January 10, 2012

Predictors Identified for Posttransplant Recurrence of Hepatitis C

01/09/12

By: SUSAN LONDON, Internal Medicine News Digital Network

SAN FRANCISCO – Both donor and recipient interleukin 28B genotype affect the risk of recurrence of hepatitis C after liver transplantation, but they do so in opposite directions.

Investigators led by Dr. Andres Duarte-Rojo of the Mayo Clinic in Rochester, Minn., studied a cohort of more than 200 patients with hepatitis C who underwent liver transplantation, finding that 32% had a histologic recurrence 1 year later.

The risk of such recurrence was reduced by more than half when the recipient had the interleukin 28B (IL28B) CC genotype, as compared with the CT or TT genotype, according to results reported at the annual meeting of the American Association for the Study of Liver Diseases. In sharp contrast, the risk was almost tripled if the donor had the CC genotype for IL28B instead of one of the others.

"Variations in the phenotypic expression of IL28B genotype occur in relation to its source, either the recipient or the donor. This paradoxical effect suggests variation in the activation of the adaptive immune system according to hepatic and nonhepatic IL28B genotype," Dr. Duarte-Rojo commented.

Other research by his group suggests that donor and recipient CC genotype have a synergistic effect in promoting sustained virologic response after transplantation. "However, according to current results, allocation of a CC allograft to hepatitis C patients may predispose to a more severe disease in those untreated or not achieving a sustained virologic response," he said.

IL28 is a cytokine playing a role in antiviral defenses. The genotype for the B isoform "affects hepatitis C virus eradication, whether spontaneous or therapy driven," Dr. Duarte-Rojo noted. "It is important to study the associations of IL28B in the posttransplant setting to unravel mechanisms driving viral-host interactions and help the understanding of this polymorphism in hepatitis C pathobiology."

The investigators studied 241 consecutive patients with hepatitis C virus infection who underwent liver transplantation between 1995 and 2010. Average age was 52 years and the mean Model for End-Stage Liver Disease (MELD) score was 15.

IL28B genotype of recipient and donor was assessed from liver biopsies done at the time of transplantation, and serial biopsies of the liver graft were done after transplantation to assess virologic and histologic measures of recurrence.

Only 31% of the recipients had the IL28B CC genotype, compared with 52% of the donors, Dr. Duarte-Rojo reported.

The time to virologic recurrence after transplantation was longer when the recipient had the CC genotype vs. a non-CC genotype (4.6 vs. 4.1 months), whereas it was nonsignificantly shorter when the donor had the CC vs. a non-CC genotype.

Similarly, the proportion of patients that developed histologic recurrence as defined by stage 2 or greater fibrosis 1 year post transplantation was lower when the recipient had the CC vs. a non-CC genotype (19% vs. 38%). In contrast, recurrence rate was higher when the donor had the CC vs. a non-CC genotype (43% vs. 23%).

And there was also an interaction, whereby the proportion with recurrence ranged from a low of 17% with a CC recipient and non-CC donor, to a high of 52% with a non-CC recipient and a CC donor.

In a multivariate analysis that included factors such as alanine aminotransferase level, MELD score, viral genotype, surgical and biliary complications, cytomegalovirus infection, and diabetes, the risk of recurrence was still markedly decreased when the recipient had the CC genotype (odds ratio, 0.40) and markedly increased when the donor had the CC genotype (OR, 2.71).

The results were essentially the same after exclusion of patients who received antiviral therapy, according to Dr. Duarte-Rojo.

He noted that the recipient and donor IL28B genotypes also had opposite effects on alanine aminotransferase levels, viral loads, and rates of acute cellular rejection during follow-up.

Dr. Duarte-Rojo reported that he had no relevant conflicts of interest.

Source

· Phase IIb NASH/Fatty Liver trial cleared without FDA raising concern

· Unmet medical need provides large global opportunity

· Immuron’s NASH/Fatty Liver therapeutic derives from the same platform as Travelan®

Melbourne, Australia, 10 January 2012: Australian biopharmaceutical company Immuron Limited (ASX: IMC), manufacturer of Travelan®, today announced that the United States Food and Drug Administration (US FDA) had cleared an Investigational New Drug (IND) submission to commence a Phase 2b clinical trial of its bovine colostrum-derived therapeutic (IMM-124E) for the treatment of Non-Alcoholic Steatohepatitis (NASH) and Fatty Liver.

The trial has been designed as a double-blind, placebo-controlled and dose ranging multi-centre trial with sites in the United States, Australia and Israel. Its principal aims are to determine the safety and efficacy of Immuron’s orally administered IMM-124E in patients with biopsy- confirmed NASH.

As previously announced Dr Arun J Sanyal, Professor of Medicine at Virginia Commonwealth University, has been appointed global principal investigator for the upcoming clinical trial.

Immuron’s Chief Executive Officer Joe Baini said: “This is a major milestone for Immuron with global significance for an unmet and rapidly growing disease. The FDA has cleared Immuron’s IND submission, without raising any concerns.”

“Based on the encouraging results generated to date, IMM-124E could be the first available and approved treatment for NASH patients in the world and the only product candidate to date that addresses the pathogenesis of the disease. From a commercial perspective it represents an extremely lucrative opportunity for Immuron. We are very excited to commence the trial, which is pending financing."

The potential NASH market is estimated to be a multi-billion dollar market and there are no effective treatments.

NASH (non-alcoholic steatohepatitis) is one of the most common liver diseases in the western world. It is associated with obesity, diabetes and hyperlipidaemia. It affects approximately 5% of the lean population, 20% of the obese population and 50% of morbidly obese people. It resembles alcoholic liver disease but occurs in people who drink little or no alcohol. The major feature in NASH is fat in the liver (hence another of its names ‘Non-alcoholic Fatty Liver Disease’ along with inflammation and damage. NASH can be severe and can lead to cirrhosis, in which the liver is permanently damaged and scarred and no longer able to function properly.

Contact

Joe Baini – Chief Executive Officer Rudi Michelson

+61 3 8637 1107 Monsoon Communications

+ 61 3 9620 3333

+ 61 411 402 737

About Immuron Limited

Immuron is a biopharmaceutical company focused on oral immunotherapy treatments using dairy-derived antibody products for humans. Immuron is uniquely positioned with a versatile technology platform capable of generating a wide range of products with a high safety profile. This high safety profile makes it possible to complete pre-clinical studies relatively quickly and increases the prospect that the clinical development of Immuron’s products will be expedited. Immuron’s current products and product candidates target infectious diseases of the gastrointestinal tract, chronic diseases such as fatty liver (NASH), and the prevention of influenza. Immuron has one product in the market, Travelan, for preventing travellers’ diarrhoea. Immuron’s main scientific alliances are with Hadassah Medical Center (Israel), the University of Melbourne and Monash University (Australia).

Monsoon Communications
Level 37 530 Collins Street
Melbourne VIC 3000
p: 03 9620 3333
e: info@monsoon.com.au
w: www.monsoon.com.au

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Hep-C-Psychedelic-Warriors1-300x203

10 Jan 2012 | 16:29 EST | Posted by Rebecca Hersher

With the global market for hepatitis C therapies expected to be worth $20 billion by the end of the decade, drugmakers have been racing to consolidate their hep C pipelines. In November, California’s Gilead bought Pharmasset, a New Jersey-based company with three experimental compounds targeting the hepatitis C virus (HCV), for a whopping $11 billion. And over the weekend, New York’s Bristol-Myers Squibb announced a $2.5 billion deal to acquire Inhibitex, a small Georgia-based company with an HCV polymerase inhibitor called INX-189 in phase 2 development. But, despite the growing interest in HCV therapies—Merck executives went as far as telling Bloomberg News at this week’s JP Morgan Healthcare Conference in San Francisco that the drug giant will “do anything” to be the leader in hepatitis C—some analysts say it’s too soon to know whether the HCV market will be as lucrative as it appears.

“It’s really tough to predict,” says Saurabh Aggarwal, an analyst at Novel Health Strategies in New York. “There is a lot of speculation.”

Predicting the HCV market is complicated by the geography of the virus: an estimated 200 million people worldwide carry HCV, but only around 5% of those infected live in the US and EU—the regions where drugmakers can expect to reap the most profits.

Those figures could still stack up to a potentially enormous untapped market, which helps explain why pharma companies have been willing to pay such premiums to acquire smaller firms with promising HCV therapies. But with two-thirds of HCV-positive individuals in the developed world over the age of 50 and three-quarters of people unaware that they’re even infected, HCV drugs still remain a financial gamble. “Companies are betting on the American market because the pricing is much higher,” says Aggarwal. “But in the US, [HCV is] not like other therapies that have ongoing incidence and prevalence. The window of opportunity is limited.”

That limited time window has pushed drug companies to invest quickly in new HCV treatments. Vertex of Cambridge, Massachusetts and Merck of Whitehouse Station, New Jersey both won regulatory approval last year for the first generation of targeted anti-HCV therapies, but these drugs still don’t work for around a third of all HCV infections that are caused by genotypic subtypes not currently hit by the existing compounds. Allan Haberman, founder of the Biopharmaceutical Consortium in Waverly, Massachusetts, says that the unaddressed subtypes set HCV apart from past investment frenzies around a single therapeutic area. “Everyone jumped on statins,” he points out, “but it turned out there was only room for one blockbuster in the end. Here there is an entirely untapped market in the genotypes that can’t be treated yet.”

Still, the question of whether the drug industry is paying too much for promising HCV acquisitions is still up in the air. Joe DiMasi, director of economic analysis at the Tufts Center for the Study of Drug Development in Boston, says that identifying irrational exuberance in drug investments is a notoriously difficult game.

Aggarwal agrees. “There is an additional challenge in predicting the future sales curve for hepatitis C because there’s a big education aspect to getting asymptomatic people diagnosed,” he says. And as baby boomers age, the clock is ticking for companies that have already poured hopeful billions into HCV.

Image courtesy of James Cavallini/Photo Researchers Inc via Wikimedia Commons

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January 10, 2012

A new classification for diagnosing fibrosis in patients with chronic hepatitis C virus (HCV) has shown to be as accurate as currently used algorithms, but required no further liver biopsy. The study appearing in the January issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases, details a method that synchronously combines two fibrosis tests, providing a non-invasive and more precise fibrosis diagnosis.

HCV affects up to 170,000 million individuals worldwide and is a leading cause of chronic liver disease and a primary indication for liver transplantation according to the World Health Organization (WHO). The Centers for Disease Control and Prevention (CDC) estimates that 2.7 to 3.9 million Americans are living with chronic HCV with roughly 12,000 deaths reported each year. WHO has reported up to 20% of HCV patients develop cirrhosis and 1% to 5% die from cirrhosis or liver cancer.

"Fibrosis progression can be highly unpredictable and accurate classification of the stage of fibrosis is extremely important," said Dr. Jérôme Boursier from Centre Hospitalier Universitaire d'Angers in France. "A diagnostic algorithm that provides similar accuracy as successive classifications without the need of liver biopsy to determine the extent of fibrosis is highly beneficial to patients."

Dr. Boursier and colleagues evaluated the Sequential Algorithm for Fibrosis Evaluation (SAFE) and Bordeaux algorithm (BA), compared to a more detailed classification for determining fibrosis severity. The team used data for 1785 patients with chronic HCV who were enrolled in 3 previous study populations (SNIFF, VINDIAG, and FIBROSTAR), representing a total of 31 centers throughout France. Data included liver biopsy, blood fibrosis test, and Fibroscan—an ultrasound technology used to assess liver fibrosis (stiffness).

The team found that successive SAFE diagnostic accuracy was 87%—significantly lower than the individual SAFE devoted for the diagnosis of significant fibrosis (F≥2) at 95% or for cirrhosis (F4) at 90%. The number of liver biopsies required with successive SAFE was significantly higher than individual SAFE for F≥2 or SAFE for F4 at 71% compared to 64% and 6%, respectively. Researchers also reported similar results with successive BA diagnostic accuracy at 85% compared to individual BA at 88% (F≥2) and 94% (F4). More biopsies were required for successive versus individual BA at 50% compared to 35% and 25%, respectively.

"Our findings show that SAFE and BA diagnostic testing are highly accurate in determining fibrosis or cirrhosis in patients with HCV," said Dr. Boursier. However, a high percentage of patients also required liver biopsy to confirm the diagnosis. The authors creation of a new classification which synchronously combines two fibrosis tests (FibroMeter + Fibroscan) was as accurate as successive SAFE or BA at 87%, and did not require any liver biopsy. "The new non-invasive classification of fibrosis is as accurate as successive SAFE or BA, but is more precise with six fibrosis classes and entirely non-invasive with no liver biopsy required," concludes Dr. Boursier.

More information: "Comparison of 8 Diagnostic Algorithms for Liver Fibrosis in Hepatitis C: New Algorithms are More Precise and Entirely Non-invasive." Jérôme Boursier, Victor de Ledinghen, Jean-Pierre Zarski, Isabelle Fouchard- Hubert, Yves Gallois, Frédéric Oberti, Paul Calès, and multicentric groups from SNIFF 32, VINDIAG 7, AND ANRS/HC/EP23 FIBROSTAR studies. Hepatology; Published Online: December 21, 2011 (DOI: 10.1002/hep.24654); Print Issue Date: January 2012.

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From American Journal of Health-System Pharmacy

Jenny J. Kim; Colleen M; Culley; Rima A. Mohammad

Posted: 01/09/2012; American Journal of Health-System Pharmacy. 2012;69(1):19-33. © 2012 American Society of Health-System Pharmacists, Inc.

Abstract and Introduction
Abstract

Purpose The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, drug interactions, viral drug resistance, dosage and administration, and place in therapy of telaprevir are reviewed.
Summary Telaprevir is an oral NS3/4A protease inhibitor that was recently approved by the Food and Drug Administration for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in adult patients with compensated liver disease, including cirrhosis. In Phase II clinical trials, triple therapy (telaprevir with peginterferon alfa and ribavirin) demonstrated 20–39% higher rates of sustained virological response (SVR) versus standard therapy (peginterferon alfa and ribavirin) in patients with chronic HCV genotype 1. Higher SVR rates were observed in treatment-naive patients or patients who did not respond to prior therapy (did not achieve SVR). Phase III studies also found improved SVR rates in patients treated with triple therapy. Telaprevir is recommended in combination with peginterferon alfa-2a and ribavirin for treatment-naive patients and patients who did not previously respond to peginterferon alfa-2a and ribavirin therapy. Telaprevir is a substrate and inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 and P-glycoprotein. Drugs that induce or inhibit CYP3A4 may affect concentrations of telaprevir, resulting in reduced efficacy or increased concentrations of telaprevir (and an increased risk for adverse reactions). The most common adverse events reported with telaprevir monotherapy versus placebo were diarrhea, nausea, fatigue, and dry skin.
Conclusion Telaprevir, an HCV NS3/4A protease inhibitor, has been shown to be effective in increasing SVR rates when used with peginterferon alfa and ribavirin in patients with chronic HCV genotype 1 infection, regardless of treatment history

Introduction

Hepatitis C virus (HCV) affects roughly 170 million people worldwide and is a leading cause of chronic liver disease and liver transplantation.[1–3] There are two distinct phases of HCV: acute infection and chronic infection. Of patients with acute HCV infection, approximately 75–85% will develop chronic HCV, and 60–70% will develop chronic liver disease.[2] An estimated 3.2 million people in the United States have chronic HCV infection, and the mortality rate of patients who develop hepatocellular carcinoma (HCC) or cirrhosis as a consequence of chronic HCV infection is 1–5%.[2] The acute and chronic phases of HCV infection are distinguished by clinical symptoms (e.g., jaundice), history and duration of elevated alanine transaminase (ALT) levels, and the results of serum laboratory testing for anti-HCV antibody and the presence of HCV RNA.[4] HCV RNA can be detected as early as 2 weeks after an acute exposure, though anti-HCV antibodies may not be detectable before 8–12 weeks. During the first four to six months after exposure, anti-HCV antibody and HCV RNA levels should be retested to confirm the resolution of HCV infection. For patients who develop chronic HCV infection, the HCV genotype should be identified to determine the appropriate treatment and duration of therapy. HCV genotypes (1–6) are geographically specific; in the United States, the most common HCV genotype is 1 (subtypes 1a and 1b), followed by genotypes 2 and 3.[4,5] A U.S. population study of 265 individuals with HCV infection found that 75.3% of patients had HCV genotype 1, 16.3% had HCV genotype 2, and 8.5% had HCV genotype 3.[5]

The goal of therapy is the prevention of HCV-related complications (e.g., cirrhosis, HCC) and mortality.[4] Treatment is initiated for chronic HCV infection based on several factors, such as the severity of liver disease, risk:benefit ratio of therapy, and presence of bridging fibrosis or compensated liver.[4] Due to the slow progression of chronic HCV, treatment response is determined by surrogate virological measurements rather than clinical endpoints. The goal of treatment response is virological cure or sustained virological response (SVR) of undetectable HCV RNA levels 24 weeks after completion of therapy (defined as a lower limit of detection [LLOD] of <50 IU/mL). Other virological responses may help to predict the likelihood of SVR, such as rapid virological response (RVR), defined as an undetectable HCV RNA level at week 4 of treatment.[4]

Practice guidelines of the American Association for the Study of Liver Diseases (AASLD) currently recommend the combination of peginterferon alfa-2a or alfa-2b and ribavirin, which nonspecifically targets HCV, for the treatment of chronic HCV infection.[4] The treatment regimen for chronic HCV infection, treatment duration, and treatment response rate (defined by SVR) depend on the HCV genotype. With standard therapy, the SVR rate of patients with HCV genotype 1 is 42–52% and it is 76–84% for patients with HCV genotype 2 or 3.[6–8] Since patients with HCV genotype 1 are less likely to respond to treatment, they require a longer duration of therapy (48–72 weeks) compared with patients with HCV genotype 2 or 3 (24 weeks).[4,8,9] The duration of therapy may be extended to 72 weeks in patients with HCV genotype 1 who have a delayed clearance of HCV RNA between weeks 12 and 24.[4,9]

There are several limitations to combination therapy with peginterferon alfa-2a or alfa-2b and ribavirin, including significant dose-limiting safety issues (e.g., depression, flulike symptoms, thrombocytopenia), treatment discontinuation rates of 5–15% due to adverse events, and clinical considerations (e.g., coinfection with human immunodeficiency virus [HIV], decompensated liver disease, retreatment).[6–8] These limitations prompted the development of new antiviral agents to improve the efficacy and safety of treatment in patients with chronic HCV infection. Direct-acting antivirals (DAA) target important viral enzymes specific to HCV (e.g., NS3/4A serine protease, NS5B polymerase).[10] NS3/4A serine protease processes HCV polyproteins into nonstructural proteins, which are essential to the HCV replication cycle.[11]

There are two types of protease inhibitors based on the type of bond formed with NS3/4A protease: non-covalent product-based inhibitors (e.g., ciluprevir) and covalent reversible inhibitors (e.g., telaprevir, boceprevir).[11] The development of ciluprevir was discontinued after it was found to cause cardiotoxicity in experimental animal studies. Boceprevir (Victrelis, Schering, Whitehouse Station, NJ), approved by the Food and Drug Administration (FDA) on May 13, 2011, was shown to improve SVR rates in HCV treatment-naive patients and patients with chronic HCV genotype 1 infection who previously had a partial response to or relapsed after treatment with peginterferon alfa and ribavirin.[12,13] On May 23, 2011, telaprevir (Incivek, Vertex, Cambridge, MA) was approved for the treatment of chronic HCV genotype 1 infection in adult patients with compensated liver disease, including cirrhosis, who have not been previously treated with, have not responded to, have partially responded to, or have relapsed after interferon-based treatment.[14] This article reviews the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, drug interactions, viral drug resistance, dosage and administration, and place in therapy of telaprevir.

Pharmacology

Telaprevir, a tetrapeptide mimetic, is a highly selective, potent, reversible HCV NS3/4A protease inhibitor that directly targets the HCV replication cycle.[14,15] Telaprevir reversibly binds to NS3/4A protease in two phases.[15] Initially, telaprevir weakly binds to the HCV protease, followed by a slow rearrangement of the complex to form a tighter covalent bond between the serine nucleophile of the HCV protease and the α-ketoamide group of telaprevir.[15] Inhibition of the NS3/4A protease prevents viral replication and subsequently reduces HCV RNA levels. Most patients with chronic HCV infection have wild-type virus, which is fully susceptible to telaprevir;[16] however, there are concerns regarding viral resistance to telaprevir, addressed in the viral drug resistance section of this article.

Pharmacokinetics

Telaprevir is most likely absorbed in the small intestine, with a maximum plasma drug concentration achieved four to five hours after administration of a single 750-mg oral dose of telaprevir in healthy volunteers.[14] Compared with fasting conditions, the area under the plasma concentration–time curve (AUC) of telaprevir has been shown to increase by 117%, 237%, and 330% with low-fat (249 kcal, 3.6 g of fat), standard fat (33 kcal, 21 g of fat), and high-fat (928 kcal, 56 g of fat) meals, respectively.[14] In Phase III clinical trials, telaprevir was administered within 30 minutes of consuming a meal or snack containing approximately 20 g of fat; therefore, telaprevir should not be taken with a food low in fat.

Telaprevir is approximately 59–76% bound to human plasma proteins, primarily α-1-acid glycoprotein and albumin, in a concentration-dependent manner.[14] The volume of distribution is approximately 252 L, with an interindividual variability of 72% after oral administration.

Telaprevir is extensively metabolized in the liver through hydrolysis, oxidation, and reduction and by cytochrome P-450 (CYP) isoenzyme 3A4 to both inactive (α-ketoamide bond) metabolites and the R-diastereomer of telaprevir (30-fold less active than telaprevir). Telaprevir is both a substrate and an inhibitor of CYP3A4 and P-glycoprotein.[14]

The mean plasma elimination half-life of telaprevir after a single 750-mg dose is approximately 4–4.7 hours.[14] Once steady state is reached (after 5–14 days of telaprevir 750 mg every 8 hours), the half-life of telaprevir is 9–11 hours. Telaprevir is primarily eliminated in the feces (82%, 31.9% as unchanged drug and 18.8% as the R-diastereomer), followed by exhaled air (9%, 0% unchanged) and urine (1%, 0.13% unchanged).

Steady-state exposure to telaprevir in HCV-negative study participants with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment was reduced by 15% and 46%, respectively.[14] Dosage adjustments are not needed in patients with mild hepatic impairment. Because the dosage for patients with moderate or severe hepatic impairment or with decompensated liver disease has not been established, telaprevir is not recommended in this population. After administration of a single 750-mg dose in HCV-negative patients with a creatinine clearance (CLcr) of <30 mL/min, the AUC increased by 21%; however, no dosage adjustments are required for patients with renal impairment. Telaprevir has not been studied in HCV-infected patients with a CLcr of <50 mL/min, with end-stage renal disease, or undergoing hemodialysis. No dosage adjustments are needed based on sex, race, or age.

The pharmacokinetics of telaprevir has not been established in pediatric patients, in patients coinfected with HIV or hepatitis B virus, or in solid-organ transplant recipients.[14]

Pharmacodynamics

A randomized, double-blind, placebo-controlled, dose-escalation, Phase Ib study enrolled 34 adult patients with chronic HCV genotype 1 infection with HCV RNA concentrations of ≥1 × 105 IU/mL and ALT concentrations of at least four times the upper limit of normal to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of telaprevir.[17] Patients were assigned to receive telaprevir, given as an oral suspension, in the following dosages: 450 mg every 8 hours (n = 10), 750 mg every 8 hours (n = 8), 1250 mg every 12 hours (n = 10), or placebo (n = 6) for 14 days. There was a reduction of ≥ 2 log10 IU/mL from baseline in HCV RNA viral load in all telaprevir-treated patients and a reduction of ≥ 3 log10 IU/mL in the 750-mg group compared with patients receiving placebo (reduction of 0.21 log10 IU/mL). The study did not include a statistical analysis. On day 14, patients in the telaprevir 750-mg group had the greatest reduction in median HCV RNA concentration (decrease of 4.41 log10 IU/mL). Patients in the 450- and 1250-mg groups had a decrease in median HCV RNA concentration of 2.37 and 2.21 log10 IU/mL, respectively. Over-all, this study demonstrated a rapid and substantial reduction of HCV RNA viral load with all telaprevir dosage groups.

In another randomized, placebo-controlled, open-label, Phase I trial, 20 treatment-naive patients infected with HCV genotype 1 were randomized to receive telaprevir 750 mg every 8 hours (n = 8), peginterferon alfa-2a 180 μg weekly and placebo (n = 4), or the combination of telaprevir 750 mg every 8 hours and peginterferon alfa-2a 180 μg weekly (n = 8) for 14 days.[18] Statistical analysis was not conducted. Compared with the telaprevir monotherapy and peginterferon alfa-2a with placebo groups, patients who received the combination of telaprevir and peginterferon alfa-2a had a greater reduction in median HCV RNA concentration from baseline (3.99, 1.09, and 5.49 log10 IU/mL, respectively).[18]

Pharmacogenomics

More recently, pharmacogenomics has been used to predict treatment response. A strong predictor of response to peginterferon alfa-2a and ribavirin is a genetic variant (single nucleotide polymorphism [SNP] rs12979860) near the interleukin (IL) 28 gene encoding interferon-λ-3.[14,19,20] A retrospective analysis of two Phase III trials was conducted by FDA to identify the rs12979860 variant among patients treated with peginterferon alfa-2a and ribavirin (standard therapy) versus telaprevir with peginterferon alfa-2a and ribavirin to determine the genetic variant's effect on SVR rates in this population.[14] Among all patients with rs12979860 who had not previously received treatment (n = 454) or who had no response to previous treatment (n = 527), patients treated with triple therapy had higher SVR rates (60–90%) compared with patients treated with standard therapy (13–64%).[14] Recent genomewide association studies have evaluated the correlation between genetic variation in the inosine triphosphatase (ITPA) gene and anemia during treatment with peginterferon alfa-2a or alfa-2b and ribavirin;[21–23] however, the genetic variant had no effect on treatment outcome[21,22] with the exception of one univariate analysis.[23] These studies suggest that ITPA deficiency may protect against ribavirin-induced hemolytic anemia, and patients with the ITPA variant may need a reduction in the ribavirin dosage during therapy or discontinuation of ribavirin due to anemia.[21–23] Chayama et al.[24] evaluated the use of triple therapy (telaprevir, peginterferon alfa-2b, and ribavirin) to identify predictors for treatment response in 94 Japanese patients with chronic HCV genotype 1 infection who had not previously received treatment or had not responded to previous treatment. Patients were included if they had an HCV RNA concentration of ≥5.0 log10 IU/mL for more than six months, were age 20–65 years, and weighed over 40 kg but less than 120 kg. Patients were excluded if they had cirrhosis, hepatitis B virus infection, HIV infection, prior or current HCC, autoimmune hepatitis, hemochromatosis, Wilson disease, alcoholic liver disease, renal disease, baseline CLcr of <50 mL/min, a hemoglobin concentration of <12 g/dL, a neutrophil count of <1500 cells/mm3, or a platelet count of <100,000 cells/mm3. All patients received telaprevir 750 mg every eight hours, peginterferon alfa-2b 1.5 μg/kg/wk, and ribavirin (dosed according to patient weight) for 12 weeks, with an additional 12 weeks of peginterferon alfa-2b and ribavirin therapy. Patients were genotyped for two SNPs: IL28B rs8099917 and rs1127354 (ITPA variant associated with ribavirin-induced anemia). Overall, 73% of patients achieved SVR. However, patients with the rs8099917 TT genotype had a significantly higher SVR rate (94%) compared with patients without the genotype (50%, p < 0.05). The SVR rate did not significantly differ among patients with the rs1127354 genetic variant compared with patients without the variant when the ribavirin dosage was decreased (73% for both CC and non-CC genetic variants).[24] Additional prospective randomized trials are necessary to determine the clinical impact of pharmacogenomics in patients treated with triple therapy.

Clinical Efficacy

Four Phase II studies evaluated the use of telaprevir for the treatment of chronic HCV genotype 1 infection.[25–28] The study design, dosage regimen, treatment groups, SVR rates (defined as the number of patients with an LLOD of <10 IU/mL), RVR rates, and relapse rates of these studies are summarized in Table 1. The definition of RVR was consistent with that given in the AASLD guidelines.[4] Relapse was defined as an HCV RNA level that was undetectable at the end of treatment but detectable during follow-up.

In an open-label, Phase II trial, Lawitz et al.[25] evaluated the safety of telaprevir plus peginterferon alfa-2a and ribavirin administered for 28 days in 12 treatment-naive patients with chronic HCV genotype 1 infection. Secondary outcomes evaluated included RVR and SVR rates. At the end of the study period, all patients were offered an additional 44 weeks of therapy with peginterferon alfa-2a and ribavirin, for a total of 48 weeks of therapy. Patients' mean age was 42 years, and baseline HCV RNA concentration ranged from 5.33 to 7.69 log10 IU/mL. By day 28, all patients attained RVR and had a decrease of ≤4 log10 IU/mL in their HCV RNA concentration. After patients completed study treatment and continued standard therapy, only 67% of patients attained SVR. The authors concluded that triple therapy with telaprevir, peginterferon alfa-2a, and ribavirin rapidly reduced HCV RNA levels to undetectable concentrations by week 4 and resulted in SVR in most patients.[25]

Two multicenter, randomized, placebo-controlled, Phase IIb studies—Protease Inhibition for Viral Evaluation (PROVE) 1 (n = 250) and PROVE 2 (n = 323)—evaluated telaprevir in combination with peginterferon alfa-2a and ribavirin in treatment-naive adult patients with chronic HCV genotype 1 infection.[26,27] Patients were excluded from PROVE 1 if they had decompensated liver disease, liver disease unrelated to HCV, HCC, HIV infection, a platelet count of <90 × 103 cells/μL, an absolute neutrophil count of <1500 cells/μL, a low hemoglobin level, or histological evidence of cirrhosis confirmed by liver biopsy within two years before the study.[26] Exclusion criteria for PROVE 2 included undetectable plasma HCV RNA levels and histological evidence of cirrhosis within two years before study initiation.[27] Each study randomized patients to one of three telaprevir-based treatment groups (PROVE 1: 12 weeks of telaprevir and peginterferon alfa-2a plus ribavirin [T12PR12], 12 weeks of telaprevir and peginterferon alfa-2a plus ribavirin followed by 12 weeks of peginterferon alfa-2a plus ribavirin [T12PR24], or 12 weeks of telaprevir and peginterferon alfa-2a plus ribavirin followed by 36 weeks of peginterferon alfa-2a plus ribavirin [T12PR48]; PROVE 2: 12 weeks of telaprevir and peginterferon alfa-2a [T12P12], T12PR24, or 12 weeks of placebo and peginterferon alfa-2a plus ribavirin followed by 36 weeks of peginterferon alfa-2a plus ribavirin [PR48]) (Table 1). The patients in the T12P12 group were not blinded to treatment because of the concern for distinguishable hematologic effects (e.g., hemolytic anemia) specific to ribavirin therapy.

In PROVE 1, baseline characteristics were similar among groups, with the exception of baseline HCV RNA concentrations, which were significantly higher in the PR48 group than in the T12PR48 group (6.68 ± 0.49 log10 IU/mL versus 6.47 ± 0.60 log10 IU/mL, respectively; p = 0.03).[26] SVR rates were 20–26% higher in the T12PR24 (p = 0.02) and T12PR48 (p = 0.002) groups compared with the PR48 group. The T12PR12 group was not compared with the PR48 group because it was an exploratory group and included a small patient sample. In addition, RVR rates were significantly higher (by 70%) in the T12PR24 and T12PR48 groups compared with the PR48 group (p < 0.001). No additional benefit in SVR was seen between the T12PR48 and T12PR24 groups. The rate of relapse was lowest in the T12PR24 group (2%).

In PROVE 2, baseline characteristics were similar among groups.[27] SVR rates were 23% higher in the T12PR24 group compared with the PR48 group (p = 0.004). There were no significant differences in SVR rates between the T12P12 (p = 0.20) and T12PR12 (p = 0.12) groups compared with the PR48 group. However, the SVR rate was significantly higher in the T12PR12 group versus the T12P12 group (p = 0.003). All telaprevir-based groups had significantly higher RVR rates compared with the PR48 group (p < 0.001). The relapse rate was lowest in the T12PR24 group (14%).

McHutchison et al.[28] (PROVE 3) evaluated the use of telaprevir plus peginterferon alfa-2a and ribavirin in adult patients with chronic HCV genotype 1 infection previously treated with peginterferon alfa-2a and ribavirin. Inclusion criteria were similar to those of the PROVE 1 study;[26] however, older patients (≤70 years) and patients previously treated with peginterferon alfa-2a and ribavirin for at least 12 weeks who did not attain an SVR were eligible for study enrollment. Previous responses to peginterferon alfa-2a and ribavirin were further categorized as nonresponse, relapse, or breakthrough. Nonresponse was defined as failure to clear HCV RNA during or by the end of therapy. Relapse was defined as HCV RNA levels that were undetectable for at least 42 weeks but detectable during follow-up. Breakthrough was defined as HCV RNA levels that were undetectable during treatment but detectable before the end of treatment. Unlike the PROVE 1 and 2 studies, patients with cirrhosis were not excluded. All patients were randomized to one of four regimens: T12PR24, 24 weeks of telaprevir and peginterferon alfa-2a plus ribavirin followed by 24 weeks of peginterferon alfa-2a plus ribavirin (T24PR48), 24 weeks of telaprevir and peginterferon alfa-2a (T24P24), or PR48 (Table 1). The loading dose of telaprevir was lower in this study compared with that used in the PROVE 1 and 2 studies (1125 mg versus 1250 mg, respectively).

Baseline characteristics were similar among groups, except for a significant difference in median age in the placebo group compared with the T24P24 group (50 years versus 53 years, respectively; p = 0.01). At baseline, 57% of patients were considered nonresponders to previous HCV treatment, 36% had a relapse, and 7% had viral breakthrough. Compared with the PR48 group, SVR rates were 37–39% higher in the T12PR24 group (p < 0.001) and T24PR48 group (p < 0.001) and 10% higher in the T24P24 group (p = 0.02). SVR rates were higher among patients, regardless of treatment group, who had a relapse to previous treatment (20–76%) than among nonresponders (9–39%). Relapse rates were highest in the PR48 and T24P24 groups (53%) and lowest in the T24PR48 group (13%).

The results from PROVE 3 showed improved SVR rates in patients whose previous treatment of peginterferon alfa-2a and ribavirin did not achieve SVR and who received telaprevir plus peginterferon alfa-2a and ribavirin (T12PR24 and T24PR48 groups) compared with the PR48 group. In the PROVE 2 study, treatment-naive patients not receiving ribavirin in combination with peginterferon alfa-2a and telaprevir (T12P12) had a 26% higher relapse rate compared with the PR48 group.[27] In the PROVE 3 study, patients who had previous treatment failure and were not retreated with ribavirin in combination with peginterferon alfa-2a and telaprevir (T24P24) had a relapse rate (53%) similar to that of the control group.[28] The strengths of the PROVE trials were the study design (multicenter, randomized, placebo-controlled), similar sample population (patients with chronic HCV genotype 1 infection), intent-to-treat analysis, and evaluation of various treatment regimens. A significant limitation of these studies was the lack of inclusion of special populations (e.g., HIV coinfection, presence of liver decompensation, infection with other HCV genotypes). Further, the LLODs for HCV RNA levels were inconsistent with current practice guidelines.[25–28] All of the studies were funded by the manufacturer of telaprevir.

Three Phase III studies further evaluated the efficacy and safety of telaprevir in the treatment of patients with chronic HCV genotype 1 infection.[29–31] The study design, dosage regimen, treatment groups, and SVR (LLOD of <10 IU/mL) rates of these studies are summarized in Table 2. Extended RVR (eRVR), a new virological measurement, was evaluated in these trials to determine the total duration of combination therapy with peginterferon alfa-2a and ribavirin. Patients received a total of 24 or 48 weeks of peginterferon alfa-2a and ribavirin based on their eRVR (defined as undetectable HCV RNA levels at weeks 4 and 12). Patients without an eRVR received a total of 48 weeks of peginterferon alfa-2a and ribavirin therapy.

ADVANCE (A New Direction In HCV Care: A Study Of Treatment Naive Hepatitis C Patients With Telaprevir) randomized HCV treatment-naive patients with chronic HCV genotype 1 infection to one of three treatment groups: 12 weeks of telaprevir plus peginterferon alfa-2a (T12PR), 8 weeks of telaprevir plus peginterferon alfa-2a and ribavirin (T8PR), or PR48.[29] The dosages of all agents administered were the same as those in the PROVE 1 and 2 studies, except a loading dose of telaprevir was not given.[26,27] The overall SVR rate was 25–31% higher in the telaprevir-based groups compared with the PR48 group (p < 0.001).[29] Patients in the telaprevir-based groups demonstrated greater RVR rates (57–59% higher) compared with the control group. Subgroup analyses of various patient characteristics revealed that SVR rates were significantly higher with telaprevir therapy compared with PR48; however, SVR rates did not significantly differ between patients with baseline HCV RNA concentrations of <800,000 IU/mL and patients with cirrhosis. The relapse rate was similar among the telaprevir-based groups and 19% lower than that in the standard therapy group.

The ILLUMINATE (Illustrating The Effects Of Combination Therapy With Telaprevir) trial evaluated the efficacy noninferiority of response-guided and extended duration of treatment in treatment-naive patients with HCV genotype 1 infection.[30] All patients received 12 weeks of telaprevir plus peginterferon alfa-2a and ribavirin. Of the 540 patients treated with telaprevir for 12 weeks, 322 (59.6%) were randomized to either 24 or 48 weeks of peginterferon alfa-2a and ribavirin treatment. The overall SVR rate was 71.9%. The treatment response of the 24-week group was noninferior to that of the 48-week group, with a difference of 4.5% in SVR rate (95% confidence interval, –2.1% to 11.1%). The authors concluded that response-guided therapy after 12 weeks of telaprevir plus peginterferon alfa-2a and ribavirin therapy led to an overall SVR rate of 71.9% and a shorter total duration (24 weeks) of therapy with peginterferon alfa-2a and ribavirin.

The investigators of ADVANCE and the ILLUMINATE trial, published SVR rates based on an LLOD of <10 IU/mL; however, the SVR results reported in the package insert were based on an LLOD of <25 IU/mL. SVR rates were 26–33% higher in the telaprevir-based groups compared with the group receiving only peginterferon alfa-2a and ribavirin in ADVANCE (p values not available).[14] In the ILLUMINATE trial, SVR rates were comparable between the T12PR24 (92%) and T12PR48 (90%) groups.[14]

The REALIZE trial was conducted to determine the efficacy and safety of telaprevir-based regimens compared with standard therapy (combination of peginterferon alfa-2a or alfa-2b and ribavirin) in 662 patients with chronic HCV genotype 1 infection who did not achieve SVR with standard therapy.[31] This randomized, double-blind, placebo-controlled study enrolled patients who had previously relapsed (defined as an HCV RNA level that was undetectable at the end of treatment but detectable within 24 weeks of follow-up) and prior nonresponders (defined as having a detectable HCV RNA level during or at the end of at least 12 weeks of treatment). Nonresponders were further divided into two groups: prior partial responders (≥ 2 log10 reduction in HCV RNA level at week 12, but HCV RNA was detectable at the end of treatment) and prior null responders (<2 log10 reduction in HCV RNA level at week 12 of previous treatment). Dosages of all medications administered were the same as previously described in the PROVE 1 trial;[26] however, the timing of telaprevir initiation varied from early to delayed start (DS) in the treatment regimen. Patients were randomized to one of three treatment groups (T12PR48, T12DSPR48, or PR48). Baseline characteristics were similar among treatment groups.[31] SVR rates were comparable between the early and DS telaprevir regimens. Patients in the two telaprevir groups had significantly higher SVR rates compared with the PR48 group. SVR rates were significantly higher in the T12PR48 and T12DSPR48 groups, regardless of response to previous therapy, compared with the PR48 group (59–64% higher in patients with prior relapse, 32% higher in patients with no prior virological response, 39–44% higher in patients with prior partial response, and 24–28% higher in patients with no prior response; p < 0.001). The relapse rate was lowest in prior relapsers treated with telaprevir (7%).[31]

All of the Phase III trials included a small population of patients with cirrhosis at baseline (21% in ADVANCE and 26% in the REALIZE study).[29,31] Treatment-naive patients with cirrhosis treated with telaprevir plus peginterferon alfa-2a and ribavirin had an overall SVR rate of 62–92%.[14] Patients with cirrhosis who had previous treatment failure and were treated with triple therapy had higher SVR rates (14–87%, depending on prior response) compared with patients treated with peginterferon alfa-2a and ribavirin (10–20%).

Preliminary results for one Phase IIa study (C209) evaluating the use of telaprevir in patients with HCV genotype 2 or 3 infection were presented in at the European Association for the Study of the Liver Meeting 2010. Foster et al.[32] evaluated the use of telaprevir monotherapy or in combination with peginterferon alfa-2a and ribavirin in treatment-naive adult patients with HCV genotype 2 and 3 infections. A total of 49 patients were randomized to one of three treatment groups: 2 weeks of placebo and peginterferon alfa-2a plus ribavirin followed by 22 weeks of peginterferon alfa-2a plus ribavirin (PR24), 2 weeks of telaprevir followed by 24 weeks of peginterferon alfa-2a plus ribavirin (T2PR24), and 2 weeks of telaprevir plus peginterferon alfa-2a and ribavirin followed by 22 weeks of peginterferon alfa-2a and ribavirin (TPR2PR22) (Table 1). On day 15, patients with HCV genotype 2 infections in the T2PR24 group had a higher median decrease in HCV RNA concentration (3.66 IU/mL) compared with patients with HCV genotype 3 infection in the T2PR24 group (0.54 IU/mL) (p not reported). For the TPR2PR22 group, the median decrease in HCV RNA concentration was 5.51 IU/mL in patients with HCV genotype 2 and 4.85 IU/mL in patients with HCV genotype 3. The SVR rate was highest in the TPR2PR22 group, regardless of genotype, compared with the other treatment groups.[32]

Marcellin et al.[33] evaluated a dosage regimen of telaprevir 1125 mg administered every 12 hours compared with a regimen of telaprevir 750 mg every 8 hours in combination with peginterferon alfa-2a or alfa-2b and ribavirin in treatment-naive patients with chronic HCV genotype 1 infection. A loading dose of telaprevir was not used, and SVR rates (81–85%) were similar among all groups (p ≥ 0.05).

Safety and Contraindications

Ten of the identified efficacy studies also assessed the safety profile of telaprevir in patients with chronic HCV infection.[14,17,18,25–31] The most common adverse events reported with telaprevir monotherapy versus placebo were diarrhea, nausea, fatigue, and dry skin (frequency unavailable).[17] However, the frequency of adverse events was higher in both the peginterferon alfa-2a group and the telaprevir plus peginterferon alfa-2a group compared with telaprevir monotherapy, with the most common events being headache (50% in the peginterferon alfa-2a group, 63% in the telaprevir plus peginterferon alfa-2a group, and 25% in the telaprevir monotherapy group), myalgia (50%, 63%, and 25%, respectively), and nausea (25%, 38%, and 13%, respectively).[18] The rate of rash was higher in the telaprevir plus peginterferon alfa-2a (38%) and telaprevir monotherapy (13%) groups compared with the peginterferon alfa-2a group (0%).

Lawitz et al.[25] evaluated the use of telaprevir plus peginterferon alfa-2a and ribavirin without a comparison group for 28 days. The most frequent adverse events reported were influenzalike illness (58%), fatigue (50%), headache (42%), nausea (42%), anemia (33%), depression (25%), and pruritus (25%); however, no serious adverse events or premature treatment discontinuations were observed. Based on pooled data analysis, serious adverse drug reactions were reported for 3% of 1791 patients treated with triple therapy compared with no adverse reactions for 493 patients treated with peginterferon alfa-2a and ribavirin.[14]

In the PROVE studies, the most common adverse events reported were influenzalike illness (25–49% in the telaprevir-based groups and 32–52% in the PR48 group), fatigue (26–82% and 37–76%, respectively), headache (35–53% and 36–60%, respectively), insomnia (14–44% and 17–39%, respectively), and depression (11–22% and 17–23%, respectively).[26–28] The rate of nausea was higher in the telaprevir plus peginterferon alfa-2a and ribavirin groups (36–65%) than in the PR48 group (29–40%). Diarrhea occurred more frequently in the telaprevir plus peginterferon alfa-2a and ribavirin groups (24–43%) compared with the PR48 group (19–28%). However, pruritus and rash were reported more frequently in all the telaprevir-based groups (24–63% of patients had pruritus and 41–61% had rash) than in the PR48 group (15–35% had pruritis and 20–41% had rash). The severity of rash (grades 1–4) was determined by onsite investigators.[27,28] Severe (grade 3) rash occurred in 3–7% of patients in the telaprevir-based groups compared with 0–1% in the PR48 group.[26–28] The authors of another study reported rash (56.4–72.5%) and pruritus (47.5–64.1%) in patients treated with telaprevir.[33] Results from ADVANCE and the REALIZE study and preliminary results from the ILLUMINATE trial revealed adverse events similar to those described in the PROVE trials, such as influenzalike illness and rash.[29–31] Other adverse events reported in ADVANCE included pruritus, anemia, nausea, and diarrhea, the frequency of which was at least 10% higher with telaprevir compared with standard therapy.[29] In the REALIZE study, adverse events that occurred in more than 25% of patients who received telaprevir therapy included fatigue, pruritus, rash, nausea, influenzalike illness, anemia, and diarrhea.[31] The adverse events reported from pooled clinical data of 1797 patients treated with triple therapy and 493 patients treated with peginterferon alfa-2a and ribavirin are listed in Table 3.[14]

The types of rash reported in clinical trials were described as drug-induced maculopapular rashes with or without pruritus that resolved after treatment discontinuation.[25–28] A published report described the case of a 57-year-old woman who developed a drug rash with eosinophilia and systemic symptoms, possibly due to telaprevir.[34] The patient was enrolled in the PROVE 2 trial and treated with peginterferon alfa-2a and ribavirin for 48 weeks; however, seven months later she received telaprevir plus peginterferon alfa-2a and ribavirin because of detectable HCV RNA levels. After 6 weeks of treatment with telaprevir plus peg-interferon alfa-2a and ribavirin, the patient developed a pruritic maculopapular rash with malaise, fever, dyspnea, lymph node swelling, and eosinophilia (eosinophil count, 2.7 × 109 cells/L). The patient was treated with oral and topical corticosteroids, and her symptoms resolved within one month after treatment discontinuation. The median time to the development of rash during clinical trials ranged from 7 to 34 days.[27,28,33] The time for resolution of severe rash ranged from 9 to 104 days after onset.[28]

Treatment withdrawal due to any adverse events during clinical studies in telaprevir-based groups was 7–21% versus 3–11% in the PR48 group.[26–29,31] Discontinuation of treatment due to rash in the telaprevir-based groups occurred in 0.5–7% of patients, while none of the patients in the PR48 group discontinued treatment for this reason.[14,27–31] The observed median times to treatment discontinuation due to rash were 51[28]–73[26] days (range, 4–123 days).

At week 12 of therapy, a median decrease in hemoglobin concentrations was more common during treatment with telaprevir (median decreases of 0.1–1 g/dL greater compared with a median decrease of 3 g/dL in the PR48 group).[26,27] Hemoglobin concentrations of ≤10 g/dL were reported in 36% of patients who received triple therapy compared with 17% of patients who received the combination of peginterferon alfa-2a and ribavirin (p not reported).[14] However, hemoglobin concentrations increased to similar mean levels in the PR48 group after completion of telaprevir treatment.[14,26,28] Results of one study revealed that hemoglobin concentrations of <8–8.5 g/dL (based on sex) occurred in 11.8% of patients, and erythropoietin was administered in 25% of patients.[33] Patients in the REALIZE and ADVANCE studies were prohibited use of erythropoietin, and hemoglobin concentrations of <8.5 g/dL occurred in 11–14% of patients (reported in ADVANCE).[29,31] Overall, 4% of patients discontinued telaprevir and 1% discontinued triple therapy due to anemia; however, 32% of patients had a modification in the ribavirin dosage.[14] Chayama et al.[24] found that patients with chronic HCV genotype 1 infection with ITPA SNP rs1127354 genotype CC required a reduction in ribavirin dosage significantly earlier (18 days) than did patients with non-CC genotypes (29 days) (p < 0.05). The reduction in ribavirin dosage did not significantly affect the SVR rate.

All contraindications (e.g., pregnancy) to peginterferon alfa-2a and ribavirin apply to telaprevir, since telaprevir must be administered in combination with these agents. Peg-interferon alfa-2a and ribavirin are pregnancy category X drugs based on animal studies that found birth defects from ribavirin, fetal deaths with peginterferon alfa-2a, or both; however, telaprevir is a pregnancy category B drug, as no harm to the fetus of mice and rats has been observed with its use.[14] Women of childbearing age and male patients with female partners should be advised to use two effective nonhormonal methods of contraception during triple therapy and for up to two weeks after treatment discontinuation. Concomitant administration of telaprevir with drugs that are highly dependent on CYP3A for metabolism and would potentially increase the risk of serious or life-threatening events due to elevated drug concentrations (i.e., alfuzosin, rifampin, ergot derivatives, cisapride, statins, pimozide, phosphodiesterase-5-enzyme inhibitors, midazolam, and triazolam) is contraindicated.[14] Concomitant use of telaprevir with drugs that strongly induce CYP3A and decrease the telaprevir concentration (e.g., St. John's wort), leading to reduced telaprevir efficacy, is contraindicated.

Drug Interactions

Telaprevir is a substrate and inhibitor of CYP3A4 and P-glycoprotein.[14] Drugs that induce or inhibit CYP3A4 may decrease concentrations of telaprevir, resulting in reduced efficacy or increased concentrations of telaprevir (e.g., antibacterials, anticonvulsants, ketoconazole, rifabutin, dexamethasone, HIV-protease inhibitors) and an increased risk for adverse reactions. Administration of telaprevir with drugs that are substrates of CYP3A4 or P-glycoprotein may increase plasma concentrations of these drugs and result in potentially adverse events. There are several drugs with established and potentially significant drug interactions with telaprevir.[14] Telaprevir concentrations also increase when administered with food.

Unlike other antiretroviral agents, which target aspartate, telaprevir targets serine.[35] However, there is concern about drug–drug interactions between telaprevir and anti-retroviral agents due to structural similarities and common metabolic pathways. Kempf et al.[36] assessed the interactions between telaprevir and ritonavir, a potent CYP3A4 inhibitor, in rats and pooled human liver microsomes. In rats, the administration of ritonavir increased plasma exposure to telaprevir by greater than 15-fold. Eight hours after the administration of telaprevir and ritonavir, the telaprevir concentration increased by greater than 50-fold. In human liver microsomes, ritonavir concentrations of 0.4 and 4.0 μM resulted in a mean inhibition of 71% and 100% of telaprevir, respectively. However, when the interactions of ritonavir and telaprevir were evaluated in humans, ritonavir 100 mg every 12 hours reduced the least- squares mean concentration ratio of telaprevir (750 mg every 12 hours) at steady state to 0.76 (comparison concentration not available).[14] Other protease inhibitors (e.g., atazanavir, darunavir, fosamprenavir, lopinavir) also reduced steady-state concentrations of telaprevir.[14] Therefore, telaprevir and protease inhibitors should not be administered together.

One Phase I study evaluated the interaction of telaprevir with cyclosporine and tacrolimus.[37] In this open-label, nonrandomized, parallel, single-sequence evaluation of 20 healthy patients, 10 patients received cyclosporine as a single 100-mg oral dose followed by an 8-day washout period and then received a single dose of cyclosporine 10 mg with either a single dose of telaprevir 750 mg or telaprevir 750 mg every 8 hours for 8 days. The remaining 10 patients received a single dose of tacrolimus 2 mg followed by a 14-day washout period and then received a single dose of tacrolimus 0.5 mg with telaprevir 750 mg every 8 hours. Telaprevir increased both the cyclosporine AUC and tacrolimus AUC by 4.6-fold and 70-fold, respectively. Telaprevir increased the mean ± S.D. elimination half-life of cyclosporine (from 12 ± 1.67 hours to 42.1 ± 11.3 hours) and tacrolimus (from 40.7 ± 5.85 hours to 196 ± 159 hours). This study was not designed to evaluate the effects of cyclosporine and tacrolimus on telaprevir exposure.[37] The coadministration of telaprevir and cyclosporine or tacrolimus is not recommended due to the significant increase in drug concentrations, the prolonged elimination half-life of cyclosporine and tacrolimus, and the lack of data evaluating the use of telaprevir in solid-organ transplant recipients.

Viral Drug Resistance

In addition to the possible dose-limiting adverse effects of telaprevir, the development of HCV drug resistance may limit its clinical efficacy. Possible mechanisms for drug resistance are the high viral replication rate and the intrinsically error-prone nature of HCV polymerase and the ability of viral variants to rapidly adapt resistance to drug therapy.[16] During viral replication, HCV polymerase lacks a "proofreading ability," resulting in random viral mutations and a potential reduced susceptibility to telaprevir even before treatment. Further, HCV rapidly replicates as a quasi-species, producing a multitude of genetically distinct but related viral variants with short half-lives. These viral variants have the ability to quickly adapt to changes in their environment (e.g., drug exposure). Therefore, a low level of a resistant variant to telaprevir can become the dominant viral species if it demonstrates a selective advantage to replicate.[16]

Genotypic assays that analyze either population-based sequences or clonal sequences are used to identify specific resistant viral variants.[16] Population-based sequencing is less sensitive than clonal sequencing because it cannot determine the linkage between mutations of a single variant or detect low levels of resistant variants. Although clonal sequencing is a highly sensitive method, it is more time-consuming and costly.[16] Phenotypic assays are used to determine the significance of resistant viral variants by measuring the increase in the 50% inhibitory concentration (IC50).[16,38] Sarrazin et al.[38] evaluated plasma samples from 34 patients infected with HCV genotype 1 who were treated with telaprevir in a previous study.[17] The investigators identified two types of HCV viral variants: those with low-level resistance and those with high-level resistance.[38] The common viral variants with low-level resistance (less than 25-fold increase in IC50 ) were T54A, V36A/M, R155K/T, and A156S. Common high-level resistance (viral variants with greater than 60-fold increase in IC50) included A156T/V, V36M/A+R155K/T, and V36M+A156T. Other in vitro studies using both biochemical and HCV genotype 1b replicon assays to evaluate resistance to telaprevir identified additional variants T54A/S, R155T+D168N, and V36A+T54A, which conferred a 3- to 25-fold decreased susceptibility to telaprevir, and T54S/A+A156S/T double variants, which have a greater than 62-fold decreased susceptibility to telaprevir.[14] Genotypic analyses revealed a cross-resistance of viral variants (V36A/M, T54A/S, R155K/T, A156S, and D168) with telaprevir and boceprevir, suggesting that HCV genotype 1 viral resistance may be a class effect.[14,39,40] Cross-resistance is not anticipated between telaprevir and peginterferon alfa-2a, telaprevir, ribavirin, or other DAA with different mechanisms of action (e.g., NS5B polymerase inhibitors).[14]

Kuntzen et al.[41] analyzed HCV population-based sequences of 507 treatment-naive patients with HCV genotype 1 infection to determine the prevalence of dominant resistance mutations against telaprevir. They discovered varying rates of viral resistance, from 0.3% to 2.8%, and found that 8.6% of patients with HCV genotype 1a infection and 1.4% of patients with HCV genotype 1b infection carried at least one dominant resistant mutation, such as R155K and V36M. None of the patients carried the A156 mutation, which is known to confer a high level of drug resistance. The authors concluded that dominant resistant mutations are common in HCV treatment-naive patients; however, the clinical significance of this finding on treatment outcomes requires further investigation to determine the benefit of drug-resistance testing, as preexisting viral variants may not predict treatment failure. In a pooled analysis of patients enrolled in the Phase III trials, 5% of patients had a resistant viral variant (i.e., V36, T54, R155, or D168) at baseline; however, the effect on treatment response could not be determined due to the small sample size.[14]

Overall, treatment of HCV infection with telaprevir alone should be avoided due to the naturally occurring resistant viral variants leading to viral breakthrough (defined as reappearance of HCV RNA levels during treatment).[25,41] However, in patients with chronic HCV genotype 1 infection who received the combination of telaprevir, peginterferon alfa-2a, and ribavirin, 1–57% had viral breakthrough.[14,25–29,31,33] The resistant viral variants observed were V36M/A/L, R155K/T, T54A/S, and A156S/T.[14,26–29,31] Forty-one percent of these patients had low-level resistant variants, and 55% had high-level resistant variants.[27] In the REALIZE study, 73% of all virological treatment failures and relapses were due to the emergence of variants with decreased sensitivity to telaprevir.[31] Prior null responders to standard therapy who were treated with triple therapy had higher rates of viral breakthrough (47–57%) compared with prior relapsers (1%, p not reported).[31] In ADVANCE, rates of virological failure were 5% higher among patients who received 8 weeks of telaprevir (T8PR) compared with patients who received 12 weeks of telaprevir (T12PR).[29] In patients who received telaprevir and peginterferon alfa-2a without ribavirin, the viral breakthrough rate was 24–32%.[27,28] The addition of ribavirin to treatment groups resulted in lower viral breakthrough rates. A three-year follow-up study of a Phase II study evaluated 56 treatment-naive patients and patients who had not responded to previous treatment who did not achieve SVR with telaprevir due to viral breakthrough to determine the persistence of resistant HCV variants.[14] At three years, population sequencing found that telaprevir-resistant variants V36M, T54A/S, and A156N/S/T were below the detectable levels, but 3% of patients had detectable R155K variants. Although resistant HCV variants persisted in a small percentage of patients, their impact on long-term clinical outcomes is unknown. Data are not available on the efficacy of retreating patients who were previously treated with telaprevir.[14] There is concern regarding varying HCV resistance to telaprevir by HCV genotype. In an in vitro study, Imhof and Simmonds[42] analyzed phenotypic assays and found that HCV genotypes 1a and 6a were susceptible to telaprevir, genotypes 4a and 5a were resistant to telaprevir, and genotypes 2a and 3a demonstrated intermediate susceptibility to telaprevir. Currently, no commercially standardized assays are available to evaluate HCV drug resistance in routine clinical practice. The potential long-term clinical effect of viral drug resistance in patients who do not achieve SVR warrants further investigation.

Dosing and Administration

Telaprevir is an orally bioavailable agent that is administered every eight hours due to its short half-life.[14,15,17] For treatment-naive and prior-relapse patients, the recommended dosage of telaprevir is 750 mg by mouth every eight hours with food (not low fat) for 12 weeks in combination with peginterferon alfa-2a and ribavirin, followed by a response-guided regimen (based on eRVR at weeks 4 and 12) of 12 or 36 weeks of peginterferon alfa-2a and ribavirin. For prior partial and null responders, the recommended dosage and duration of triple therapy are the same as above, followed by an additional 36 weeks of peginterferon alfa-2a and ribavirin.[14] Treatment-naive patients with cirrhosis and undetectable HCV RNA levels at weeks 4 and 12 with triple therapy may benefit from an additional 36 weeks of peginterferon alfa-2a and ribavirin. The current average wholesale price of telaprevir is $117.14 per 375-mg capsule.[14]

There are limited data supporting the use of telaprevir in specific populations.[14] Telaprevir is not recommended for patients with moderate-to-severe hepatic impairment (Child-Pugh class B or C); however, dosage adjustment is not necessary for patients with mild hepatic impairment (Child-Pugh class A). The dosage of telaprevir does require adjustment in patients with renal impairment; however, caution is advised in patients with a CLcr of <50 mL/min, with end-stage renal disease, or undergoing hemodialysis.

Place in Therapy

The goal of therapy in patients with chronic HCV infection is prevention of long-term complications, such as cirrhosis or HCC, and mortality.[4] The duration of treatment and response depends on the HCV genotype. The AASLD practice guidelines recommend treatment of patients with chronic HCV genotype 1 with peginterferon alfa-2a or alfa-2b and ribavirin for a total of 48 weeks, while patients who have delayed HCV RNA clearance are recommended to receive this combination therapy for a total of 72 weeks.[4] Patients with chronic HCV genotype 2 or 3 infection should be treated for a total of 24 weeks with peginterferon alfa-2a or alfa-2b and ribavirin. The SVR rate in patients with chronic HCV genotype 1 treated with peg-interferon alfa-2a or alfa-2b and ribavirin is approximately 42–52%, while patients with HCV genotype 2 or 3 infection have a higher SVR rate (76–84%).[6–8]

However, the combination of peginterferon alfa-2a or alfa-2b and ribavirin has dose-limiting adverse effects, which led to 5–15% of treatment discontinuation and poor SVR rates in patients with chronic HCV genotype 1 infection. The DAAs such as telaprevir directly target the HCV replication cycle and may be feasible options to improve SVR rates in these patients. In Phase II clinical trials, telaprevir plus peginterferon alfa-2a and ribavirin increased SVR rates by at least 20–35% in treatment-naive patients and those who had previous treatment failure when compared with standard therapy.[26–28]

Phase III trials found that SVR rates increased by 25–31% in treatment-naive patients and by 24–64% in patients with chronic HCV genotype 1 infection who had a prior treatment failure when treated with telaprevir, peginterferon alfa-2a, and ribavirin compared with standard therapy.[14,29,31] Telaprevir was administered for either 8 or 12 weeks; however, 12 weeks of telaprevir had less on-treatment virological failure compared with 8 weeks of telaprevir.[29] Response-guided therapy in treatment-naive patients based on eRVR rates shortened the total duration from 48 to 24 weeks of peginterferon alfa-2a and ribavirin therapy in combination with 12 weeks of telaprevir.[14] Preliminary results from the Phase IIa C209 study suggest that telaprevir is efficacious against HCV genotype 2 infection but has limited activity against HCV genotype 3 infection.[32]

Limitations of telaprevir use include the administration of doses every eight hours; the high cost of therapy; the high frequency of rash, which can lead to treatment discontinuation; and possible viral breakthrough during treatment due to the emergence of HCV variants that may be less susceptible to telaprevir. The frequency of drug-induced maculopapular rash in the telaprevir-based regimens was 20% higher compared with the combination of peginterferon alfa-2a and ribavirin.[14,26–28] The rate of treatment discontinuation attributable to rash was ≤7% in patients treated with telaprevir.[14,27–31] In most cases, rash resolved after treatment discontinuation.[26–28] Also, a higher decline (median, 0.1–1.0 g/dL) in hemoglobin concentrations was more common in patients receiving telaprevir compared with patients receiving only peginterferon alfa-2a and ribavirin.[26–28] Patients in the Phase III studies (REALIZE and ADVANCE) were prohibited from using erythropoietin, and hemoglobin concentrations of <8.5 g/dL occurred in 11–14% of patients.[29,31]

Viral variants with reduced susceptibility to telaprevir may increase the rate of viral breakthrough. In clinical trials, the frequency of viral breakthrough in telaprevir-based regimens with peginterferon alfa-2a and ribavirin was 1–57%.[14,25–29,31,33] There was a higher rate of viral breakthrough in patients who received telaprevir and peginterferon alfa-2a without ribavirin (24–32%)[27,28] and in prior null responders treated with triple therapy (47–57%).[31] Other concerns with HCV resistance to telaprevir include possible cross-resistance to other drugs within the same class (e.g., boceprevir) and varying HCV resistance by genotypes.[39,40,42] However, studies investigating the clinical utility of standardized assays to evaluate HCV resistance to telaprevir and its effect on patients who do not achieve SVR are lacking. Thus, telaprevir use should be limited to patients with chronic HCV genotype 1 infection until its efficacy and safety are further investigated in other HCV genotypes.

Conclusion

Telaprevir, an HCV NS3/4A pro-tease inhibitor, has been shown to be effective in increasing SVR rates when used with peginterferon alfa and ribavirin in patients with chronic HCV genotype 1 infection, regardless of treatment history.

References

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Source

Breaking Bad Habits Why It’s So Hard to Change

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NIH News in Health Jan. 2012

If you know something’s bad for you, why can’t you just stop? About 70% of smokers say they would like to quit. Drug and alcohol abusers struggle to give up addictions that hurt their bodies and tear apart families and friendships. And many of us have unhealthy excess weight that we could lose if only we would eat right and exercise more. So why don’t we do it?

NIH-funded scientists have been searching for answers. They’ve studied what happens in our brains as habits form. They’ve found clues to why bad habits, once established, are so difficult to kick. And they’re developing strategies to help us make the changes we’d like to make.

“Habits play an important role in our health,” says Dr. Nora Volkow, director of NIH’s National Institute on Drug Abuse. “Understanding the biology of how we develop routines that may be harmful to us, and how to break those routines and embrace new ones, could help us change our lifestyles and adopt healthier behaviors.”

Habits can arise through repetition. They are a normal part of life, and are often helpful. “We wake up every morning, shower, comb our hair or brush our teeth without being aware of it,” Volkow says. We can drive along familiar routes on mental auto-pilot without really thinking about the directions. “When behaviors become automatic, it gives us an advantage, because the brain does not have to use conscious thought to perform the activity,” Volkow says. This frees up our brains to focus on different things.

Habits can also develop when good or enjoyable events trigger the brain’s “reward” centers. This can set up potentially harmful routines, such as overeating, smoking, drug or alcohol abuse, gambling and even compulsive use of computers and social media.

“The general machinery by which we build both kinds of habits are the same, whether it’s a habit for overeating or a habit for getting to work without really thinking about the details,” says Dr. Russell Poldrack, a neurobiologist at the University of Texas at Austin. Both types of habits are based on the same types of brain mechanisms.

“But there’s one important difference,” Poldrack says. And this difference makes the pleasure-based habits so much harder to break. Enjoyable behaviors can prompt your brain to release a chemical called dopamine. “If you do something over and over, and dopamine is there when you’re doing it, that strengthens the habit even more. When you’re not doing those things, dopamine creates the craving to do it again,” Poldrack says. “This explains why some people crave drugs, even if the drug no longer makes them feel particularly good once they take it.”

In a sense, then, parts of our brains are working against us when we try to overcome bad habits. “These routines can become hardwired in our brains,” Volkow says. And the brain’s reward centers keep us craving the things we’re trying so hard to resist.

The good news is, humans are not simply creatures of habit. We have many more brain regions to help us do what’s best for our health.

“Humans are much better than any other animal at changing and orienting our behavior toward long-term goals, or long-term benefits,” says Dr. Roy Baumeister, a psychologist at Florida State University. His studies on decision-making and willpower have led him to conclude that “self-control is like a muscle. Once you’ve exerted some self-control, like a muscle it gets tired.”

After successfully resisting a temptation, Baumeister’s research shows, willpower can be temporarily drained, which can make it harder to stand firm the next time around. In recent years, though, he’s found evidence that regularly practicing different types of self-control—such as sitting up straight or keeping a food diary—can strengthen your resolve.

“We’ve found that you can improve your self-control by doing exercises over time,” Baumeister says. “Any regular act of self-control will gradually exercise your ‘muscle’ and make you stronger.”

Volkow notes that there’s no single effective way to break bad habits. “It’s not one size fits all,” she says.

One approach is to focus on becoming more aware of your unhealthy habits. Then develop strategies to counteract them. For example, habits can be linked in our minds to certain places and activities. You could develop a plan, say, to avoid walking down the hall where there’s a candy machine. Resolve to avoid going places where you’ve usually smoked. Stay away from friends and situations linked to problem drinking or drug use.

Another helpful technique is to visualize yourself in a tempting situation. “Mentally practice the good behavior over the bad,” Poldrack says. “If you’ll be at a party and want to eat vegetables instead of fattening foods, then mentally visualize yourself doing that. It’s not guaranteed to work, but it certainly can help.”

One way to kick bad habits is to actively replace unhealthy routines with new, healthy ones. Some people find they can replace a bad habit, even drug addiction, with another behavior, like exercising. “It doesn’t work for everyone,” Volkow says. “But certain groups of patients who have a history of serious addictions can engage in certain behaviors that are ritualistic and in a way compulsive—such as marathon running—and it helps them stay away from drugs. These alternative behaviors can counteract the urges to repeat a behavior to take a drug.”

Another thing that makes habits especially hard to break is that replacing a first-learned habit with a new one doesn’t erase the original behavior. Rather, both remain in your brain. But you can take steps to strengthen the new one and suppress the original one. In ongoing research, Poldrack and his colleagues are using brain imaging to study the differences between first-learned and later-learned behaviors. “We’d like to find a way to train people to improve their ability to maintain these behavioral changes,” Poldrack says.

Some NIH-funded research is exploring whether certain medications can help to disrupt hard-wired automatic behaviors in the brain and make it easier to form new memories and behaviors. Other scientific teams are searching for genes that might allow some people to easily form and others to readily suppress habits.

Bad habits may be hard to change, but it can be done. Enlist the help of friends, co-workers and family for some extra support.