytochrome P450 enzyme, CYP3A4/5. Therefore, administration of boceprevir with drugs that induce or inhibit CYP3A4/5 could decrease or increase the plasma concentration of boceprevir and significantly interfere with the metabolism of many drugs currently used in clinical practice. We will return to this point later. The optimal dosage has been fixed at 800 mg three times daily; the optimal interval between doses is 7–9 h and the capsules should be taken with food. A big meal is not necessary, a snack is sufficient. In clinical practice, since the capsules are 200 mg each, four capsules should be administered every 8 h. Therefore, the patient should take 12 capsules of boceprevir plus five or six of ribavirin each day. This could cause problems with compliance, but currently, not only for boceprevir, there is no simpler therapy. Careful monitoring of adherence to therapy is required, and patients should be informed about the importance of taking medication diligently. Boceprevir was approved by the US Food and Drug Administration in May 2011. It is indicated in combination with pegIFN plus ribavirin for the treatment of patients with genotype 1 HCV who have received no previous treatment or whose condition has failed to respond to previous treatment. The European Medicines Agency approved boceprevir in July 2011 for use in the European Union, with the same indications. Boceprevir capsules contain lactose, as excipient. Patients with problems of galactose intolerance, lactase deficiency, or glucose or galactose malabsorption should avoid taking this drug (Victrelis, 2011).

Boceprevir in Treatment-naïve Patients

The SPRINT-2 Trial

In treatment-naïve patients, the final study was published some months ago, called SPRINT-2 (Serine Protease Inhibitor Therapy 2) [Poordad et al. 2011a]. The aim of this phase III study was to verify the safety and efficacy of boceprevir in combination with pegIFN α-2b plus ribavirin. This study was an international, randomized, double-blind, placebo-controlled trial, enrolling two cohorts of adult patients: 938 nonblack and 159 black patients. Those who met the inclusion criteria were randomized into three groups after4 weeks of SOC (lead-in phase). After this phase, group 1 patients were treated for a further 44 weeks with SOC plus placebo (control group); group 2 received SOC plus boceprevir and the therapy was continued for 28 weeks. After this period, those who were HCV-RNA negative at week 8 (4 weeks of SOC plus 4 weeks of boceprevir) and at week 28 stopped treatment [response-guided therapy (RGT) group], while those who were HCV-RNA positive at any time between week 8 and week 24 continued to receive SOC plus placebo. In the third group, after the lead-in phase, the triple therapy was continued from week 5 to week 48. Treatment was stopped in all three groups if HCV-RNA was still positive at week 24. The therapeutic regimen was pegINF α-2b given subcutaneously weekly at one dose of 1.5 μg/kg body weight; ribavirin was administered orally at a dose of 600–1400 mg daily, according to body weight; and boceprevir was given at a dose of 800 mg three times daily. The SVR was as follows in the nonblack population (938 patients): SOC, 40%; group 2, 67%; while in the third group there was success in 68%. In the group of 159 black patients the SVR was 23%, 42%, and 53%, respectively. It is quite interesting that in the RGT group, those who were eligible for 28-week treatment had an SVR of 97% (nonblack) and 87% (black). Although this subgroup is not very large, even when using the triple therapy, the rapid response is a factor highly predictive of SVR. In the two cohorts considered together, the relapse rate was 22% in group 1 and 9% in each of the remaining two groups. The difference was statistically significant. The results were statistically better when compared black versus nonblack population. In the all-treated population, the boceprevir-containing regimen was always more effective than SOC. Even with triple therapy,as in SOC, there are different responses due to racial differences which must be considered in subsequent studies. However, there are many other predictive factors that may affect the response to the triple therapy. We will come back to this later.

Boceprevir in Patients Who Were Previously Treated but did not Achieve Sustained Virological Response

The RESPOND-2 Trial

The purpose of the RESPOND-2 trial (ClinicalTrials.gov number NCT00708500) was to evaluate treatment response in patients who did not achieve SVR after a cycle of SOC [Bacon et al. 2011]. A total of 403 patients whose condition had relapsed or not responded to previous treatment were enrolled with a randomization scheme of 1:2:2 (80 in group 1 as control, 162 in group 2, and 161 in group 3). The therapeutic regimen was the same as in SPRINT-2. All groups started with SOC for 4 weeks (lead-in phase). After that, group 1 (control) received SOC plus placebo for a further 44 weeks; group 2 (RGT) received SOC plus boceprevir for a further 32 weeks; and group 3 received SOC plus boceprevir for a further 44 weeks. Group 2 patients stopped treatment at week 36 if they were HCV-RNA negative at weeks 8 and 12; however, if HCV-RNA was positive at week 8 but undetectable at week 12, the treatment continued with SOC and placebo until week 48. In all three groups, treatment was considered to have failed in patients with detectable HCV-RNA at week 12 and the therapy was stopped. The SVR was 21% in the control group, while it was 59% in group 2 and 66% in group 3. Considering the results of previous treatment, patients whose condition relapsed had an SVR of 29% in group 1, 69% in group 2, and 75% in group 3, while those whose condition did not respond to prior treatment obtained an SVR of 7% in the control group, 40% in group 2, and 52% in group 3. Here again, in all the treated population, the boceprevir-containing regimen was always more effective than SOC and the results were statistically significant. It is important to note that a relatively lower SVR was seen in patients whose condition showed a poor response to SOC during the lead-in period (i.e. decrease in HCV-RNA of less than 1 log₁₀): 0% in group 1, 33% in group 2, and 34% in group 3. The rate of SVR was found to be very different in those whose condition showed a better response to SOC during the lead-in period (decrease in HCV-RNA of 1 log₁₀ or more) reaching 25% in group 1, 73% in group 2, and 79% in group 3. The relapse rate was 32% in group 1, 15% in group 2, and 12% in group 3. In this group of patients, viral monitoring is crucial because there is no point in continuing therapy if at week 12 there is no decrease in HCV-RNA. Viral breakthrough (HCV-RNA detectable after a period of undetectability while on therapy) was very uncommon: 1% in group 1, 6% in group 2, and 4% in group 3.

The PROVIDE Study

In RESPOND-2, patients with a null response to previous treatment failure were excluded. The aim of the PROVIDE study was to understand if boceprevir could improve SVR in this category of patients [Vierling et al. 2011]. The patients with a null response who were dropped from SPRINT-2 and RESPOND-2 were enrolled in this prospective study. The number of patients was relatively small at 46. The treatment was based on boceprevir plus SOC for 44 weeks, after the lead-in phase. A total of 41% achieved HCV-RNA negativity at the end of therapy, but the study is in progress and we do not know how many patients will achieve a SVR. Despite that, this result is remarkable in null responders who are the patients most difficult to treat.

Practical Considerations

HCV-RNA Measurement

Measurement of HCV-RNA is a critical issue in the management of this new antiviral therapy. The physician must ask the laboratory to use a test with the highest sensitivity otherwise there is a real risk of making the wrong decision. In fact, using the RGT approach, patients may be classified incorrectly, with the result that they may receive less prolonged therapy with less SVR [Lawitz et al. 2011]. However, the RGT approach is also important because we can significantly reduce the risk of side effects and decrease costs. Another critical factor is the time that the laboratory takes to provide the results of HCV-RNA tests. Many institutions have difficulties because sometimes laboratories take up to 2 weeks to provide the data. It is important, therefore, to ask the laboratory to be very quick in providing the results for these tests.

The studies described above have taught us many things and created a new perspective in the treatment of patients with genotype 1 HCV – those who are treatment naïve and those whose condition has not responded to treatment or whose condition has relapsed. At present, triple therapy has no indication for any other genotype and therapy based on pegINF α plus ribavirin remains the cornerstone for the treatment of all the other genotypes. Moreover, boceprevir must not be used alone due to the high probability of emerging resistance when it is not combined with SOC. In addition, boceprevir must not be used in patients under the age of 18 as it has not been tested in this patient group.

Optimizing Treatment

It is very important to follow the recommendations for stopping treatment: all therapy must stop if HCV-RNA is equal to or more than 100 IU/ml at week 12 and if it is still detectable at week 24 [Jacobson et al. 2011]. In this way we can avoid side effects and, above all, the onset of mutation that may induce resistance to future therapies.

It is now well established that, at least for genotype 1, we have a new SOC, however the lead-in phase could give the hepatologist some insight on how to proceed further. It is quite clear that if the patient is young (up to 40 years old, with no advanced fibrosis or cirrhosis, with basal HCV-RNA of less 400.00 IU/ml and no comorbidities) it is likely they will achieve an SVR. The difficulties in managing this therapy are more complex than before for physicians and patients. Physicians should carefully follow the recommendations for stopping treatment, appropriately manage any adverse events, ensure the laboratories use the most sensitive systems to detect HCV-RNA, give patients advice, especially on how to administer medications, and inform them that perfect adherence to the treatment program is essential to avoid mutations and maximize the result.

The educational role of the physician is crucial for successful therapy and counseling should also be carefully given. First, because patients need to take boceprevir every 8 h (range 7–9) with food, in clinical practice it is possible that a dose may be missed. If a patient forgets to take a dose, it is important to establish whether the time until the next dose is less than or more than 2 h. If it is less than 2 h, the missed dose should not be taken. If it is more than 2 h before the next dose, then the missed dose should be taken and the normal schedule resumed. The patient must be advised before starting therapy and during therapy not to take drugs that may interact with boceprevir. Many patients have taken 'herbs' for various conditions (constipation, insomnia, nervousness) for years and they do not feel that they are taking 'drugs' that could affect treatment. In our experience, during antiviral treatment, 13% of patients took this kind of remedy (personal trial in progress). Patients should be warned not to do so because we do not know how they will interact with the prescribed drugs.

Predictors of Response

Some of the findings from the SPRINT-2 and RESPOND-2 trials confirm what we already knew from using SOC for more than 10 years. Some factors continue to be relevant for successful therapy, such as race (although less relevant with triple therapy), age of the patient (young patients respond better, but few patients over 65 have been included in the trials), baseline HCV-RNA (the lower the better; although this aspect is still relevant, triple therapy has reduced the basal viral load weight) [Gordon et al. 2011], and the absence of significant fibrosis. In SPRINT-2, patients with fibrosis grade F0–F2 had a good response rate: SVR was 38% in the control group and 67% in the two boceprevir-treated groups (p < 0.001). In patients with advanced fibrosis or cirrhosis the SVR was 38% in group 1 (control), 41% in group 2 and 52% in group 3 (this difference was not statistically significant).

The RESPOND-2 trial has given encouraging results, which is particularly relevant in practice because the patients enrolled in this trial were taken from our busy clinics. In patients whose condition had not responded to prior therapy, the SVR in those with minimal fibrosis (F0–F2) was 9% in the SOC group, and from 47% to 55% in the two boceprevir-treated groups. In the group of patients with advanced fibrosis or cirrhosis the results were 13% in the control group, 44% in group 2, and 68% in group 3, reaching 90% in patients with undetectable HCV-RNA at week 8. In this analysis, the patients who received boceprevir for 48 weeks did much better than those treated in the RGT group (group 2 in both trials). But it is important to note that, although these results are very encouraging, the number of patients enrolled in this retrospective subanalysis was small and the population was not stratified according to Metavir score at enrollment into the study [Bruno et al. 2011]. A randomized controlled trial should be performed in this group of patients to understand the true benefit of this regimen. For the time being, a trial of triple therapy is indicated and it appears ethically justified and correct to give hope to these patients with no further treatment options at present. The results in terms of SVR in this trial again confirm the great importance of the decline in viral load at week 4 and negativity at week 8, and the role of these measures as favorable and strong predictive factors.

Fibrosis Assessment

Because the assessment of fibrosis grade is crucial, it is important to ask how we can assess fibrosis in clinical practice. In registration trials, liver biopsy was mandatory, but 'at the bedside' the story is different. Personally speaking, the author has in 40 years of clinical practice met only one patient who enthusiastically agreed to receive a needle in the liver. Nowadays noninvasive methods can be used (clinical examination, biochemistry, ultrasound, liver stiffness measurement and upper gastrointestinal endoscopy) to obtain a good staging of the disease, as suggested by the European Association for the Study of the Liver (EASL) guidelines recently published [EASL, 2011]. In the setting of HCV chronic liver disease, it is very rare in clinical practice that liver biopsy helps in determining the utility or the treatment strategy [Almasio et al. 2005].

Viral Response to Therapy

Another important finding from the boceprevir trials is that the treatment period could be shortened if the viral response is quick and complete. Cumulative data from SPRINT-2 demonstrate that patients with undetectable HCV-RNA at weeks 8 and 24 could stop treatment at week 28 (considering the lead-in period) with a 97% SVR rate, while those with detectable HCV-RNA at week 8 but undetectable at week 24 had an SVR of 74%. Those who had to stop treatment for any reason (detectable HCV-RNA at week 24, adverse events, personal choice, etc.) and had treatment for less than 28 weeks achieved an SVR of 15%. Unfortunately, patients in the group with rapid response accounted for 44%, while 22% were HCV-RNA negative only at week 24 and 33% had to discontinue therapy.

In the RESPOND-2 trial, the decision to reduce the treatment period in the RGT group was taken at week 8 (SOC for 4 weeks plus triple therapy for a further 4 weeks) for those with undetectable HCV-RNA. This group had the highest SVR rate: 100% in group 1 (only seven patients in this group), 86% in group 2 (74 patients), and 88% in group 3 (84 patients). The difference between groups 2 and 3 was not statistically significant. Even with detectable HCV-RNA at week 8 but a reduction in viral replication of more than 1 log₁₀, the SVR was quite good: 25% in the control group, 73% in group 2, and 79% in group 3. This difference is not statistically significant. The message from both studies seems to be that if the response is rapid, the treatment period can be safely reduced without losing effect in both treatment-naïve patients and those whose condition has previously relapsed or not responded to treatment. In boceprevir-treated patients, negative HCV-RNA at week 8 seems to be the strongest predictive factor of successful therapy.

Other Predictors of Response

Other predictors of response have been established during SOC therapy over the years, however some of them will be less relevant to triple therapy, especially for patients who received treatment in the past and showed poor response to SOC. Among the predictors of response to triple therapy, we have already analyzed some individual characteristics of patients but baseline viral load and fibrosis or cirrhosis appear to be the most relevant for determining SVR. The decline in HCV-RNA levels while on therapy is one of the most important factors affecting final viral eradication [Bacon et al. 2011]. Among the predictive response factors, the interleukin (IL)-28B genotype also has great importance in boceprevir therapy [Poordad et al. 2011b]. In SPRINT-2 and RESPOND-2, despite the CC genotype showing a good correlation with SVR, when the virological response at week 4 was introduced into a multiple stepwise logistic regression model, IL-28B was no longer a strong predictor of response. However, these data should be analyzed with caution because this is a retrospective analysis, IL-28B genotyping was not available for all patients in the two studies, and the numbers are quite small in some subgroups. However, despite all the caveats described above, in the RESPOND-2 trial, people with a favorable genotype (CC) reported an SVR of nearly 80% in all boceprevir-treated groups, and those with an unfavorable genotype (CT) had an SVR of 61% and 73% in the triple therapy groups, while those treated with SOC reported an SVR of 17%. Therefore, at this stage we cannot tell patients that they have a less favorable outcome on the basis of IL-28B – this applies to patients who are treatment naïve and, especially, those whose condition has failed to respond to previous treatment. Further studies are necessary.

Another interesting and intriguing observation is that ribavirin is still essential in this type of treatment. In the SPRINT-1 study, an arm was included with low-dose ribavirin due to anemia [Kwo et al. 2010]. The SVR was reduced in this arm (less than 14%) in comparison with patients taking the standard ribavirin dose. Although we do not know exactly how ribavirin works, in new therapy protocols it is important to maintain the ribavirin dose and reduce it by only 200 mg, unless the initial dose is 1400 mg. Moreover, anemia appears to be associated with SVR for pegINF plus ribavirin and when boceprevir is added to pegINF plus ribavirin. Thus, maximizing the ribavirin dose allows anemia to be a pharmacodynamic marker of ribavirin exposure. This observation was also observed in in vitro studies of protease inhibitors [Hofmann al. 2011]. So, the mystery of ribavirin continues [Brillanti et al. 2011].

HCV Subtypes

Triple therapy has changed our opinion on the response rate of HCV subtype 1a versus 1b. Data from a multicenter Italian study [Alberti et al. 2007] in more than 1000 patients show that SOC gives an SVR of 51% for subtype 1a versus 38% for 1b (p = 0.01). The same situation has been reported in the control arm of the boceprevir trials: 1a achieves an SVR of 23.9% versus 17.6% for 1b. However, when the results obtained in the two groups of boceprevir-treated patients are analyzed, the SVR in group 2 is 53.2% in 1a and 66.7% in 1b; and in group 3 the percentage is 63.5% in 1a and 70.5% in 1b. These results also highlight the fact that old ideas need to be forgotten and there is a need to understand how to manage patients with the new antiviral treatment.

Another important difference between subtypes 1a and 1b is that resistance is more frequent in subtype 1a, and double mutation has nearly always been reported in subtype 1a. Also, the variants in the two subtypes are different. Analyses of data from SPRINT-2 and RESPOND-2 showed that the patterns of boceprevir resistance variants are different in the two genotype 1 subtypes. In 1a the commonest variants were found to be V36M, T54S, and R155K, while in 1b, T54A/S, V55A, A156S, and l/V170A were more frequent [Ogert et al. 2011]. More data are necessary to understand the true meaning of these variations, however the wild-type virus emerges sooner or later when therapy is stopped [Barnard et al. 2011]. We must remember that we are dealing with the first generation of protease inhibitors with quite a low genetic barrier. Also, a certain percentage of patients (approximately 10%) have variants resistant to treatment before the start of therapy, although this does not seem to preclude successful treatment. The tools for monitoring resistance are not commercially available – they are only available to research centers and cannot be used in clinical settings for therapeutic decisions. In addition, there are many systems for detecting variants but they all have some kind of problem in terms of sensitivity, specificity, standardization, possibility of automatization and cost [Halfon and Locarnini, 2011]. In conclusion, we need more data in order to understand these mutations and whether there is any cross reaction among the other DAAs.

Contraindications and Drug Interactions

Contraindications for boceprevir-based triple therapy are the same as those for SOC: decompensated liver disease, decompensated metabolic diseases, pregnancy, autoimmune disease, and any kind of serious/life-threatening chronic disease of other organs (kidney, heart, and lung). A negative pregnancy test before therapy and monthly during therapy should be mandatory during SOC. Obviously, a system of contraception must be used during therapy by both partners, bearing in mind that there are no data on administration of SOC with oral contraceptives.

There are some specific contraindications related to boceprevir as detailed by the manufacturer, such as administration with medicines that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious or life-threatening events. This warning is due to the observation that boceprevir is a strong inhibitor of CYP3A4/5. Drugs metabolized primarily by CYP3A4/5 may have increased exposure when administered with boceprevir, which could increase or prolong their therapeutic and adverse effects. These drugs are orally administered midazolam, amiodarone, bepridil, ergot derivatives (dihydroergotamine, ergotamine, methylergonovine), flecainide, pimozide, propafenone, and quinidine. In clinical practice, these drugs should not be used during therapy. For other drugs widely used in clinical practice there are no data available, for example, oral contraceptives, opioids (methadone, buprenorphine), immunosuppressants, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, rifampicin, and hypericum. However, medications taken by patients during participation in the SPRINT-1, SPRINT-2, and RESPOND-2 trials were analyzed and the results were encouraging because there were no adverse effects (including no severe adverse effects) [Poordad et al. 2011c]. Therefore, the physician's level of attention must be high, especially when the drug can be freely used.

Adverse Effects

So far, we have examined the results in terms of elimination of viral replication and there is no doubt that regimens that include boceprevir produce much better eradication rates than SOC in different types of patients. But what is the cost?

When considering any kind of adverse event, there are no differences among all treated groups and all studies done so far. Nearly 100% of treated patients have some kind of side effect in SOC and in boceprevir groups. Even when serious adverse events are considered, there are no significant differences between groups (SOC 9%, boceprevir 12%), and only 1%, equally distributed in all groups, had life-threatening adverse events. Erythema at injection site, influenza-like syndrome, pyrexia, asthenia, fatigue, myalgia, arthralgia, nausea, insomnia, irritability, depression, and anxiety were not statistically different in patients treated with SOC compared with boceprevir-treated groups. However, triple therapy showed a good safety profile [Flamm et al. 2011; Manns et al. 2011]. The most important statistically significant differences in patients treated with boceprevir compared with those treated with SOC were reported for anemia (p < 0.001), drop in neutrophil count between 500 and 750/mm³ (p < 0.001) [Reddy et al. 2011], and the use of erythropoietin (EPO) (24% in the SOC group versus 43% in the boceprevir group, p < 0.001). The need for red blood cell transfusion was more frequent in boceprevir-treated patients, but only in the group treated for 44 weeks versus SOC; the difference was statistically significant (p = 0.006). How can we manage anemia? Traditionally, during SOC, we reduced ribavirin in steps of 200 mg and then watched and waited, but this action clearly depends on two aspects: symptoms and decreased hemoglobin levels. We already know that this policy might not be enough in patients treated with triple therapy, especially in those taking the drugs for 44 weeks. Reducing boceprevir dosage would not help because of the pharmacokinetic and pharmacodynamic properties of the drug [Stone et al. 2011]. One emerging finding that may explain the decrease in hemoglobin levels has recently been confirmed and involves inosine triphospatase activity. Patients with a deficiency of this enzyme have reduced anemia and less need for EPO [Sulkowski et al. 2011]. There is no doubt that, in patients with hemoglobin levels less than 10 g/dl, EPO should start at a dose of 40,000 units weekly and then hemoglobin levels should be checked weekly. A recent meta-analysis clearly demonstrated that administration of EPO results in a higher SVR rate than the reduction in dose of ribavirin to correct anemia [Alavian et al. 2012]. When the hemoglobin level increases, EPO must be reduced according to the levels reached. Close monitoring is necessary. Although a drop in hemoglobin to below 6.5 g/dl was found to be rare, it is necessary to give a blood transfusion in these cases.

Two other relevant adverse effects for treated patients were dysgeusia (11% in the SOC group, 37–45% in the boceprevir-treated groups, p < 0.001) and dry skin, but again the difference was statistically significant only when the SOC group was compared with the group of patients treated for the longest period of time. Discontinuation of therapy rates because of adverse events in SPRINT-2 were identical in all treated groups, while in RESPOND-2 discontinuation was necessary in 2% of the control group, 8% in group 2, and 12% in group 3. Here again, as was expected, the group treated for a prolonged period of time had more problems compared with the SOC and RGT groups. As for side effects, the risk–benefit ratio is in favor of boceprevir therapy.

Cost Effectiveness

Finally, at a time of global economic crisis, we cannot ignore the cost effectiveness of any drug. Recently, two studies reported on SOC and boceprevir therapy in treatment-naïve patients and those whose condition had relapsed or not responded to previous treatment. Both studies showed that boceprevir plus SOC is cost effective when considering the lifetime incidence of liver complications, quality-adjusted life years and the incremental cost-effectiveness ratio [Ferrante et al. 2011; Chhatwal et al. 2011].

Conclusion

Triple-based therapy with DAA drugs, such as boceprevir, heralds a new approach to HCV genotype 1 treatment. The SPRINT-2 and RESPOND-2 studies in treatment-naïve patients and those whose condition had relapsed or not responded to previous treatment provide new hope for the successful treatment of chronic hepatitis C with boceprevir-based triple therapy in genotype 1 HCV infection.

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11. Chhatwal, J., Ferrante, S.A., Dasbach, E.J., El Khoury, A., Brass, C.A., Burroughs, M. et al. (2011) Cost-effectiveness of boceprevir use in patients with chronic hepatitis C genotype-1 who failed prior treatment with peginterferon/ribavirin. Hepatology 54 (Suppl.): 801A.
12. Craxi, A., Almasio, P.L., Ingrassia, D., Ascione, A. and Di Costanzo, G.G. (2008) The natural history of HCV infection: a systematic review. In: Buti, M. and Esteban, R. (eds), BC)VH Viral Hepatitis(pp. 250-266). Madrid: AG RUPEM S. Coop.
13. EASL (2011) Clinical practice guidelines: management of hepatitis C virus infection. J Hepatol 55: 245–264.
14. Ferrante, S.A., Chhatwal, J., Elbasha, E., Dasbach, E.J., El Khoury, A., Poordad, F. et al. (2011) Cost-effectiveness of boceprevir based regimens in previously untreated adult subjects with chronic hepatitis C genotype 1. Hepatology 54 (Suppl.): 795A.
15. Flamm, S.L., Lawitz, E., Jacobson, I.M., Bourliere, M., Hezode C., Vierling, J.M. et al. (2011) Overall safety profile of boceprevir (BOC) plus peginterferon alfa-2a/ribavirin in genotype 1 previous non-responders and relapsers to peginterferon/ribavirin. Hepatology 54 (Suppl.):838A.
16. Foote, B.C., Spooner, L.M. and Belliveau, P.P. (2011) Boceprevir: a protease inhibitor for the treatment of chronic hepatitis C. Ann Pharmacother 45: 1085–1093.
17. Gordon, S.C., Reddy, K., McCone, J., Jacobson, I.M., Esteban, R., Pedicone, L. et al. (2011) Effect of baseline viral load (VL) on response to boceprevir (BOC) plus peginterferon alfa-2b/ribavirin (PR) in patients infected with HCV genotype 1. Hepatology 54 (Suppl.): 812A.
18. Halfon, P. and Locarnini, S. (2011) Hepatitis C virus resistance to protease inhibitors. J Hepatol 55: 192–206.
19. Hofmann, W.P., Chung, T.L., Osbahr, C., Susser, S., Karey, U., Mihm, U. et al. (2011) Impact of ribavirin on HCV replicon RNA decline during treatment with interferon-α and the protease inhibitors boceprevir or telaprevir. Antivir Ther 16: 695–704.
20. Jacobson, I.M., Marcellin, P., Zeuzem, S., Sulkowski, M.S., Esteban, R., Pedicone, L. et al. (2011) Treatment week 12/24 stopping rules for boceprevir (BOC) combination therapy with peginterferon+ribavirin (PR): exploratory analyses of SPRINT-2 and RESPOND-2. Hepatology 54 (4 Suppl): 808A.
21. Jensen, D.M. (2011) A new therapy era of hepatitis C therapy begins. N Engl J Med 364: 1272–1274.
22. Jensen, D.M. and Ascione, A. (2008) Future directions in therapy for chronic hepatitis C. Antivir Ther 13 (Suppl. 1): 31–36.
23. Kwo, P.Y., Lawitz, E.J., McCone, J., Schiff, E.R., Vierling, J.M., Pound, D. et al. (2010) Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment naïve patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 376: 705–716.
24. Lawitz, E., Poordad, F., Bronowicki, J., Marcellin, P., Feinman, V.S., Kwo P.Y. et al. (2011) The effect of using lower limit of quantitation (LLQ) vs lower limit of detection (LLD) for the definition of undetectable HCV RNA: data from the RESPOND-2 and SPINT-2 trials. Hepatology 54 (Suppl.): 442A.
25. Manns, M.P., McCone, J., Davis, M., Shiffman, M.L., Rossaro L., Bourliere, M. et al. (2011) Safety benefits of response-guided therapy with boceprevir (BOC) plus peginterferon alfa – 2b/ribavirin (PR) in previously untreated patients with HCV genotype 1 infection. Hepatology 54 (Suppl.): 813A.
26. McHutchison, J.G., Lawitz, E.J., Shiffman, M.L., Muir, A.J., Galler, G.W., McCone, J. et al. (2009) Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 361: 580–593.
27. Ogert, R.A., McMonagle, P., Black, S., Curry, S., Guo, Z., Lesburg, C. et al. (2011) Genotypic and phenotypic correlates of resistance in HCV genotype 1a and 1b infected patients treated with boceprevir plus peginterferon alpha and ribavirin. Hepatology 54 (Suppl.): 794A.
28. Poordad, F., Bronowicki, J.-P., Gordon, S.C., Zeuzem, S., Jacobson, I.M., Sulkowski, M.S.,et al. (2011c) Il28b Polymorphism predicts virologic response in patients with hepatitis C genotype 1 treated with boceprevir (Boc) combination therapy. J Hepatol 54 (Suppl. 1): S6.
29. Poordad, F., Lawitz, E., Gordon, S.C., Bourli, M., Vierling J.M., Poynard, T. et al. (2011b) Concomitant medication use in patients with hepatitis c genotype 1 treated with boceprevir (BOC) combination therapy. Hepatology 54 (Suppl.): 799A.
30. Poordad, F., McCone, J., Jr, Bacon, B.R., Bruno, S., Manns, M.P., Sulkowski, M.S. et al. (2011a) Boceprevir for untreated chronic HCV genotype 1. N Engl J Med 364: 1195–1206.
31. Reddy, K., Nunes, F., Balart, L.A., Sjogren, R., Pedicone, L., Burroughs, M. et al. (2011) An evaluation of neutropenia in the pivotal studies of boceprevir (BOC) plus peginterferonalfa – 2b/ribavirin (PR). Hepatology 54 (Suppl.): 814A.
32. Rumi, M.G., Aghemo, A., Prati, G.M., D'Ambrosio, R., Donato, M.F., Soffredini, R. et al. (2010) Randomized study of peginterferon-alpha2a plus ribavirin vs peginterferon-alpha2b plus ribavirin in chronic hepatitis C. Gastroenterology 138: 108–115.
33. Stone, J.A., Wenning, L.A., Hang Y., Su, J., Gupta, S., Tsai, K. et al. (2011) Assessment of Boceprevir pharmacokinetic/pharmacodynamic relationships for sustained viral response and occurrence of anemia from phase 3 data. Hepatology 54 (Suppl.): 993A.
34. Sulkowski, M.S., Reddy, K., Pedicone, L., Shen, J.,Burroughs, M., Brass, C.A. et al. (2011) ITPA deficiency is associated with lower rates of anemia and EPO use in patients treated with boceprevir (BOC) plus peginterferon/ribavirin (PR). Hepatology 54 (Suppl.): 798A.
35. Victrelis (2011) Package insert. Merck & Co., Inc. Whitehouse Station, NJ, USA.
36. Vierling, J.M., Flamm, S.L., Gordon, S.C., Lawitz E., Bronowicki J., Davis, M. et al. (2011) Efficacy of boceprevir in prior null responders to peginterferon/ribavirin: the PROVIDE study. Hepatology 54 (Suppl.): 796A.

Source

Hepatitis C Therapy Update

From Current Opinion in Gastroenterology

Lisa C. Casey; William M. Lee

Posted: 05/04/2012; Curr Opin Gastroenterol. 2012;28(3):188-192. © 2012 Lippincott Williams & Wilkins

Abstract and Introduction

Abstract

Purpose of review We review here the recent literature regarding hepatitis C treatment through January 2012. We discuss newly approved therapies and their clinical trial data and discuss what can be expected in this rapidly changing field.
Recent findings Two new directly acting antiviral agents were approved in 2011 for use in hepatitis C treatment, bringing shortened treatment durations, and increased treatment success to some patients with genotype 1 hepatitis C. Additional drugs using different viral targets are in development to further improve response rates, tolerance, and increase access to therapy.
Summary Telaprevir and boceprevir were approved in 2011 for use against genotype 1 hepatitis C, in combination with pegylated interferon and ribavirin. In most populations of genotype 1 patients, response rates are much improved but increased treatment related anemia has been seen. Additional options for therapy, including interferon-free regimens, are still needed and are under development.

Introduction

An estimated 130–170 million people are infected with hepatitis C virus (HCV) worldwide leading to significant morbidity, mortality, and financial burden on healthcare.^[1] Most of the patients in the United States, an estimated 3.2–3.5 million people, were born between 1945 and 1964 and likely contracted the virus in the 1970s and 1980s when transmission rates were highest.^[2] With the contribution of blood product screening, disposable medical equipment and public health education efforts, the US incidence of infection has been decreasing but in many parts of the world the virus remains unchecked due to unsafe medical practices, lack of public health education, and lack of funding for research and treatment. Currently, hepatitis C is the leading cause for liver transplantation worldwide. Out of 100 people that contract the infection, 75–85 people will develop chronic infection, 60–70 people will develop chronic liver disease, five to 20 people will develop cirrhosis over the course of their chronic infection and one to five people will die of complications including hepatocellular carcinoma (HCC).^[3] Perz et al.^[4] looked at 11 WHO-based regions in 2006 and estimated that globally 27% of cirrhosis was attributable to HCV and 25% of HCC was attributable to HCV. In addition to new infections, as the currently infected population ages, we are more likely to see increased consequences of the chronic infection. Studies confirming this have shown increases in HCV-related mortality and increasing prevalence of hepatitis C-related HCC and cirrhosis since the mid-1990s.^[5,6] A sustained viral response (SVR) to hepatitis C therapy reduces liver-related, as well as all-cause mortality for patients with hepatitis C. Failure to respond to treatment correlates with poor liverrelated outcomes including death and liver transplantation.^[7,8]

For the past 10 years, standard therapy has been some form of pegylated interferon and ribavirin for 24–48 weeks, based on genotype. The limitations of these medications are well known. For genotype 1, the most common genotype in the United States nd Europe, this has produced an SVR (equated with cure) rate of only about 40%. Pregnant patients or those with advanced renal disease are prohibited from using ribavirin. Likewise, interferon therapy excludes patients with autoimmune diseases, uncontrolled depression and mental illness, decompensated liver disease (Child-Turcotte-Pugh score more than 6), or decompensated cardiac or pulmonary disease. In addition to contraindications, side effects and low response rates have led to an aggressive search for treatment alternatives. Beginning in mid-2011, two new agents, known as direct-acting antivirals (DAA) were approved for use in conjunction with pegylated interferon and ribavirin.

Viral Structure

What we first knew as non-A, non-B hepatitis was designated hepatitis C in 1989 by Michael Houghton and scientists at Chiron Corporation while searching for the blood-borne cause of hepatitis in transfusion recipients.^[9] Hepatitis C is a single stranded RNA flavivirus of the hepacivirus genus. It lacks proofreading ability leading to considerable genetic diversity and at least six different genotypes. Of the six genotypes, genotype 1 is the most prominent in the United States. When the virus enters a liver cell, it releases its RNA and is translated into a polyprotein containing structural and nonstructural regions. The polyprotein is processed by cellular and noncellular proteases into numerous polypeptides with functional roles in the virus life cycle. The virus replicates with the help of a polymerase and then is assembled, transported, and released from the cell. The nonstructural region codes for the polypeptides NS2, NS3, NS4A, NS4B, and NS5A and NS5B and these have become the focus of much recent interest, given that each of these polypeptides is a potential target for drug therapy. The NS3 region encodes a serine protease, RNA helicase and NTPase. The NS4A region produces cofactors for the serine protease. The NS4B product is the membranous web – a sort of scaffolding for the replication complex. The NS5B region encodes an RNA-dependent polymerase and the NS5A other products felt to be involved in replication, assembly, and release of HCV.^[10,11] Initial cleavage of the polyprotein is performed by the NS3/4A protease, which seemsto be highly conserved across most strains and without which the HCV life cycle evolution cannot proceed. This region is the target of the newest drugs: telaprevir and boceprevir.

Direct-acting Antivirals

Until mid-2011, therapy of hepatitis C was limited to a pegylated interferon, which activates the immune system and inhibits viral replication, and ribavirin, a nonspecific antiviral that likely inhibits viral replication but also plays a role in viral clearance from the liver once replication declines. Given suboptimal success with nonspecific agents, many different drugs directly targeting aspects of the virus itself are being tested. These will reduce treatment duration and side effects, and improve efficacy and cost. Telaprevir, and boceprevir are both NS3–4A inhibitors, targeting the protease that cleaves the HCV polyprotein, inhibiting the replication process. Of note, these newer agents are specifically focused on the treatment of genotype 1 disease.

Telaprevir: The History

The data leading to the approval of telaprevir have been published over several studies: PROVE-1, PROVE-2, ADVANCE, and REALIZE. PROVE-1 and PROVE-2 were the phase II studies published in 2009. PROVE-1 included genotype 1 treatment naive patients and evaluated SVR data comparing standard therapy to differing treatment lengths of triple therapy with telaprevir, pegylated interferon, and ribavirin. PROVE-2 was similar except that it included an arm with telaprevir and pegylated interferon alone without ribavirin. An SVR rate of 61% in PROVE-1 and 69% in PROVE-2 was shown with 12 weeks telaprevir combined with 24 weeks of pegylated interferon and ribavirin (as compared with 46–48% SVR for standard of care). The important lessons from these trials come from the relapse rates (defined as detectable RNA during 24-week follow-up) and subgroup analyses.^[12] In the PROVE-2 patients without ribavirin, there was 24% viral breakthrough by 12 weeks and a 48% relapse rate for patients that were virus negative at the end of treatment, suggesting the critical importance of ribavirin to prevent both viral breakthrough during treatment and relapse after treatment. In addition, low rates of relapse for 24-week triple therapy of only 14% after completion of therapy suggested that this shortened duration was acceptable for patients meeting certain criteria.^[13] In PROVE-1 a small subgroup of black patients was studied for their individual responses. With standard therapy, the black cohort only had an 11% response rate whereas their SVR rates were demonstrated collectively to be 44% in all of those in a telaprevir arm. These studies excluded patients with cirrhosis.

Phase III trials of telaprevir were published in June 2011 including ADVANCE and REALIZE. The ADVANCE trial enrolled 1088 treatment naive patients, evaluating response guided therapy, the length of therapy being determined by the time of first detectable viral clearance, the initial response. In addition, the study compared 12 versus 8 weeks of telaprevir combined with a total of 24 or 48 weeks of pegylated interferon and ribavirin. This study introduced the concept of eRVR (extended rapid viral response) as defined by undetectable RNA at weeks 4 and 12. Using this parameter, more than half (58%) of the patients in the telaprevir groups had eRVR, qualifying them for 24 weeks of therapy. Among the patients with eRVR assigned to receive a total of 24 weeks of therapy, 89% in the telaprevir 12-week group, and 83% in the telaprevir 8-week group achieved SVR.^[14•] Of note, at week 12 in the telaprevir arms, there was a higher level of viral resistance in the patients that had received 8 weeks of telaprevir versus 12 weeks (10 versus 5%). Virologic failure was also more common in HCV genotype 1a infections than in genotype 1b infections suggesting that the genotype variation itself may have a relationship to the development of resistance patterns. Subgroup analyses compared the telaprevir groups with standard therapy in black patients, patients with baseline viral load more than 800 000 and in patients with bridging fibrosis or cirrhosis – in all of these groups, the telaprevir arms showed significantly higher SVR rates. Comparing the 12 week telaprevir dose regimens to standard therapy the response rates virtually doubled suggesting that the addition of DAA in these patients may overcome some of the previous barriers to therapeutic success. Another significant lesson in this trial was that of side effects – predominantly anemia and gastrointestinal side effects which were more apparent than observed with standard therapy. The REALIZE trial included 662 previously experienced patients (relapse, partial response, or null response) assigning them to 48 weeks of standard therapy, 12 weeks of telaprevir, and a total of 48 weeks of pegylated interferon and ribavirin, or a 4-week lead-in with pegylated interferon and ribavirin followed by 12 weeks of triple therapy ending with pegylated interferon and ribavirin alone for a total of 48 weeks.Of the study population 26% had cirrhosis. In prior null responders and partial responders, the presence of advanced fibrosis heralded a poorer response to triple therapy. Overall, adding 12 weeks of telaprevir to a 48-week course of pegylated interferon and ribavirin increased SVR rates from 24 to as high as 88% in relapsers, from 15 to 59% in partial responders and from 5 to 33% in null responders. Adding a lead-in phase did not significantly change response rates. In both trials, nausea, diarrhea, itching, rash, and anemia were at least 10% higher in either telaprevir group than in the standard therapy group and there were treatment discontinuations related to rash and anemia.^[15•]

Boceprevir: The History

Boceprevir is the alternative NS3 protease inhibitor recently approved by the Food and Drug Administration. Although employing a similar mechanism to telaprevir, the approved treatment protocols are slightly different. Initially phase II trials were published beginning in 2009 with SPRINT-1. In SPRINT-1, the safety and efficacy of triple therapy with pegylated interferon, ribavirin, and boceprevir was assessed. Five hundred and twenty treatment naive patients were randomized from the United States, Canada, and Europe. Part 1 evaluated differing treatment durations and dosing with or without lead-in compared with 48 weeks of standard therapy. The patients were stratified by race and presence or absence of cirrhosis and then divided into five groups: standard therapy of pegylated interferon and ribavirin for 48 weeks, pegylated interferon, ribavirin, and bocepravir (triple therapy) for 28 or 48 weeks or therapy including a 4-week lead-in of pegylated interferon and ribavirin followed by an additional 24 or 44 weeks of triple therapy. SVR rates were significantly better than standard therapy in all four treatment groups containing boceprevir regardless of lead-in or duration of therapy. The SVR for 48 weeks of standard therapy in this study was 38%. In the combined (or triple) therapy groups with a 4-week lead-in interval, total therapy of 28 and 48 weeks had SVR¼56 and 75%, respectively. In the groups representing combined therapy without lead-in, 28 weeks of triple therapy had SVR¼54% and 48 weeks had SVR¼67%. The most common adverse events included anemia and dysgeusia. In response to anemia in this study, ribavirin dose reduction was encouraged and the use of concomitant epoietin and boceprevir dose reductions were allowed. Given that anemia is a common side effect of HCV therapy, part 2 of this study was developed to assess the result of reduced ribavirin dosing and its effect on outcomes. Treatment naive patients were randomized without stratification to triple therapy for 48 weeks with standard or reduced dose ribavirin based on weight. Triple therapy SVR was 50% and low-dose ribavirin triple therapy SVR was only 36%. There were significantly lower relapse rates in the 48-week triple therapy groups than in the standard therapy group and in the 28-week groups who were virus negative at week 4 (RVR). Overall, RVR while on triple therapy (undetectable virus at week 4) was associated with higher SVR – 74–94% across all boceprevir containing groups in part 1. In part 2, low-dose ribavirin was associated with higher relapse rates, again suggesting the important role of ribavirin in preventing viral breakthrough. Conceptually, lead-in was introduced to bring the baseline viral load down prior to starting boceprevir and, in turn, decrease the emergence of drug-resistant mutations. The lead-in groups showed a modestly lower rate of viral breakthrough than without lead-in (4 versus 9%) and there was no viral breakthrough in the control groups not exposed to boceprevir. SVR was similar in the 28 and 48-week groups that achieved at least a 1.5 log drop in viral load after the 4-week lead-in therapy phase. In 28-week patients, those patients not demonstrating at least a 1.5 log drop showed poor SVR of 30% or less at 28 weeks which was much higher in patients completing 48 weeks of therapy. These data support the conclusion that responseguided therapy based on 4-week labs would help predict best duration of treatment. The study discussion does suggest increased rates of SVR in patients receiving epoietin treatment for their anemia. The implication is that these patients could be supported through side effects and complete treatment though further studies are needed.^[16•]

Phase III trial data was reported in SPRINT 2, a superiority study to determine best regimen. Nine hundred and thirty eight patients were enrolled and separated into black and nonblack cohorts given the marked differences in SVR in these populations. After a 4-week pegylated interferon/ribavirin leadin, patients were assigned to one of three groups: standard therapy with placebo for 44 weeks, triple therapy for 44 weeks, or triple for 24 weeks with the caveat that those patients with detectable virus between weeks 8 and 24 would receive an additional 20 weeks of pegylated interferon and ribavirin with a placebo pill (response guided therapy) with SVR rates comparable to previous data. Results supported the use of response-guided therapy in treatment naive patients and the data regarding the black versus nonblack patients was compelling in terms of improved response for black patients with addition of boceprevir (almost double that of standard therapy) but with persistently lower SVR rates than nonblacks, suggesting interferon resistance continued to play a role. The decision to include a lead-in with the final protocol was again supported by the goal to reduce viral resistance but also reinforced by the opportunity this provides to assess interferon responsiveness. Patients with a poor response to interferon in this setting might be best served by waiting for better upcoming therapies.^[17•]

Where Are We Now?

Over the last year, we have seen great strides made in the treatment of hepatitis C genotype 1, but we are still a long way from the goal of being able to treat and cure all of our patients with hepatitis C. DAAs provide a tremendous improvement in SVR for many patients but there are still treatment failures, side effects, and many patients excluded. Ongoing research supports their successful use in the naive population as well as in previous nonresponders. The newer drugs provide an opportunity to treat these patients, most with mid to later-stage disease who cannot wait for additional options. We have seen greater anemia issues with the addition of these medications as well as new gastrointestinal side effects and rashes, which may be an important consideration in patient tolerance and selection of DAA.^[18]

There is cross-resistance among the NS3/4A drugs, and therefore treatment failure/resistance to one drug in this category will likely be seen in all of them.^[19•] New promise is anticipated with the polymerase inhibitors and other agents targeting cyclophilin or other intracellular proteins. Current DAA medications do show some efficacy against alternate genotypes and this expanded efficacy will likely be true for the newer generations.^[20•,21] We anticipate that the longer-term picture will include a cocktail of several different DAA medications targeting different sites. Data from two recent trials suggest this is coming sooner than expected. Pharmasset, Inc., a wholly owned subsidiary of Gilead Sciences, Inc., Foster City, California, presented data at last years European Association for the Study of the Liver and American Association for the Study of Liver Diseases meetings regarding the success of their new drug PSI-7977, a uridine nucleotide analog, that has shown promise with a phase IIb trial in genotype 1 patients with pegylated interferon and ribavirin in early data and in genotypes 2 and 3 without interferon.^{[22•,23•]} Bristol-Meyers Squibb also recently published data in a small open label phase IIb study combining daclatasvir (an NS5A replication complex inhibitor) and asunaprevir (a NS3 protease inhibitor) in previous genotype 1 nonresponders without or with pegylated interferon and ribavirin.^[24••] While the study was small and resistance mutations were found with both study drugs, reasonable SVR rates were achieved in the interferon free regimen.

Conclusion

We are entering a dynamic and exciting time in the therapy of HCV. An important point in the treatment of HCV is that, as opposed to HIV or HBV, a cure is possible. Directly acting antivirals provide the opportunity to reduce treatment times in many patients and may increase cure rates to up to 70%. We are seeing new side effects and new resistance patterns as we employ DAA, but almost daily the literature reports improved tolerability of later generation drugs, new targets of action, innovative ways to approach resistance, efficacy with alternate genotypes, and the success of interferon free regimens. We anticipate well tolerated cocktails of oral medications in the not too distant future, providing the opportunity to change the face of hepatitis C therapy once again.

References

1. World Health Organization Hepatitis C fact sheet 2011. (http://www.who.int/mediacentre/factsheets/fs164/en/). [Accessed 16 March 2012]
2. Armstrong G, Wasley A, Simard E, et al. The prevalence of hepatitis C virus infection in the United States, 1999-2002. Ann Inten Med 2006; 144:705–714.
3. Alter H, Aragon T, AuBuchon J, et al. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Morb Mortal Wkly Rep 1998; 47 (RR19):1–39.
4. Perz J, Armstrong G, Farrington L, et al. The contribution of hepatitis B and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006; 45:529–538.
5. Wise M, Bialek S, Finelli L, et al. Changing trends in hepatitis C – related mortality in the United States, 1995•2004. Hepatology 2008; 47:1128–1135.
6. Kanwal F, Hoang T, Kramer JR, et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology 2011; 140:1182–1188.
7. Backus L, Boothroyd D, Phillips B, et al. A sustained virologic response reduces risk of all cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol 2011; 9:509–516.
8. Dienstag J, Ghany M, Morgan T, et al. A prospective study of the rate of progression in compensated, histologically advanced chronic hepatitis C. Hepatology 2011; 54:396–405.
9. Houghton M. The long and winding road leading to the identification of the hepatitis C virus. J Hepatol 2009; 51:939–948.
10. Rosen H. Chronic hepatitis C infection. N Engl J Med 2011; 364:2429–2438.
11. Davis G. Hepatitis C. Diseases of the, Liver, 10th ed. In: Schiff E, Sorrell M, Maddrey W, editors. Philadelphia: Lippincott Williams and Wilkins; 2007. pp. 807–835.
12. McHutchison J, Everson G, Gordon C, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360:1827–1838.
13. Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360:1839–1850.
14. Jacobson I, McHutchison J, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405–2416.
    •ADVANCE trial, phase III treatment naive response guided therapy trial, subgroups showed much improved response in blacks, fibrosis and high viral load with telaprevir.
15. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364:2417–2428.
    •REALIZE – treatment experienced patients including cirrhotics, all groups improved SVR.
16. Kwo P, Lawitz E, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatmentnaive patients with genotype 1 hepatitis C infection (SPRINT-1): an open label, randomized, multicentre phase 2 trial. Lancet 2010; 376:705–716.
    •The study tested various durations of treatment and lead-in concept.
17. Poordad F, McCone J, Bacon B, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195–1206.
    •SPRINT 2 – phase III, established lead-in use of response guided therapy.
18. Schlutter J. Therapeutics: new drugs with the target. Nature 2011; 474:s5–s7.
19. Halfon P, Locarnini S. Hepatitis C virus resistance to protease inhibitors. J Hepatol 2011; 55:192–206.
    •A detailed review of the viral structure, medications in development, and the development of resistance.
20. Foster G, Hezode C, Bronowicki J, et al. Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections. Gastroenterology 2011; 141:881–889.
    •This study demonstrates some activity of DAA against alternate genotypes.
21. Gottwein J, Scheel T, Jensen T, et al. Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a and 6a NS3/4A protease recombinant viruses. Gastroenterology 2011; 141:1067–1079.
22. Gane E, Stedman C, Hyland R, et al. Once daily PSI-7977 plus RBV; pegylated interferon-alfa not required for complete response in treatmentnaive patients with HCV GT2 or GT3. (AASLD Abstract) Hepatology 2011; 54:377A.
    •Demonstrates effectiveness of PSI-7977 against other genotypes as monotherapy and the high barrier to resistance of this drug, a uridine nucleotide analog.
23. Lawitz E, Lalezari J, Hassanein T, et al. Once-daily PSI-7977 plus PEG/RBV in treatment-naive patients with HCV GT1: robust end of treatment response rates are sustained post treatment. Hepatology 2011; 54:472A.
    Phase II data dose finding for unique target new drug, very high RVR and eRVR in combined therapy
24. Lok A, Gardiner D, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366:216–224.
    ••A small study of previous nonresponders with interferon-free regimen of NS3 protease inhibitor and NS5A replication complex inhibitor, demonstrates proof of concept that SVR can be achieved without interferon.

Papers of particular interest, published within the annual period of review, have been highlighted as:

•of special interest
••of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 287–288).

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Boehringer Ingelheim Research Vision

Despite recent treatment progress, the burden of HCV on patients and physicians remains. Boehringer Ingelheim recognizes the need for an HCV cure that addresses more of the challenges that these patients face.

Boehringer Ingelheim strives to achieve a far reaching and inclusive cure for more HCV patients, including those who are the most difficult to treat. In partnership with the scientific community, our clinical trial program, HCVersoTM, is rigorously designed to find answers to challenges that HCV patients face. The program extends to diverse HCV patient populations across the world, including HIV co-infected patients and those who have previously failed treatment. Our goal is to improve cure rates, shorten treatment and eliminate interferon in HCV treatment for as many patients as possible.

History of Treatment

Pegylated interferon and ribavirin (PegIFN/RBV) have historically been the standard-of-care for treatment of HCV, but are only effective in about half of patients with chronic HCV infection.

Interferon is the backbone of current HCV treatment regimens and is challenging for a number of patients due to contraindications of use, side effects, adherence and treatment duration. Currently available protease inhibitors are approved for use in combination with PegIFN/RBV.

Treatment success is primarily determined by viral genotype, the most common of which are types 1, 2 and 3. HCV genotype-1 patients are the most difficult to treat and often require the longest course of therapy. Genotype-2 and-3 patients typically are more easily treated with only PegIFN/RBV.

The scientists at Boehringer Ingelheim have a long-standing commitment to virology including innovations in HIV/AIDS, and have been focused on HCV for many years. In 2003, these researchers were the first to publish results describing the clinical application of a novel agent that directly targets the HCV protease. This early work spawned today’s significant research effort into new ways of directly inhibiting the virus's ability to replicate, which has led to the Company’s current portfolio of investigational direct-acting HCV antivirals.

Boehringer Ingelheim maintains a Virology Center of Excellence, dedicated to research and drug discovery for viral diseases for which there is no vaccine or where current therapy is lacking.

Across the industry, HCV research is directed towards advancing inhibitors that target essential viral enzymes, such as the HCV serine protease and RNA polymerase. These approaches may lead to the development of novel classes of direct acting antivirals (DAAs), further enhancing the standard-of-care for HCV patients.

Boehringer Ingelheim HCV Portfolio Key Research Areas

From within our HCV pipeline, we are advancing two investigational DAAs: BI 201335, a protease inhibitor that has shown the potential to improve cure rates and shorten treatment duration compared to PegIFN/RBV therapy, as well as BI 207127, a polymerase inhibitor that has the potential to eliminate interferon from HCV treatment when combined with BI 201335 and RBV.

BI 201335

BI 201335 is an investigational, once-daily oral HCV NS3/4A protease inhibitor discovered from Boehringer Ingelheim’s own research and development. A multi-study, Phase 3 clinical trial program is currently underway to evaluate BI 201335 combined with PegIFN/RBV in both treatment-naive and -experienced patients with chronic genotype-1 HCV, as well as HCV/HIV co-infected patients. The trial program is being performed at sites across the world, including Europe, the United States, Canada and Asia Pacific.

BI 201335 binds to a shallow active site on an enzyme critical in HCV replication. The shallow nature of the enzyme active site makes it a challenge to design a molecule with the correct properties to effectively inhibit the enzyme. BI 201335 is optimized to target genotype-1 HCV, the most difficult type to effectively treat with current therapy.

BI 207127

BI 207127 is an investigational NS5B polymerase inhibitor that is currently being evaluated in Phase 2 clinical trials. The HCV NS5B is believed to be the central enzyme responsible for HCV replication. BI 207127 works by blocking a specific step in the viral lifecycle, targeting the polymerase enzyme, and consequently preventing HCV from replicating. BI 207127 is being evaluated as part of combination therapy regimens including BI 201335.

BI 201335 + BI 207127 Combination Therapy without Interferon

A Phase 2b trial (SOUND-C2) evaluating dual DAA treatment, with the combination of BI 207127 and BI 201335 in interferon-free regimens, both with and without ribavirin, in treatment-naïve HCV patients is currently under way. Data from a pre-specified interim analysis of SOUND-C2 show the potential for BI’s DAA compounds in combination with RBV, without interferon.

Planning for Phase 3 interferon-free clinical trials is underway.

FDA Fast Track Designation

The U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the development programs for BI 201335 in combination with PegIFN/RBV, and the development program for the interferon-free combination of BI 201335 plus BI 207127. Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious diseases and fill an unmet medical need. The purpose is to get important new drugs to patients earlier.

About Boehringer Ingelheim Pharmaceuticals, Inc.

Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 145 affiliates and more than 42,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim pledges to act socially responsible. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.

For more information, please visit http://us.boehringer-ingelheim.com and follow us on Twitter at http://twitter.com/boehringerus.

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Contact:
Susan Holz
Boehringer Ingelheim Pharmaceuticals, Inc.
(203) 798-4265
usnews@boehringer-ingelheim.com

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