May 21, 2012

Since Gaining European Authority Approval for Victrelis in July and Incivo in September, Protease Inhibitor Share Has Penetrated Nearly One-Third of the Genotype 1 Market

Since Gaining European Authority Approval for Victrelis in July and Incivo in September, Protease Inhibitor Share Has Penetrated Nearly One-Third of the Genotype 1 Market and is Anticipated to Significantly Increase Over the Next Six Months

BioTrends Research Group Posted on:21 May 12

BioTrends Research Group, one of the world’s leading research and advisory firms for specialized biopharmaceutical issues, finds that Vertex and Janssen / Tibotec’s Incivo (telaprevir) and Merck / Roche’s Victrelis (boceprevir) are quickly being adopted as the new standard of care in genotype 1 hepatitis C (HCV) patients in the EU5. Since their European launch, the protease inhibitors (PIs) have penetrated approximately one-third of the genotype 1 hepatitis C (HCV) market, however surveyed physicians anticipate that PI share will account for over half of this market in the next six months. Currently, Incivo makes up 5 percent more of the EU5 protease inhibitor market than Victrelis, though share for each is expected to significantly increase in the future, according to the recently released TreatmentTrends®: Hepatitis C (EU)report.

Furthermore, the 186 gastroenterologists and 69 hepatologists included in the survey are significantly more satisfied with, and view Incivo as performing significantly better than all other HCV treatments, including Victrelis. Specifically, physicians perceive Incivo as significantly outperforming Victrelis on the top three most important attributes for HCV treatments: ‘efficacy in genotype 1 patients,’ ‘efficacy in prior non-responders and partial responders,’ and ‘efficacy in treatment naïve patients.’

Though the majority of surveyed physicians agree that the PIs, Incivo and Victrelis, are important advances for the treatment of HCV, they also agree that there is a need for alternative therapies in the treatment and management of HCV. Moreover, physicians report that nearly one-third of their genotype 1 HCV patients, and slightly over one-quarter of their genotype 2/3 patients, are actively delaying treatment to wait for interferon-free regimens to become available.

With regard to products in development, surveyed physicians report the greatest interest with Gilead’s GS-7977, followed closely by Bristol-Myers Squibb’s daclatasvir. However, GS-7977 and Tibotec / Medivir’s TMC-435 are anticipated to bring the most value to practices for the treatment of HCV, primarily due to GS-7977’s efficacy in trials, pan-genotype usage and mechanism of action, and TMC-435’s efficacy and ease of administration.

Specific analysis of Incivek (Incivo) and Victrelis at one-year post U.S. launch is available via the LaunchTrends®: Incivek and Victrelis, Wave 4 report, publishing at the end of May 2012. Additional analysis of the U.S. hepatitis C market will be covered in TreatmentTrends: Hepatitis C in the U.S., a two-wave report series publishing in June and November 2012.

TreatmentTrends: Hepatitis C (EU) is a syndicated annual report that examines current trends in the management of hepatitis C from the perspective of gastroenterologists and hepatologists with a focus on analyzing their attitudes, perceptions and self-reported prescribing behavior. In addition, this report provides insight into the practice patterns, and current and projected use of various products. TreatmentTrends® also evaluates perceived product advantages and disadvantages, as well as sales and messaging efforts of key market players. This study was fielded with a total of 186 gastroenterologists and 69 hepatologists across France, Germany, Spain, Italy and the United Kingdom via an online survey.

About BioTrends Research Group

BioTrends Research Group provides syndicated and custom market research to pharmaceutical manufacturers competing in clinically evolving, specialty pharmaceutical markets. For information on BioTrends publications and research capabilities, please contact us at (610) 321-9400 or

About Decision Resources Group

Decision Resources Group is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources Group at

All company, brand, or product names contained in this document may be trademarks of their respective holders.

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Last updated on: 21/05/2012 14:00:01


Studies examine potential treatments for UC, hep C and other gastrointestinal conditions


May 21st, 2012

New research being presented at Digestive Disease Week® (DDW) reveals effective treatments for a number of gastrointestinal conditions, which are often chronic and costly. One study found that statin therapy may be safe and potentially beneficial in individuals with cirrhosis, a condition that elevates heart disease risk, while another produced positive outcomes by adding telaprevir to a drug regimen for the most common and difficult-to-treat form of chronic hepatitis C. Researchers also saw benefits from using a subcutaneously injected anti-tumor necrosis factor drug in patients with moderate to severe ulcerative colitis, for which existing treatment options are limited. And probiotic dairy consumption that can affect bacteria in the gut was potentially linked to changes in the activity of regions of the brain that control emotional arousal.

"Gastrointestinal disorders are often hard-to-treat diseases requiring drugs that can lead to diminished quality of life," said Bruce Sands, MD, MS, AGAF, chief, division of gastroenterology, Mount Sinai School of Medicine, New York, NY. "Addtionally, due to the functions of the gastrointestinal track, we are often unsure how drugs for other diseases may affect patients' disorders. New and better treatments are essential to improving quality of life, saving lives and reducing the impact of disease. A number of studies being presented during DDW help further our knowledge of how to best treat our patients while helping to maintain, and in some cases improve, their quality of life." DDW is the largest international gathering of physicians and resarchers in the field of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

Statin Therapy Decreases the Risk of Hepatic Decompensation in Cirrhosis (Abstract #595)

Statin therapy may be safe and potentially beneficial in individuals with cirrhosis, according to new research from Brigham and Women's Hospital, Boston, MA.

While recent studies have shown that treatment with statins in patients with various liver conditions, including hepatitis C and fatty liver disease, is generally well tolerated compared to the general population, both patients and health-care professionals remain concerned about the use of these drugs in patients with liver disease, particularly cirrhosis. However, patients with liver disease are also at risk of heart disease, and treatment with statins may decrease the risk of heart attack and death.

Researchers led by Sonal Kumar, MD, gastroenterology fellow, Brigham and Women's Hospital, aimed to evaluate the safety of statin use in patients confirmed to have advanced liver disease, defined as cirrhosis, by a liver biopsy. They compared 81 patients with cirrhosis who were treated with statins to 162 patients who were not to evaluate the effect of statins. Investigators found fewer deaths in the patients who had cirrhosis and were treated with statins.

Recent studies have suggested that statins may reduce pressures in the liver called portal hypertension, which causes complications such as jaundice, vomiting blood due to enlarged veins in the upper gastrointestinal tract, fluid retention in the abdomen, and confusion. Researchers in this study found that among the group receiving statins, overall decompensation rates were less and the overall time to decompensation was longer. But Dr. Kumar added that further studies are needed to confirm these findings and to better understand the role statins have in patients with cirrhosis.

Despite the findings, Dr. Kumar cautioned that the study reviewed patient chart data retrospectively, and further prospective studies will be needed to clarify the role of statin therapy in cirrhosis. "We can't conclude that everyone with liver disease should get statins, but we did find that in this population, it may not only be safe, but also beneficial to take statins," she said.

No pharmaceutical funding was provided for this study.

Dr. Kumar will present these data on Monday, May 21 at 8:30 a.m. PT in Room 6d of the San Diego Convention Center.

Health-related quality of life among genotype 1 treatment-naïve chronic Hepatitis C patients receiving Telaprevir (Abstract #Sa1048)

Adding telaprevir to two drugs commonly used to treat chronic hepatitis C (peginterferon alfa-2a/ribavirin) does not appear to worsen quality of life substantially compared to using only peginterferon alfa-2a/ribavirin, according to new research from an analysis of the multi-center, multi-national ADVANCE clinical trial. The study looked at patients with genotype 1 hepatitis C who had not been treated previously with telaprevir. These findings are important because genotype 1 is not only the most common form of hepatitis C virus (HCV), is it also the most difficult to treat.

Researchers led by Zobair Younossi, MD, vice president of research and chairman of department of medicine at Inova Health System, Falls Church, VA, analyzed data from 722 patients enrolled in the ADVANCE clinical trial who also had completed the EuroQol Group questionnaire at the beginning of the study and at weeks four, 12, 24, 36, 48 and 72. Patients answered questions about their health-related quality of life in five areas: mobility, self care, usual activities, pain/discomfort and anxiety/depression. Percentages of patients reporting problems in each area and mean scores were calculated.

As expected with any interferon-based regimen, quality of life scores worsened during the first 12 weeks, but returned to normal by week 72; percentages of patients reporting problems at week 12 were high in usual activities, anxiety/depression and pain/discomfort. However, the findings showed that the addition of telaprevir to peginterferon alfa-2a/ribavirin was not associated with substantially lower quality of life scores during treatment. In fact, among those undergoing a shorter treatment duration, improvements in quality of life were observed earlier. Importantly, at week 72, sustained virologic response was independently associated with improved quality of life scores.

"Although impairment of quality of life is expected with two or three drug regimens for hepatitis C, it was encouraging to see that addition of the third drug did not substantially impact quality of life," said Dr. Younossi. "In addition, patients who received the three drugs were shown to have a substantially better sustained virologic response. Therefore, for patients with H CV genotype 1, the three-drug regimen with telaprevir not only improves sustained virologic response, but also does not seem to substantially worsen quality of life."

The sustained virologic response is important because it is statistically significant and is a meaningful predictor of health-related quality of life, Dr. Younossi said. Sustained virologic response is linked to long-term eradication of HCV from the body while liver disease improves.

Dr. Younossi cautioned that patients should not assume that they will feel better on the telaprevir-based regimen. As the third drug is added to peginterferon alfa-2a and ribavirin, it is associated with its own side effect profile.

He added that future research in this field should look at the impact of potential new hepatitis C treatments on patients' quality of life.

The study was funded by Vertex Pharmaceuticals.

Dr. Younossi will present these data on Saturday, May 19 at 8 a.m. PT in Halls C-G of the San Diego Convention Center.

A phase 2/3 randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of subcutaneous golimumab induction therapy in patients with moderately to severely active ulcerative colitis (UC): Pursuit SC (Abstract #943d)

A large new study from the University of California, San Diego (UCSD) shows the benefit of the subcutaneously injected anti-tumor necrosis factor (TNF) drug, golimumab (Simponi®), in the treatment of ulcerative colitis.

Investigators led by William J. Sandborn, MD, professor of clinical medicine, UCSD; and chief, division of gastroenterology, and director, UCSD Inflammatory Bowel Disease Center, looked at adult patients with moderate to severe ulcerative colitis who previously had an inadequate response to conventional ulcerative colitis medications and had not already tried anti-TNF therapies. Anti-TNF therapies are biologic medications that block a protein called tumor necrosis factor, which plays an important role in causing ulcerative colitis.

More than 1,000 patients were enrolled. The primary endpoint was clinical response at week six. Secondary endpoints at week six were clinical remission and mucosal healing, and change from baseline in quality of life. Three groups were administered injection regimens of the drug to effectively identify the safety and efficacy of the therapy. Group one received 100 milligrams of the drug through the first phase of injections and 50 milligrams of the drug through the second phase. Group two received slightly higher levels with 200 milligrams during phase one and 100 milligrams during phase two. Group three was provided a placebo to allow for control.

The data demonstrated that golimumab administered subcutaneously was significantly better than a placebo in inducing clinical response, clinical remission, mucosal healing and improving quality of life in patients participating in the study. The safety of golimumab was consistent with the FDA-approved safety profile of golimumab in rheumatologic indications and of other anti-TNFs.

"These findings are important because there are limited treatment options for patients with moderate to severe ulcerative colitis who have had inadequate responses to conventional therapies," said Dr. Sandborn. He added that currently, there is only one biologic treatment (Remicade®) approved in the U.S. for this disease. These findings support the effectiveness of an intravenous anti-TNF therapy, infliximab, in the treatment of ulcerative colitis and demonstrate the usefulness of golimuamb to rapidly control symptoms and induce significant and meaningful clinical benefit, Dr. Sandborn said.

Dr. Sandborn cautioned that while golimumab is currently approved for rheumatologic conditions, it is not approved for the treatment of ulcerative colitis.

Funding for this study was provided by Janssen Research and Development, LLC.

Dr. Sandborn will present these data on Tuesday, May 22 at 9:15 a.m. PT in Room 20d of the San Diego Convention Center.

Modulation of the Brain-gut Axis After 4-week Intervention with a Probiotic Fermented Dairy Product (Abstract #589)

Probiotic dairy consumption can affect bacteria in the gut and may be linked to changes in the activity of regions of the brain that control emotional arousal and change the body's response to emotional images, according to new research from the University of California, Los Angeles (UCLA).

Previous animal studies have shown that bacteria in the colon can influence emotional behavior, but there has not been extensive study of this issue in humans. While it is known that some probiotics help people with irritable bowel syndrome feel better, it is less known whether people feel better because of improved digestive function or if other factors are responsible.

Researchers led by Kirsten Tillisch, MD, assistant professor of medicine, Oppenheimer Family Center for Neurobiology of Stress, division of digestive diseases, David Geffen School of Medicine at UCLA, sought to build on previous research conducted in animals to determine whether probiotic consumption can alter brain activity in humans. They enrolled 45 healthy women aged 18 to 50 with no digestive or psychological illnesses, and studied brain scans to identify a link between probiotic ingestion and brain response.

Investigators studied women who were generally healthy (no abdominal pain, no complaints about bowel movements, and no known physical or mental problems) and divided them into three groups to see how they changed or did not change. The groups were no product (NoP), control milk-based non-fermented dairy product (CTRL) and probiotic dairy product (TEST). The women were asked questions about their stomach health and continued their normal regimen with the exception that they could not take any antibiotics or non-study probiotics during the time of the study. Investigators reviewed each group a month later and compared the findings.

The CTRL and TEST groups consumed 125 gram products twice daily for four weeks, and all the groups performed an emotional reactivity task during functional magnetic resonance imaging (MRI) in which the brain was scanned while investigators asked participants questions about overall health and mood before starting the treatment and at the end of the four-week period. The emotional reactivity task consisted of viewing negative emotional faces compared to viewing shapes. A measure called blood oxygen level-dependent response, which is an estimate of brain activity, was measured using an MRI scanner.

The TEST group showed less blood oxygen level-dependent response during the emotional reactivity task compared to the CTRL and NoP groups in areas of the brain involved in the processing and modulation of gastrointestinal sensation.

The study suggests that the probiotic may dampen the signals that come from the gut and go to the brain when faced with a negative stimulus. The probiotic used in this study may alter signaling molecules and nerve activity in the enteric nervous system. So, by changing the balance of bacteria in the gut, chronic ingestion of the probiotic may alter the body's response to emotional stimulation.

"By changing what's going on inside of the gut, we hope we can decrease the activity in the nervous system within the wall of the gut, so when we are confronted by a stimulus that may excite it, it should be more relaxed and less responsive to stress, and thus lead to less stimulation in the brain," Dr. Tillisch said. She cautioned against over-interpretation of the findings and emphasized that one should not conclude that a probiotic is going to make you less emotional or more at ease.

Dr. Tillisch said the findings are not surprising given that the gut and the brain are very closely connected. For example, stimulation of the autonomic nervous system associated with emotions can change the level of gut activity, creating sensations like "butterflies in the stomach." Sensations from the gut can feed back to the brain and may stimulate emotions like anxiety or depression. The conscious awareness of these signals may be the basis for what people refer to as "gut feelings." A potentially threatening signal from the environment (like an angry face) creates a body response (including changes in gut activity), which feeds back to the brain, and is integrated with memories and emotions to create a conscious feeling in response to the angry face.

Funding for this study was provided by Danone Research.

Dr. Tillisch will present these data on Monday, May 21 at 8:27 a.m. PT in Room 20d of the San Diego Convention Center.

Provided by Digestive Disease Week


Neuropsychological Tools in Hepatology

From Journal of Viral Hepatitis

A Survival Guide for the Clinician

S. Montagnese; S. Schiff; M. De Rui; M. M. E. Crossey; P. Amodio; S. D. Taylor-Robinson

Posted: 05/17/2012; J Viral Hepat. 2012;19(5):307-315. © 2012 Blackwell Publishing

Abstract and Introduction

Neuropsychological assessment has three main applications in clinical hepatology: (i) to detect, grade and monitor liver failure-related cognitive alterations in end-stage liver disease (hepatic encephalopathy), (ii) to substantiate complaints of attention or concentration difficulties in patients with non-cirrhotic chronic hepatitis C viral infection, and (iii) to screen patients who are being considered for liver transplantation for early signs of dementia. However, there is limited agreement on how cognitive assessment should be conducted in these patients, and how results should be interpreted and used to implement clinical decisions. In this review, we summarize the available literature on neuropsychological dysfunction in patients with cirrhosis and with chronic hepatitis C viral infection and provide some guidance on how to utilize neuropsychological assessment in practice.


Patients with end-stage liver disease have long been known to exhibit cognitive deficits in a variety of forms, which have been termed hepatic encephalopathy (HE). This spectrum ranges from minimal impairment, only detected on neuropsychological assessment (so called 'minimal hepatic encephalopathy' [MHE] – formerly labelled 'subclinical'),[1,2] through to overt hepatic encephalopathy (OHE), which can manifest as mild confusion and behavioural change through to deep coma.[3,4] More recently, it has become apparent that patients with chronic hepatitis C virus (HCV) infection complain of a variety of neuropsychiatric sequela including confusion ('brain fog'), anxiety and depression, in the absence of significant liver disease.[5] Most studies on these issues have been performed by hepatologists who have acted as amateur psychologists. In this review, we discuss some of the pitfalls of neuropsychological assessment and put the published studies on HE and non-cirrhotic chronic HCV infection into context.

Neuropsychological Assessment

The human mind produces an enormous set of complex behaviours. These events represent the net result of what cognitive psychologists refer to as mental operations and, as a whole, make up an individual's cognitive ability. This can be separated into domains, such as language, memory and attention (Appendix 1), and each domain can be assessed by specific neuropsychological tests.

Many conditions, including liver disease, impinge on the brain and on the patients' capacity to perform mental operations, thus on their cognitive ability. Neuropsychological assessment is the diagnostic process aimed at measuring an individual's cognitive ability by means of specific neuropsychological tests.[6] Neuropsychological evaluation is not based on the patient's history or complaints, or on his/her carer's observations, but relies on direct assessment of the patient's performance. Neuropsychological diagnosis is based on the systematic exploration of cognitive performance, with a view to defining mental functioning in patients with potential neurological or psychiatric illnesses.

In general, neuropsychological evaluation aims at defining impairment in aspects of cognition (i.e. memory, attention, language, executive function, etc.), which are thought to be sensitive to certain pathologies, and thus to be reliable indicators of their presence or absence. In this context, the scores obtained by a patient in a set of neuropsychological tests define the neuropsychological profile of the patient. The concept of neuropsychological profiling is an important one because, despite inter-individual differences (vide infra), a neuropsychological profile can, to some extent, 'define' a disease. For example, in individuals with suspected cerebro-vascular or Alzheimer-type mild cognitive impairment, isolated memory deficits on neuropsychological testing would support the diagnostic hypothesis.

Neuropsychological assessment requires meticulous attention to confounding variables. For example, physical pain may easily distract the patient from test instructions and test performance. As a consequence, the patient may be wrongly qualified as having attention or concentration deficits. Other variables that often confound neuropsychological assessment are mood (such as anxiety or depression) and sleep-wake disturbances. In addition, the evaluation of cognitive function needs to take into account socio-biological variables, such as age, sex, level of education and occupation, which are all known to affect performance. In recent years, considerable interest has arisen in the novel concept of cognitive reserve, or the degree of neuroprotection that derives from chronic enhancement of mental, social and physical activity.[7] Cognitive reserve can heavily impinge on performance in one or more cognitive domains. For example, professional sportspeople have been shown to have above average skills in certain cognitive domains, in relation to the type of sport practiced and the level of expertise.[8] Along the same lines, a London taxi-driver, who has learnt the geography of a big city almost by heart, may perform well on tests involving spatial attention abilities, despite a progressive disease that is impinging on his cognitive ability, including spatial attention. The same applies to accountants being tested on calculus and so on and so forth. This is because when an individual is tested, his/her baseline, premorbid performance is generally unknown. In addition, neuropsychological tests are scored in relation to reference, normative data obtained from large, supposedly healthy groups, stratified by country of origin or ethnicity, sex, age and level of education. Variables which make up the cognitive reserve, such as occupation and hobbies, are virtually impossible to account for in any meaningful way. Of importance to the hepatologist, the impact of cognitive reserve on both specific neuropsychological functions[9] and activities of daily living (i.e. driving)[10] has been documented also in patients with cirrhosis.

It is therefore obvious that to obtain clinically meaningful results, a neuropsychological assessment needs to be performed in a systematic fashion by adequately trained, experienced personnel.

Neuropsychological Assessment in Hepatology

In routine hepatological practice, neuropsychological assessment has different aims:

  • To detect, grade and monitor liver failure-related cognitive alterations (HE).
  • To substantiate complaints of 'brain fog' or 'concentration difficulties' in patients with HCV infection. In these patients, it has also been used to monitor treatment-related cognitive alterations (i.e. the side effects of interferon).
  • To screen individuals undergoing a transplant work-up for early signs of neuropsychiatric impairment (i.e. early dementia).
Hepatic Encephalopathy

HE is a reversible neuropsychiatric syndrome, which occurs in patients with cirrhosis and/or significant portal-systemic shunting.[3] HE manifests as a spectrum of change, which may or may not be clinically apparent. The neuropsychiatric changes detected in patients with cirrhosis by clinical examination are collectively termed OHE. The patient typically appears 'slow', somnolent, and sometimes euphoric, while in other instances obviously confused and disorientated. An involuntary jerking of the outstretched hands (flapping tremor) can be detected. The diagnosis can be difficult, especially in mild forms, thus a history obtained from a family member is valuable.[11] The detection of an obvious precipitating factor (i.e. infection or dehydration) can also help. It is important to notice how patients with cirrhosis are prone to the development of metabolic encephalopathies other than HE, such as those related to hyponatremia, hypoglycaemia and nutritional deficits, which should be ruled out.

The term MHE is used to describe the occurrence of neuropsychological and/or neurophysiological abnormalities (i.e. slowing of the electroencephalogram) in patients with cirrhosis who appear neuropsychiatrically normal on clinical examination.[1,12,13] The prevalence of MHE varies considerably, depending on the patient population studied and the tools utilized for the diagnosis. MHE predicts the subsequent occurrence of OHE,[14] impinging on the patient's ability to perform complex tasks, such as driving,[10,15,16] and usually impairing quality of life.[17] Therefore, it is important to screen for, recognize and adequately treat this syndrome.

Neuropsychological Dysfunction in Hepatic Encephalopathy: The Underlying Theory

Over the years, several different neuropsychological tests have been utilized to describe the effect of HE on various cognitive domains, to 'quantify' OHE and to diagnose MHE.[1,18] A review of the literature between 1970 and 2004 retrieved over 80 different tests, often exploring more than one cognitive domain.[19] Still, the large majority explored attention, motor speed and executive function (Appendix 1); a smaller number explored memory and the remainder other cognitive domains.

Attention has a crucial role within the cognitive system,[20] and it impinges on other cognitive functions. It is common experience that if a person does not pay attention to something, he or she may not be able to remember it later on, which does not necessarily imply that memory is not functioning properly. In addition, attention is the net result of three separate sub-functions: vigilance, spatial attention and selective attention (Appendix 1). Vigilance has not been directly measured in patients with HE, but there are both clinical[21] and electrophysiological data[22] to suggest that it is affected.[23] Selective attention seems to be more compromised than spatial attention in these patients, possibly explaining why they may be easily distracted[24] and why there is an inability to cope with conflicting tasks, or tasks which require to 'switch' between different sets of information.[25] The simplest, paper-and-pencil switching test is Trail-making test B: the patient is asked to connect numbers and letters in alternating order (1-A-2-B-3-C-4-D…), thus continuously switching between the alphabetical and the numerical sequence. Trail-making test B has been widely used in patients with cirrhosis and has proven more sensitive in detecting HE-related cognitive changes than Trail-making test A,[26] where the patient is only asked to connect numbers from 1 to 25. This is in line with results obtained by computerized neuropsychological tests, which can be helpful in dissecting a complex task in its components, and measure the time taken to perform each of them.[23] However, the delay in reaction time also depends on the complexity of the task, being progressively more marked in simple reaction times (i.e. reaction to a visual stimulus by pressing a key), compared with choice reaction times (i.e. pressing different keys in response to different visual stimuli), compared with reverse selection choice reaction times (i.e. reaction/inhibition to different visual stimuli).[27] In agreement with this concept, and based on the profound delay observed in patients with cirrhosis on reverse selection choice tasks,[28] a computerized inhibition test was recently proposed for MHE screening.[29,30] Along similar lines, a motor delay which was proportional to the cognitive load/difficulty of the task was observed in a working memory test.[31]

Limited consensus or solid data exist on which neuropsychological tests should be used to diagnose MHE and/or to quantify mild OHE. The approaches utilized so far to address this problem can be criticized as they have been 'circular' (i.e. choosing neuropsychological tests to measure functions that have been shown to be abnormal in patients with HE by neuropsychological tests), 'statistical' (i.e. choosing tests that are more often abnormal in these patients) or 'comparative' (i.e. choosing tests that often agree/overlap with other, non-neuropsychological measures of HE, regardless of the absence of a gold standard). Despite these problems, a set of reasonable suggestions were first provided by an expert panel at the 11th World Congress of Gastroenterology in 1998, and published in 2001.[12] The experts suggested that the presence of MHE should be defined by either: (i) two abnormal tests of a set of four (Trail-making Tests A and B, Symbol Digit, Block Design), or (ii) an abnormal Psychometric Hepatic Encephalopathy Score (PHES), based on a battery including Trail-making Tests A and B, Digit Symbol, Serial Dotting and Line Tracing.[32,33] The first criterion was derived from a previous, substantially arbitrary definition of MHE as a condition in which two psychometric tests are abnormal;[34] no information was provided on the total number/type of tests to administer. The second criterion was more solid, as the PHES battery was derived using discriminant analysis, in a formal attempt to maximize the separation of patients with cirrhosis with no electroencephalographic abnormalities from normal subjects and from alcohol misusers with no liver disease.[32,33]

The experts of the 11th World Congress of Gastroenterology panel recommended the use of neuropsychology as an alternative to that of neurophysiology, and, where possible, the combination of both techniques.[12]

More recent guidelines were produced by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN), separately for neuropsychology[35] and neurophysiology.[36] The former endorsed either the use of PHES or that of a more comprehensive battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS),[37] which had been used in studies of patients with end-stage liver disease on a transplant list.[38] However, there is limited experience with RBANS in hepatology; the battery is time-consuming and it seems to exceed the requirements for standard, routine HE assessment.

The ISHEN guidelines did not formally endorse any of the computerized tests utilized so far in patients with cirrhosis, which include the Posner Test,[24] the Scan Test,[31] the Inhibitory Control Test[29] and the Cognitive Drug Research battery.[39] These have generally been chosen based on known cognitive features of HE and cover psychomotor speed, selective attention, inhibition and working memory. However, their use has not yet become widespread, and available normative data are limited.

Neuropsychological Dysfunction in Hepatic Encephalopathy: Actual Practice

Two of the authors of this review, SM (hepatologist) and SS (neuropsychologist), run a joint clinic for the assessment of neuropsychiatric dysfunction in Internal Medicine at the University of Padova, Italy. Our experience is that real patients are generally more complex than those enrolled in trials and observational studies and that attribution of reported or detected neuropsychological abnormalities to liver disease may not necessarily be straightforward. A standard HE evaluation at the Padova clinic includes: (i) a doctor's review, clinical and neurological examination, (ii) a structured interview with the neuropsychologist, (iii) a comprehensive neuropsychological evaluation, including both paper-and-pencil and computerized tests, (iv) an electroencephalogram, (v) a full blood count, liver function tests, renal function and electrolytes, venous ammonia, vitamin B12 and thyroid function tests. The case reports in Figs 1 & 2 illustrate how even this may not be enough and a definitive diagnosis may require further laboratory tests, cerebral imaging and re-evaluation after treatment. While it is difficult to imagine that such a comprehensive system may be routinely implemented in busy clinics and district hospital wards, it is equally important to remember that inaccurate neuropsychological diagnoses may impinge on quality of life,[17] post-transplant neurological outcome[40] and even survival.

(Click on picture to enlarge)


Figure 1. Example of neuropsychiatric evaluation in a patient with alcohol-related cirrhosis. PHES, Psychometric Hepatic Encephalopathy Score, CRP, C-reactive protein, EEG, electroencephalogram, MRI, magnetic resonance imaging.

(Click on picture to enlarge)


Figure 2. Example of neuropsychiatric evaluation in a patient with hepatitis C virus-related cirrhosis. PHES, Psychometric Hepatic Encephalopathy Score, EEG, electroencephalogram, TIPS, transjugual intrahepatic portal-systemic shunt.

Hepatitis C Virus and the Brain

In recent years, there has been growing evidence that neuropsychological changes in patients with chronic HCV infection may occur long before the development of significant liver fibrosis/cirrhosis.[41] A considerable proportion of patients with HCV infection complain of 'brain fog', weakness, fatigue and difficulties concentrating.[5] These problems do not seem to relate to HCV genotype or HCV replication, and their exact pathophysiology remains unknown, although a number of potential mechanisms have been proposed.[42]

Neuropsychological Dysfunction in Hepatitis C Virus: The Underlying Theory

In 2001, Forton et al.[43] described the presence of cerebral metabolic abnormalities – elevated choline/creatine ratio – in the frontal white matter and basal ganglia of HCV-infected patients by use of proton magnetic resonance spectroscopy. These alterations were not detected in either healthy age-matched controls or in patients with hepatitis B.[43] The following year, the same group of authors showed significant impairment in concentration and working memory in 27 patients with HCV infection and active viral replication, compared with 20 controls and 16 anti-HCV antibody positive, but HCV RNA-negative patients.[44]

Since these seminal observations, a number of studies have been published on neuropsychological performance in patients with hepatitis C.[45–51] Unfortunately, these have often included (i) patients with cirrhosis, (ii) patients who had acquired the infection by previous intravenous drug misuse, (iii) patients who had co-infections, (iv) patients who had had treatment with interferon not long before the study, (v) patients who were on psychoactive medication, or (vi) patients who complained of significant fatigue, which may all impinge on cognitive performance. More importantly, neuropsychological examination was not necessarily conducted in a systematic way, with different studies testing different, often isolated cognitive functions, making the results even more heterogeneous. Finally, very stringent cut-off values for abnormality were utilized (i.e. 1.5 SD from the reference values), at least in some instances.[48] Nevertheless, impairment was reported in sustained attention, executive function, verbal learning, verbal recall, memory and working memory.[5] To date, only two studies have been completely negative. In the first, HCV-positive patients were selected amongst supposedly healthy individuals, screened for purposes of blood donation, although the medical provenance of all subjects in the study was not fully elicited;[51] in the second, they were children/teenagers, probably with a shorter interval between infection and cognitive assessment, compared with all other studies.[52]

Interestingly, limited research has been performed to compare the neuropsychological burden of HCV-related cirrhosis and that of cirrhosis of other aetiologies, although clinical experience does not suggest there are significant differences.

Therefore, while patients with HCV infection have fairly definite magnetic resonance spectroscopy alterations,[43,44,47,48] which are unlikely to be explained by previous drug misuse or HE, their neuropsychological profile remains poorly defined. This is certainly worthy of further investigation, and so are the complex interactions between neuropsychological impairment, disease perception, mood, fatigue, daily functioning and quality of life.[53] These aspects are likely to become key to treatment choices for HCV-infected patients in the near future.

Neuropsychological Dysfunction in Hepatitis C Virus: Actual Practice

The practical difficulties of neuropsychological evaluation in patients with hepatitis C are even greater than those described for HE, for two main reasons: (i) the neuropsychological profile of these patients is not defined, and there is no consensus on which tests should be used, (ii) these patients often have additional reasons for cognitive dysfunction, such as psychoactive treatment, co-infections, previous drug/alcohol misuse and even the innate impulsiveness that characterizes addictive personalities.[54,55] This trait can affect both the approach to and the performance on several tests.

Within this very complex setting, also attention to common confounders needs to be meticulous, as illustrated in Fig. 3.

(Click on picture to enlarge)


Figure 3. Example of neuropsychiatric evaluation in a patient with chronic hepatitis C infection. PHES, Psychometric Hepatic Encephalopathy Score, Lp(a), lipoprotein(a), HDL/LDL, high/low-density lipoprotein, MRI, magnetic resonance imaging.


When patients with cirrhosis or with non-cirrhotic chronic hepatitis C infection present with cognitive disturbance, it is often difficult to establish a causal relationship between their liver disease and their neuropsychological problems. Alcohol-related cerebral damage, bacterial infection, malnutrition, anaemia, vitamin deficiencies and renal failure can all be present in these patients, together with unrelated diseases of high prevalence, such as hypothyroidism and vascular/degenerative dementia.

For these reasons, neuropsychological batteries should be chosen, which include: (i) specific tests for the liver disease-related cognitive alterations of interest, and (ii) tests aimed at excluding gross, unrelated cognitive damage. The latter are even more important for patients who are being considered for transplantation, as subsequent treatment with immunosuppressants, especially calcineurin inhibitors, may unmask or accelerate cerebro-vascular disease.[40] Thus, when we evaluate a patient with cirrhosis, the battery will need to cover attention, visual-constructive, visual-motor and motor abilities (like PHES). If the patient is older than 55 years or is on a transplant list, long-term memory and executive function should also be tested, as an abnormal performance on Digit Symbol or Trail-Making test B, which are part of PHES, is also observed in early dementia. Similarly, visual-constructive impairment is common to both HE and Alzheimer's type dementia. However, the latter is also characterized by disturbance in long-term memory and praxis (Appendix 1). The presence of risk factors for cerebro-vascular disease, such as systemic hypertension, diabetes and hypercholesterolaemia, should prompt even more accurate differential diagnosis, as cerebro-vascular disease is associated, like HE, with extra-pyramidal motor disturbance. Previous substance or alcohol misuse is associated with working memory, planning, inhibition and decision-making issues, which can be picked up not only on test results but also on the patient's approach to tests performance.[55] Therefore, while hepatologists require simple tools for routine neuropsychiatric screening of their patients,[56] accurate neuropsychiatric diagnosis often requires the interaction between hepatologists and neuropsychologists, meticulous history taking, laboratory tests, neurophysiology, brain imaging and re-evaluation over time. A consensus is required as to a practical approach for neuropsychological testing in both HE and in chronic HCV infection. While no consensus exists on simple tests to use in the clinic, the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) have commissioned a joint working party on this subject. The results of the working party's report are awaited in the next year.

  1. Rikkers L, Jenko P, Rudman D, Freides D. Subclinical hepatic encephalopathy: detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology 1978; 75: 462– 469.
  2. Parsons-Smith BG, Summerskill WH, Dawson AM, Sherlock S. The electroencephalograph in liver disease. Lancet 1957; 273: 867–871.
  3. Sherlock S, Summerskill WH, White LP, Phear EA. Portal-systemic encephalopathy; neurological complications of liver disease. Lancet 1954; 267: 454–457.
  4. Conn HO, Leevy CM, Vlahcevic ZR et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 1977; 72: 573–583.
  5. Forton DM, Allsop JM, Cox IJ et al. A review of cognitive impairment and cerebral metabolite abnormalities in patients with hepatitis C infection. AIDS 2005; 19(Suppl. 3): S53–S63.
  6. Lezak MD. Neuropsychological Assessment, 3rd edn. New York: Oxford University Press, 1995.
  7. Nithianantharajah J, Hannan AJ. The neurobiology of brain and cognitive reserve: mental and physical activity as modulators of brain disorders. Prog Neurobiol 2009; 89: 369–382.
  8. Mann DT, Williams AM, Ward P, Janelle CM. Perceptual-cognitive expertise in sport: a meta-analysis. J Sport Exerc Psychol 2007; 29: 457– 478.
  9. Montagnese S, Cona G, Schiff S et al. The hunter and the pianist: two hepatic encephalopathy tales. J Clin Gastroenterol 2011; 45: 563–566.
  10. Srivastava A, Mehta R, Rothke SP, Rademaker AW, Blei AT. Fitness to drive in patients with cirrhosis and portal-systemic shunting: a pilot study evaluating driving performance. J Hepatol 1994; 21: 1023– 1028.
  11. Montagnese S, Amodio P, Morgan MY. Methods for diagnosing hepatic encephalopathy in patients with cirrhosis: a multidimensional approach. Metab Brain Dis 2004; 19: 281–312.
  12. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy – definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002; 35: 716–721.
  13. Amodio P, Montagnese S, Gatta A, Morgan MY. Characteristics of minimal hepatic encephalopathy. Metab Brain Dis 2004; 19: 253–267.
  14. Montagnese S, Biancardi A, Schiff S et al. Different biochemical correlates for different neuropsychiatric abnormalities in patients with cirrhosis. Hepatology 2011; 53: 558–566.
  15. Wein C, Koch H, Popp B, Oehler G, Schauder P. Minimal hepatic encephalopathy impairs fitness to drive. Hepatology 2004; 39: 739–745.
  16. Bajaj JS, Saeian K, Schubert CM et al. Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. Hepatology 2009; 50: 1175– 1183.
  17. Groeneweg M, Quero JC, De BI et al. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology 1998; 28: 45–49.
  18. Blei AT, Cordoba J. Subclinical encephalopathy. Dig Dis 1996; 14(Suppl. 1): 2–11.
  19. Mapelli D, Iannizzi P, Biancardi A et al. Neuropsychological dysfunction in minimal hepatic encephalopathy: a review compared with own experience. In: Haussinger D, Kircheis G, Schliess F, eds. Hepatic Encephalopathy and Nitrogen Metabolism. Dordrecht, The Netherlands: Springer, 2006: 467–473.
  20. Weissenborn K, Giewekemeyer K, Heidenreich S, Bokemeyer M, Berding G, Ahl B. Attention, memory, and cognitive function in hepatic encephalopathy. Metab Brain Dis 2005; 20: 359–367.
  21. Bersagliere A, Raduazzo ID, Nardi M et al. Induced hyperammonaemia may compromise the ability to generate restful sleep in patients with cirrhosis. Hepatology 2012; 55: 869– 878.
  22. Montagnese S, Jackson C, Morgan MY. Spatio-temporal decomposition of the electroencephalogram in patients with cirrhosis. J Hepatol 2007; 46: 447–458.
  23. Amodio P, Schiff S, Del PF, Mapelli D, Gatta A, Umilta C. Attention dysfunction in cirrhotic patients: an inquiry on the role of executive control, attention orienting and focusing. Metab Brain Dis 2005; 20: 115–127.
  24. Amodio P, Marchetti P, Del Piccolo F et al. Visual attention in cirrhotic patients: a study on covert visual attention orienting. Hepatology 1998; 27: 1517–1523.
  25. Schiff S, Vallesi A, Mapelli D et al. Impairment of response inhibition precedes motor alteration in the early stage of liver cirrhosis: a behavioral and electrophysiological study. Metab Brain Dis 2005; 20: 381–392.
  26. Weissenborn K, Scholz M, Hinrichs H, Wiltfang J, Schmidt FW, Kunkel H. Neurophysiological assessment of early hepatic encephalopathy. Electroencephalogr Clin Neurophysiol 1990; 75: 289–295.
  27. Schomerus H, Hamster W, Blunck H, Reinhard U, Mayer K, Dolle W. Latent portasystemic encephalopathy. I. Nature of cerebral functional defects and their effect on fitness to drive. Dig Dis Sci 1981; 26: 622– 630.
  28. Amodio P, Del Piccolo F, Marchetti P et al. Clinical features and survivial of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests. Hepatology 1999; 29: 1662– 1667.
  29. Bajaj JS, Saeian K, Verber MD et al. Inhibitory control test is a simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy. Am J Gastroenterol 2007; 102: 754–760.
  30. Amodio P, Ridola L, Schiff S et al. Improving the inhibitory control task to detect minimal hepatic encephalopathy. Gastroenterology 2010; 139: 510–518, 518.
  31. Amodio P, Marchetti P, Del Piccolo F et al. Study on the Sternberg paradigm in cirrhotic patients without overt hepatic encephalopathy. Metab Brain Dis 1998; 13: 159–172.
  32. Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol 2001; 34: 768–773.
  33. Schomerus H, Hamster W. Neuropsychological aspects of portal-systemic encephalopathy. Metab Brain Dis 1998; 13: 361–377.
  34. Gitlin N, Lewis DC, Hinkley L. The diagnosis and prevalence of subclinical hepatic encephalopathy in apparently healthy, ambulant, nonshunted patients with cirrhosis. J Hepatol 1986; 3: 75–82.
  35. Randolph C, Hilsabeck R, Kato A et al. Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines. Liver Int 2009; 29: 629–635.
  36. Guerit JM, Amantini A, Fischer C et al. Neurophysiological investigations of hepatic encephalopathy: ISHEN practice guidelines. Liver Int 2009; 29: 789–796.
  37. Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol 1998; 20: 310–319.
  38. Sotil EU, Gottstein J, Ayala E, Randolph C, Blei AT. Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation. Liver Transpl 2009; 15: 184–192.
  39. Mardini H, Saxby BK, Record CO. Computerized psychometric testing in minimal encephalopathy and modulation by nitrogen challenge and liver transplant. Gastroenterology 2008; 135: 1582–1590.
  40. Amodio P, Biancardi A, Montagnese S et al. Neurological complications after orthotopic liver transplantation. Dig Liver Dis 2007; 39: 740– 747.
  41. Forton DM, Taylor-Robinson SD, Thomas HC. Cerebral dysfunction in chronic hepatitis C infection. J Viral Hepat 2003; 10: 81–86.
  42. Stasi C, Zignego AL, Laffi G, Rosselli M. The liver-cytokine-brain circuit in interferon-based treatment of patients with chronic viral hepatitis. J Viral Hepat 2011; 18: 525–532.
  43. Forton DM, Allsop JM, Main J, Foster GR, Thomas HC, Taylor-Robinson SD. Evidence for a cerebral effect of the hepatitis C virus. Lancet 2001; 358: 38–39.
  44. Forton DM, Thomas HC, Murphy CA et al. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 2002; 35: 433–439.
  45. Hilsabeck RC, Perry W, Hassanein TI. Neuropsychological impairment in patients with chronic hepatitis C. Hepatology 2002; 35: 440–446.
  46. Hilsabeck RC, Hassanein TI, Carlson MD, Ziegler EA, Perry W. Cognitive functioning and psychiatric symptomatology in patients with chronic hepatitis C. J Int Neuropsychol Soc 2003; 9: 847–854.
  47. Weissenborn K, Krause J, Bokemeyer M et al. Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy. J Hepatol 2004; 41: 845–851.
  48. McAndrews MP, Farcnik K, Carlen P et al. Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology 2005; 41: 801–808.
  49. Fontana RJ, Bieliauskas LA, Back-Madruga C et al. Cognitive function in hepatitis C patients with advanced fibrosis enrolled in the HALT-C trial. J Hepatol 2005; 43: 614–622.
  50. Lowry D, Coughlan B, McCarthy O, Crowe J. Investigating health-related quality of life, mood and neuropsychological test performance in a homogeneous cohort of Irish female hepatitis C patients. J Viral Hepat 2010; 17: 352–359.
  51. Cordoba J, Flavia M, Jacas C et al. Quality of life and cognitive function in hepatitis C at different stages of liver disease. J Hepatol 2003; 39: 231–238.
  52. Soogoor M, Lynn HS, Donfield SM, Gomperts E, Bell TS, Daar ES. Hepatitis C virus infection and neurocognitive function. Neurology 2006; 67: 1482–1485.


Boceprevir: A Novel Nonstructural 3 (NS3) Protease Inhibitor for the Treatment of Chronic Hepatitis C Infection

From Therapeutic Advances in Gastroenterology

Paul Y. Kwo, MD

Posted: 05/16/2012; Ther Adv Gastroenterol. 2012;5(3):179-188. © 2012 Sage Publications, Inc.

Abstract and Introduction

Chronic hepatitis C infection is a leading cause of morbidity and mortality worldwide, with hepatitis C related cirrhosis being the most common indication for transplant and a major cause for the increase in hepatocellular carcinoma worldwide. Treatment for hepatitis C has consisted of nonspecific immunomodulatory therapies that stimulate the immune system and inhibit hepatitis C replication. Pegylated (peg-)interferon and ribavirin have been the standard of care with an overall sustained response rate of 40–50% in patients with genotype 1 infection, and 80% in genotype 2 or 3. Recently, direct-acting antiviral agents, including boceprevir, have demonstrated improved sustained response rates in patients with genotype 1 infection when given in combination with interferon and ribavirin. Boceprevir is a structurally novel hepatitis C virus (HCV) nonstructural 3 (NS3) protease inhibitor that has demonstrated robust antiviral activity in HCV replicons. Clinically, in phase II and III trials, boceprevir 800 mg three times daily with peginterferon and ribavirin has led to improved sustained response rates in genotype 1 infection treatment-naive patients, relapsers, partial responders, and null responders. Phase II data have demonstrated that ribavirin is essential for optimal boceprevir response. Moreover, phase II data have suggested that a 4-week peginterferon or ribavirin lead-in strategy may reduce relapse rates and provide crucial on-treatment data for treatment response with boceprevir addition. Side effects of boceprevir when added to peginterferon and ribavirin are similar to peginterferon and ribavirin, though higher rates of anemia have been noted, with an incremental increase in erythropoietin use. The addition of boceprevir represents a major advance in patients with genotype 1 infection who are treatment naïve.


Chronic hepatitis C affects approximately 170 million people worldwide [National Institutes of Health, 2002; Alter, 2007; McHutchison and Bacon, 2005]. It is the most common blood-borne infection in many parts of the world and is a major cause of chronic liver disease, which if left untreated, may progress to cirrhosis with or without hepatocellular carcinoma. Hepatitis C remains the most common indication for liver transplantation worldwide, with over 500,000 deaths annually due to complications of hepatitis C [Davis et al. 2010; El-Serag and Rudolph, 2007]

Therapy of Hepatitis C

Until this year, the therapy for hepatitis C has consisted of nonspecific treatments that stimulate the immune system and interfere in a nonspecific manner with hepatitis C viral replication [Hoofnagle and Seeff, 2006]. The standard of care for all genotypes of hepatitis C is pegylated (peg-)interferon and ribavirin for 24 weeks (genotypes 2 and 3) or 48 weeks (genotype 1), which results in overall sustained response rates of approximately 50% [Lauer and Walker, 2001b]. Other groups have lower sustained response rates due to poor interferon responsiveness. Sustained response rates for black patients are substantially lower, with two studies demonstrating sustained response rates of 19–28% in black patients and lower sustained response rates also seen in patients of Hispanic origin [Conjeevaram et al. 2006; Muir et al. 2004; Rodriguez-Torres et al. 2009]. In patients who achieve sustained response, long-term benefits may be seen, including a reduction in inflammation, improvement in liver fibrosis and better quality of life [Poynard et al. 2000]. Most recently, the concept of response-guided therapy through the use of viral kinetics has allowed for tailoring of duration of therapy in genotype 1 and genotypes 2 and 3 [Diago et al. 2010; Ferenci et al. 2010; Shiffman et al. 2007].

Prior to discussing new therapies for hepatitis C, it is important to have a basic understanding of the hepatitis C viral lifecycle. The hepatitis C virus (HCV) is a single-stranded RNA molecule that is approximately 9600 nucleotides in length [Lauer and Walker, 2001a]. Viral protein synthesis is mediated by an internal ribosome entry site that binds directly to ribosomes. RNA is translated into a polyprotein of 3000 amino acids that is proteolytically cleaved into four structural and six nonstructural (NS) proteins (Figure 1) [Bartenschlager and Lohmann, 2000; Bartenschlager, 2002]. The structural proteins are used to assemble new viral particles and the NS proteins support viral RNA replication. The NS3/4A is a serine protease (NS3) and cofactor (NS 4A) that catalyzes the post-translational processing of NS proteins from the polyprotein, which is important for viral replication. The NS3 protease cleaves NS4A–NS4B, NS4B–NS5A and NS5A–NS5B junctions. The products released go on to form a replicative complex responsible for forming viral RNA. Thus, NS3/4A provides an ideal target for antiviral therapy.


Figure 1. Sites for direct-acting antiviral agents. UTR, untranslated region.

HCV replicons have provided an important tool in the investigation of the serine protease as a potential target for anti-HCV therapies. Prior to HCV replicons, in vitro HCV replication models had been difficult to establish. In 1999, Lohmann and colleagues described a reliable method of HCV replication with subgenomic HCV RNA in a hepatoma cell line [Lohmann et al. 1999]. Based on the finding that in other viral replication models, structural proteins are not required for RNA replication, the HCV RNA genome was modified. Structural proteins were replaced with a selectable marker; in this case, a gene encoding neomycin phosphotransferase (NPT), which inactivates the cytotoxic drug G418. The hepatoma cells were then transfected with the subgenomic RNA replicon and placed in a medium containing G418. Only cells in which the replicon amplified sufficiently were able to produce NPT and confer G418 resistance. The surviving cells were isolated to form colonies of cell clones that carry stable replicating HCV replicons. This technique has allowed evaluation of therapeutic agents that inhibit viral replication and characterization of resistant mutants [Bartenschlager, 2002].

Boceprevir Early Clinical Results

Boceprevir is a structurally novel ketoamide HCV NS3 linear protease inhibitor that forms a covalent and reversible bond to the NS3 protease active site (Figure 2). In vitro studies have demonstrated robust antiviral activity in an HCV replicon model, with treatment of HCV replicons resulting in a 2 log10 reduction of HCV RNA level at 72 h and 4 log10 reduction by day 15 [Malcolm et al. 2006]. In these preliminary studies, boceprevir demonstrated no toxic effects. The addition of interferon appeared to be additive, rather than synergistic, and these promising preliminary data were used as the foundation to design clinical trials for boceprevir.


Figure 2. Boceprevir bound to NS3 active site 520 Da ketoamide.

Phase I Studies: Boceprevir Monotherapy

The initial phase I trial evaluated the safety, tolerability, and efficacy of the NS3 protease inhibitor, boceprevir, at doses ranging from 100 to 400 mg daily in a genotype 1 population whose condition had not responded to interferon and ribavirin. In this European trial, 26 patients with genotype 1a or 1b infection without early virologic response were randomized to a three-way crossover study with boceprevir at doses of 200 or 400 mg three times a day for 1 week, peginterferon α2b, 1.5 μg/kg weekly for 2 weeks, and a combination of peginterferon and boceprevir [Sarrazin et al. 2007]. At least 2 weeks between treatments was mandated for washout of therapy. The combination of peginterferon and boceprevir gave the greatest viral reductions which were additive. The HCV RNA reductions ranged from 2.28 logs in the group receiving boceprevir 200 mg three times a day to a maximum of 2.7 logs in the group receiving boceprevir 400 mg three times a day. Pharmacokinetic data did not reveal significant interaction between peginterferon and boceprevir with area under the curve (AUC) for each drug comparable to AUC results noted with monotherapy for either drug.

With the preliminary data from the phase I studies, a phase II dose-finding study, RESPOND-1 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol), was initiated with multiple goals. The first goal was to ascertain the optimal boceprevir dose to maximize sustained response while minimizing toxicity. The second goal was to determine whether ribavirin would be required in combination with peginterferon α2b and boceprevir in the treatment of null responders. Finally, this study sought to determine the optimal duration of boceprevir in the treatment of a null responder population. In this phase II study, 357 null responders who failed to achieve early virologic response (<2 log10 reduction), or failed to clear the virus after 12 weeks of therapy and who demonstrated an 80% compliance with medicines and duration, were enrolled. These null responders were treated with peginterferon α2b and boceprevir in ascending doses (100, 200, 400, 800 mg three times daily) or with peginterferon α2b, boceprevir 400 mg three times a day and ribavirin [Schiff et al. 2008]. The control arm received peginterferon α2b plus ribavirin. An interim analysis by the Data Safety Monitoring Board led to a protocol amendment in that all patients who responded (who have <10,000 IU/ml on their original randomized therapy) were assigned to receive open-label peginterferon α2b, weight-based ribavirin, and boceprevir 800 mg three times a day for 24 weeks. The sustained response rates were low in this study; however, the results establish several important concepts that have been carried forward in the treatment of hepatitis C with NS3 protease inhibitors. For the treatment of null responders (and all patients with genotype 1 infection as later determined), ribavirin is required for optimal response. The study also determined an optimal boceprevir dose of 800 mg three times daily, a dose that no patient initially received. With boceprevir in null responders, a more rapid clearance of HCV RNA and longer duration of therapy with undetectable HCV RNA levels also predicted sustained response. Finally, null responders who initially received peginterferon α2b and ribavirin without boceprevir (control arm) with interferon responsiveness (1–2 log10 reduction at week 13) were more likely to go on to a sustained response with boceprevir addition, regardless of the dose.

These preliminary results led to a design of a phase II clinical trial, the HCV Serine Protease Inhibitor Therapy I (SPRINT I) study, evaluating boceprevir in combination with peginterferon α2b and ribavirin in genotype 1 treatment-naïve patients [Kwo et al. 2010]. There were two parts to this multiarm study, which enrolled patients with genotype 1 infection. In the first part, patients received peginterferon α2b, weight-based ribavirin, and boceprevir therapy 800 mg three times a day for 28 (PRB28) or 48 weeks (PRB48), or a lead-in strategy with 4 weeks of peginterferon α2b and ribavirin, followed by boceprevir 800 mg three times a day with peginterferon and ribavirin for 24 weeks (PR4/PRB24) or 44 weeks (PR4/PRB44), and these therapies were compared with peginterferon α2b and ribavirin for 48 weeks. A second part explored a low-dose ribavirin arm due to an anemia signal with boceprevir, in which patients were randomized to receive peginterferon α2b, boceprevir 800 mg three times a day, and ribavirin 400–1000 mg, and this was compared with triple therapy with full-dose ribavirin (800–1400 mg) with peginterferon α2b, and boceprevir.

The rationale for the potential benefit of the lead-in strategy with 4 weeks of peginterferon α2b and ribavirin was based on allowing peginterferon α2b and ribavirin to reach steady-state concentrations by week 4. This meant that boceprevir could be added when the backbone drug levels were optimized and the patient's immune system fully activated. It was hoped that this approach would minimize the time on functional monotherapy, given the relatively low barrier to resistance seen with the linear NS3 protease inhibitors, and reduce the development of drug resistance and breakthrough. In this multicenter international trial, 100 patients were enrolled in each arm in part 1 and stratified according to the presence of cirrhosis (6–9% per arm) and African American race (14–17% per arm). Demographic data from the SPRINT I study are shown in Table 1.

In all treatment arms, the addition of boceprevir improved sustained virologic response (SVR) rates (Figure 3). In the 28-week treatment arms, SVR rates were 56% for the PR4/PRB24 lead-in arm and 54% with triple therapy (PRB28). Extending boceprevir therapy for 44 weeks (PR4/PRB44 ) improved the SVR rate to 75% in the peginterferon α2b and ribavirin lead-in arm with 44 weeks of peginterferon α2b, ribavirin, and boceprevir and 67% in the triple therapy arm with peginterferon α2b, ribavirin, and boceprevir (PRB48) all given for 48 weeks. In addition, improved SVR rates were seen in difficult-to-treat patients. Up to 53% of black patients achieved sustained response with the addition of boceprevir. This number represents a substantial improvement over the 21–23% SVR rate that has been reported for 48 weeks of peginterferon α2b and ribavirin [Muir et al. 2004; Conjeevaram et al. 2006]. Moreover, patients with cirrhosis also demonstrated substantial improvement in SVR rates, with rates as high as 67% reported. In part 2 of the study, low-dose ribavirin was shown to be associated with reduced SVR rates with high rates of breakthrough and relapse.


Figure 3. Sustained virologic response rates for the SPRINT I trial.
aRoche COBAS TaqMan LLD <15 IU/ml; bp = 0.013; cp = 0.005; dp <0.0001; ep <0.0001 compared with P/R control; fone late relapser after follow-up week 24, not included in SVR.
B, boceprevir; HCV, hepatitis C virus; P, pegylated interferon α2b; R, ribavirin; SVR, sustained virologic response; wk, week.

Achieving rapid virologic response (RVR) with the addition of boceprevir could also predictsustained response. Compared with the control group of peginterferon α2b and ribavirin, substantially more patients in the boceprevir treatment groups achieved RVR (week 4 of boceprevir addition), and this predicted high rates of sustained response with shorter duration of therapy. In the SPRINT I study, RVR and complete early virologic response (cEVR) were defined by the week of boceprevir therapy; therefore, the week 4 RVR and cEVR were at weeks 8 and 16 of total therapy with peginterferon α2b and ribavirin. RVR rates were observed in 60% of the PR4/PRB24 arm, 39% in the triple therapy PRB28 arm, and 8% in the PR48 control arm. Similar rates were seen in the 48-week treatment arms, with an RVR rate of 64% in the PR4/PRB44 arm, and 37% in the PRB48 arm. Regardless of the treatment arm, achieving RVR predicted sustained response, with 82% of the PR4/PRB24 arm achieving SVR and 74% of the PRB28 RVR patients achieving SVR. In the PR4/PRB44 treatment arm, 94% of patients achieved an RVR at week 4 of boceprevir, and 84% of patients inthe PRB48 arm achieved sustained response. Achieving cEVR (undetectable HCV RNA at week 12 of boceprevir) also predicted sustained response. Moreover, patients who cleared the virus between weeks 4 and 12 of boceprevir therapy (late responders) were more likely to go on to achieve sustained response in the lead-in arms if they received a total of 48 weeks of therapy (Table 2). Indeed, approximately two-thirds of patients achieved undetectable HCV RNA (RVR at week 4 of boceprevir). An additional 19 patients in both lead-in arms cleared the virus between weeks 4 and 12, and in those who received extended therapy for 48 weeks, 15 of 19 went on to achieve sustained response. These results suggest that a response-guided paradigm may be appropriate for boceprevir, with those clearing the virus early requiring just 28 weeks of therapy and those who are late responders benefiting from an extension of therapy.

The addition of boceprevir after the 4-week lead-in period also demonstrated that SVR could be predicted by the degree of peginterferon α2b/ribavirin responsiveness achieved during the initial 4 weeks of therapy. If a reduction of more than 1.5 log10 was achieved during the lead-in period, high rates of SVR were achieved with boceprevir addition regardless of treatment duration. However, even patients whose condition responded poorly to peginterferon α2b/ribavirin with less than 1 log10 reduction at week 4 of the lead-in period could achieve SVR with boceprevir addition. A total treatment duration of 48 weeks led to better SVR rates (55%) than the 28-week treatment duration (28%) in these patients. Thus the lead-in period may be used to assess the degree of peginterferon α2b/ribavirin responsiveness and could help predict SVR with boceprevir addition.

The relapse rates in the 28-week treatment arms were comparable and the presence of RVR markedly reduced relapse rates (Figure 4). In the 48-week treatment arms, a lower relapse rate was noted in the peginterferon α2b/ribavirin lead-in arm, although it was not statistically superior to the non-lead-in arm. Similarly, a modest reduction in viral breakthrough in the lead-in arms was noted compared with the no-lead-in arm, though this did not reach statistical significance.


Figure 4. Relapse for all treatment arms in the SPRINT I trial.
ap = 0.0079; bp = 0.0002 compared with P/R control.
B, boceprevir; P, pegylated interferon α2b; pt, patient; R, ribavirin; RVR, rapid virologic response; wk, week.

The most common side effects of boceprevir were anemia, nausea, vomiting, and dysgeusia, and treatment discontinuation rates were higher in the boceprevir groups compared with the standard therapy groups (26–40% versus 15%). The majority of hemoglobin reductions were grade 1 and 2 according to the World Health Organization criteria, and no increase in skin or subcutaneous disorders was noted. Treatment discontinuation for anemia was rare in all boceprevir-containing arms. A recent study suggested that anemia may represent a surrogate marker of ribavirin exposure in patients with genotype 1 infection, with higher rates of anemia correlating with sustained response [Sulkowski et al. 2010]. In the SPRINT I study, in which erythropoietin was used to manage anemia at the investigator's discretion, the development of anemia and erythropoietin use were associated with improved SVR rates (Figure 5). A large trial is currently under way and will explore the role of erythropoietin α administration versus ribavirin dose reduction as an anemia management strategy in patients receiving peginterferon α2b, ribavirin, and boceprevir.


Figure 5. Sustained virologic response rates and development of anemia are shown for the lead-in arms of the SPRINT I trial.
aOne patient in each group missing in-treatment hemoglobin values.
B, boceprevir; Epo, erythropoietin; HCV, hepatitis C virus; Hgb, hemoglobin; P, pegylated interferon α2b; R, ribavirin; SVR, sustained virologic response; wk, week.

Phase III Studies

The two large phase III trials of boceprevir, SPRINT II for patients who are treatment naïve, and RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2, NCT00708500) for those whose condition has not responded, have been fully enrolled. SPRINT II enrolled over 1000 patients and will test a peginterferon α2b/ribavirin response-guided therapy paradigm with peginterferon α2b/ribavirin lead-in period and 44 weeks of boceprevirto peginterferon α2b/ribavirin control. In the response-guided paradigm, patients receive 24 weeks of peginterferon α2b, ribavirin, and boceprevir after a 4-week lead-in period, followed by a peginterferon α2b tail without boceprevir in slow responders who do not clear the virus at week 8 and week 24 of treatment. The final results have been reported and the addition of boceprevir was found to lead to an overall SVR rate of 63–66% [Poordad et al. 2011b]. In this study,two cohorts were predefined as non-black and black. The SVR rate in the non-black cohort was 67% in the response-guided therapy arm versus 68% in the 44-week boceprevir fixed-duration arm. These rates were both significantly higher than the peginterferon α2b/ribavirin control SVR rate of 40%. In the black cohort, the response-guided arm achieved an SVR rate of 42% versus 53% in the 44-week boceprevir arm, with a rate of 23% achieved in the peginterferon α2b/ribavirin control arm. The US Food and Drug Administration approved a response-guided paradigm with boceprevir, and if HCV RNA levels are undetected at weeks 8 and 24, patients may be treated for 28 weeks. If HCV RNA is detected at week 8 and undetected at week 24, then patients should receive peginterferon α2b/ribavirin with boceprevir for 36 weeks followed by a 12-week peginterferon α2b/ribavirin tail for a total of48 weeks of therapy. Patients with cirrhosis and whose condition responds poorly to peginterferon α2b/ribavirin (<1 log10 reduction after lead-in period) should receive peginterferon α2b/ribavirin for 4 weeks, followed by 44 weeks of peginterferon α2b/ribavirin and boceprevir.

The phase III RESPOND-2 trial also evaluated a response-guided therapy arm. The trial compared a peginterferon α2b/ribavirin lead-in period and 32 weeks of peginterferon α2b, ribavirin, and boceprevir, followed by a 12-week peginterferon α2b/ribavirin tail, depending on viral response, with a 4-week peginterferon α2b/ribavirin lead-in period and 44 weeks of peginterferon α2b/ribavirin, and boceprevir in relapsers and partial responders to peginterferon α2b/ribavirin. The results have been published and show that the addition of boceprevir markedly improved SVR rates in relapsers and nonresponders. Relapsers achieved an SVR rate of approximately 75%, and partial responders achieved an SVR of approximately 52% with 44 weeks of peginterferon α2b, ribavirin, and boceprevir. Again, lower SVR rates were noted in patients whose condition poorly responded to peginterferon α2b/ribavirin. In this study, null responders were not prospectively enrolled; however, a recent report of the PROVIDE study suggested that SVR rates with peginterferon α2b, ribavirin, and boceprevir are comparable to SVR rates seen with the addition of telaprevir to peginterferon α2b/ribavirin in null responders [Vierling et al. 2011]. The phase III trials allowed a retrospective analysis of the role of the interleukin (IL)-28B polymorphism in patients receiving boceprevir. The recently identified IL-28 polymorphism helps predict responsiveness to pretreatment with peginterferon α2b and ribavirin. Patients with the IL-28 CC genotype have the greatest likelihood of achieving sustained response (70–80%) with peginterferon α2b and ribavirin, and IL-28B is the strongest pretreatment predictor of SVR in patients receiving peginterferon α2b/ribavirin for genotype 1 infection [Thompson et al. 2010]. The retrospective analyses from the SPRINT II and RESPOND-2 studies suggest that patients with the IL-28 CC genotype 1 are highly likely to be treated for just 6 months with boceprevir. Interestingly, when the 4-week viral decline is analyzed, the 4-week viral load decline is a more potent predictor of SVR than IL-28B with boceprevir-based therapy [Poordad et al. 2011a]

Viral Resistance to Boceprevir

As we enter the era of direct-acting antiviral agents, clinicians will need to monitor patients for the development of resistance-associated variants when SVR is not achieved. The addition of direct-acting antiviral agents, such as boceprevir, can select for drug-resistant mutations. The early phase II RESPOND-1 study used a suboptimal dose of boceprevir without ribavirin, and high rates of viral breakthrough due to resistance-associated variants were noted. The low-dose ribavirin arm in part 2 of the SPRINT I study was associated with high rates of viral breakthrough, suggesting that full-dose ribavirin is also required for optimal response to peginterferon α2b and ribavirin. With ideally dosed boceprevir (800 mg three times a day), peginterferon α2b, and ribavirin and optimal response, there is viral suppression of wild-type strains with the replication of resistance-associated variants likely inhibited by the backbone of peginterferon α2b and ribavirin. In the SPRINT I study, population sequencing of the NS3 domain demonstrated that the major mutations noted were V36M, T54S, and R155K, with minor mutations noted of T54A, V55A, R155T, A156S, V158I, and V170A. It is likely that a greater frequency of drug-resistant mutations were generated in the low-dose ribavirin arms, in which high rates of relapse and breakthrough lower sustained response rates were observed. Additional studies with final sequencing are still ongoing and the long-term clinical significance of these resistant mutations is being assessed in follow-up trials. Optimal doses of ribavirin with full-dose boceprevir is the best strategy to minimize resistance, in combination with peginterferon α2b. In the future, combinations of direct-acting antiviral therapies may provide the ideal treatment strategy to prevent the emergence of viral resistance as has been demonstrated in an in vitro study [Flint et al. 2009].


The standard therapy for HCV genotype 1 achieves SVR in approximately 50% of patients. The addition of direct-acting antiviral agents, such as boceprevir, peginterferon α2b, and ribavirin will improve SVR rates and shorten treatment duration in patients with genotype 1 infection. Boceprevir is not approved for use in genotype 2 and 3 infection. In vitro and in vivo data have demonstrated that boceprevir has potent viral suppression, and early phase II trials have shown that the optimal boceprevir dose is 800 mg three times a day. The SPRINT I trial results have established several important findings. First, the addition of boceprevir, regardless of treatment strategy, improves SVR rates. A lead-in strategy may reduce relapse and prevent breakthrough, though the arms were not large enough to demonstrate statistical superiority. Peginterferon α2b/ribavirin responsiveness appears to be important in achieving SVR when boceprevir is added. In the 28-week and 48-week treatment arms, SVR rates were substantially improved, and in the 48-week treatment arms there was a near doubling of the rate – 75% versus the peginterferon α2b/ribavirin control SVR of 38%. Finally, response rates in African American patients with cirrhosis whose condition typically responds poorly to peginterferon α2b/ribavirin therapy were also substantially higher. These results were confirmed in the phase III SPRINT-2 and RESPOND-2 trials. Boceprevir added to peginterferon α2b/ribavirin improved SVR rates in patients who were treatment naïve and in those whose condition did not respond. Furthermore, boceprevir has been approved for the treatment of genotype 1 hepatitis C in the USA.

As with the development of other direct-acting antiviral agents, the emergence of resistance to protease inhibitors will be an important consideration. Data suggest that these drug-resistant mutations retain peginterferon α2b/ribavirin sensitivity. Optimally dosed boceprevir and ribavirin will minimize the development of these resistant strains. Finally, in vitro data on boceprevir and a polymerase inhibitor, and recently published data suggest that a combination of protease and polymerase inhibitors may be a successful strategy to reduce the risk of viral development of resistance. In addition, a combination of multiple direct-acting antiviral agents will be an emerging strategy to improve SVR rates and limit the emergence of resistance [Flint et al. 2009; Gane et al. 2010]. Moving forward, the addition of boceprevir to peginterferon α2b and ribavirin represents an important advance in the treatment of patients with genotype 1 hepatitis C.

  • Alter, M.J. (2007) Epidemiology of hepatitis C virus infection. World J Gastroenterol 13: 2436–2441.
  • Bartenschlager, R. (2002) Hepatitis C virus replicons: potential role for drug development. Nat Rev Drug Discov 1: 911–916.
  • Bartenschlager, R. and Lohmann, V. (2000) Replication of hepatitis C virus. J Gen Virol 81: 1631–1648.
  • Conjeevaram, H.S., Fried, M.W., Jeffers, L.J., Terrault, N.A., Wiley-Lucas, T.E., Afdhal, N. et al. (2006) Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology 131: 470–477.
  • Davis, G.L., Alter, M.J., El-Serag, H., Poynard, T. and Jennings, L.W. (2010) Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 138: 513–521.
  • Diago, M., Shiffman, M.L., Bronowicki, J.P., Zeuzem, S., Rodriguez-Torres, M., Pappas, S.C. et al. (2010) Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40KD) plus ribavirin. Hepatology 51: 1897–1903.
  • El-Serag, H.B. and Rudolph, K.L. (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132: 2557–2576.
  • Ferenci, P., Laferl, H., Scherzer, T.M., Maieron, A., Hofer, H., Stauber, R. et al. (2010) Peginterferon alfa-2a/ribavirin for 48 or 72 weeks in hepatitis C genotypes 1 and 4 patients with slow virologic response. Gastroenterology 138: 503–512.
  • Flint, M., Mullen, S., Deatly, A.M., Chen, W., Miller, L.Z., Ralston, R. et al. (2009) Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034). Antimicrob Agents Chemother 53: 401–411.
  • Gane, E.J., Roberts, S.K., Stedman, C.A., Angus, P.W., Ritchie, B., Elston, R. et al. (2010) Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 376: 1467–1475.
  • Hoofnagle, J.H. and Seeff, L.B. (2006) Peginterferon and ribavirin for chronic hepatitis C [see comment]. N Engl J Med 355: 2444–2451.
  • 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-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 376: 705–716.
  • Lauer, G. and Walker, B. (2001a) Hepatitis C virus infection. N Engl J Med 345: 41–52.
  • Lauer, G.M. and Walker, B.D. (2001b) Hepatitis C virus infection. N Engl J Med 345: 41–52.
  • Lohmann, V., Körner, F., Koch, J.O., Herian, U., Theilmann, L. and Bartenschlager, R. (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285: 110–113.
  • Malcolm, B.A., Liu, R., Lahser, F., Agrawal, S., Belanger, B., Butkiewicz, N. et al. (2006) SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents Chemother 50: 1013–1020.
  • McHutchison, J.G. and Bacon, B.R. (2005) Chronic hepatitis C: an age wave of disease burden. Am J Manag Care 11 (10 Suppl.): S286–S295; quiz S307–S311.
  • Muir, A.J., Bornstein, J.D., Killenberg, P.G. and Atlantic Coast Hepatitis Treatment Group (2004) Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites [see comment]. N Engl J Med 350: 2265–2271 [erratum in N Engl J Med 2004 351: 1268].
  • National Institutes of Health (2002) National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C 2002 (June 10–12, 2002). Gastroenterology 123: 2082–2099.
  • Poordad, F., Bronowicki, J.P., Gordon, S.C., Zeuzem, S., Jacobson, I.M., Sulkowski, M.S. et al. (2011a) IL28B polymorphism predicts virologic response in patients with hepatitis C genotype 1 treated with boceprevir (Boc) combination therapy. J Hepatol 54 (Suppl. 1): S6–S6.
  • Poordad, F., McCone, J., Jr., Bacon, B.R., Bruno, S., Manns, M.P., Sulkowski, M.S. et al. (2011b) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364: 1195–1206.
  • Poynard, T., McHutchison, J., Davis, G.L., Esteban-Mur, R., Goodman, Z., Bedossa, P. et al. (2000) Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C. Hepatology 32: 1131–1137.
  • Rodriguez-Torres, M., Jeffers, L.J., Sheikh, M.Y., Rossaro, L., Ankoma-Sey, V., Hamzeh, F.M. et al. (2009) Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites with hepatitis C. N Engl J Med 360: 257–267.
  • Sarrazin, C., Rouzier, R., Wagner, F., Forestier, N., Larrey, D., Gupta, S.K. et al. (2007) SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology 132: 1270–1278.
  • Schiff, E., Poordad, F.F., Jacobson, I.M., Flamm, S.L., Bacon, B.R., Lawitz, E.J. et al. (2008) Role of interferon response during RE-Treatment of null responders with boceprevir combination therapy: results of phase II trial. Gastroenterology134: A755.
  • Shiffman, M.L., Suter, F., Bacon, B.R., Nelson, D., Harley, H., Sola, R. et al. (2007) Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 357: 124–134.
  • Sulkowski, M.S., Shiffman, M.L., Afdhal, N.H., Reddy, K.R., McCone, J., Lee, W.M. et al. (2010) Hepatitis C virus treatment-related anemia is associated with higher sustained virologic response rate. Gastroenterology 139: 1602–1611.
  • Thompson, A.J., Muir, A.J., Sulkowski, M.S., Ge, D.,Fellay, J., Shianna, K.V. et al. (2010) Interleukin-28Bpolymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 139: 120–129.
  • Vierling, J., Flamm, S.L., Gordon, S.C., Lawitz, E., Bronowicki, J.P., Davis, M. et al. (2011) Efficacy of boceprevir in prior null responders to peginterferon/ribavirin: the PROVIDE study. Hepatology 54 (Suppl. 1): 796A.