Wednesday, March 28, 2012

New study shows liver cancer patients are less likely to die on wait list than candidates without cancer

Penn Researchers Call for a Re-Examination of Transplant Waitlist Prioritization
Source
New study shows liver cancer patients are less likely to die on wait list than candidates without cancer

(Philadelphia) — Patients with end-stage liver disease complicated by the most common type of liver cancer — hepatocellular carcinoma (HCC) — are less likely to die or become too sick for a transplant while waiting for a new liver than those with other complications of end-stage liver disease, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The investigators say their findings should prompt a re-examination of the criteria used to prioritize liver transplant candidates. Only three percent of patients with this common form of cancer who had been on the wait list for six to nine months were removed within 90 days because of death or advanced illness, compared to 24 percent of non-HCC candidates who were considered to be at the same level of need for transplant. The results of the study are published in the April issue of Liver Transplantation.

"With the scarcity of available livers for transplantation, it is imperative that the prioritization criteria ensure that the candidates who are at the greatest risk of dying from the disease be the first ones to receive a life-saving organ," said lead author David Goldberg, MD, an instructor in the department of Gastroenterology. "Our study compared the morality risk for patients with HCC to those with similar scores, but without liver cancer. What we found is that ultimately, the process used to determine transplant priority is making it so that these HCC patients are receiving healthy livers first, when in actuality, they are less likely to die while waiting for a new organ. This is an issue of utmost importance, because nearly 2,000 patients die each year waiting for a new liver on the transplant waitlist, while 25 to 30 percent of transplants are performed in patients with HCC."

Currently, transplant candidates are placed on the waitlist in an order determined by the results of a scoring system which determines how urgently they will need a liver transplant within the next three months. Patients with a higher score are placed higher on the waitlist. Because candidates with HCC have an increased risk of dropping off of the wait list due to progression of their tumor, they are given additional points when initially wait-listed, and receive more points the longer they remain on the waitlist. As their scores climb, it becomes more likely that these patients will receive transplants before other patients who may, according to the new study, actually be at greater risk of dying.

The Penn research team analyzed data from the Organ Procurement and Transplantation Network (OPTN) UNOS database, including candidates eighteen years of age and older who were on the wait list for liver transplantation between January 2005 and May 2009. Data for more than 10,000 patient cases was reviewed. Patients were categorized and compared according to their priority score. HCC and non-HCC patients were compared at three different stages of priority on the waitlist — those who had been on the waitlist for less than 90 days, patients who had been waiting for three to six months, and those who had been waiting for six to nine months. Across all three priority stages, a higher percentage of non-HCC patients were removed from the waitlist because they either died or became too ill to receive a transplant. Of the HCC candidates at the highest priority level — those who were determined to be sickest — only three percent were removed because of death or advanced illness, compared to 24 percent of non-HCC candidates with the same priority level.

The researchers determined that over time the risk of dying while on the waitlist or declining to the point where they are unable to accept a transplant was unchanged for HCC candidates — perhaps because of therapies that can be used to slow tumor growth such as chemo-embolization (where interventional radiologists treat the cancers with local chemotherapy) — but increased significantly for non-HCC candidates. "Our data clearly shows that HCC candidates have substantially lower chances of dying while waiting for a new organ than non-HCC candidates," said Goldberg. "While future research is planned to determine the best ways to prioritize HCC candidates and non-HCC candidates, our data strongly indicates that the current allotment of the additional points for HCC patients should be lowered."

###

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.

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IL28B Genetic Variants and Gender Are Associated With Spontaneous Clearance of Hepatitis C Virus Infection

From Journal of Viral Hepatitis

IL28B Genetic Variants and Gender Are Associated With Spontaneous Clearance of Hepatitis C Virus Infection

H.-Y. Rao; D.-G. Sun; D. Jiang; R.-F. Yang; F. Guo; J.-H. Wang; F. Liu; H.-Y. Zhang; H.-H. Zhang; S.-C. Du; Q. Jin; H. Qin; A.-S.-F. Lok; L. Wei

Posted: 03/28/2012; J Viral Hepat. 2012;19(3):173-181. © 2012 Blackwell Publishing

Discussion Only
Full Text Available At Medscape

In this study of 376 HCV-infected Chinese paid plasma donors, we found that IL28B gene variants were significantly associated with the spontaneous clearance of HCV infection. The SNP that had the strongest association with spontaneous clearance of HCV infection was rs8099917, and persons with the TT genotype were 15 times more likely to clear HCV than those with the GT genotype. However, the SNP rs12979860 that has been shown to be most strongly associated with response to pegylated interferon and ribavirin and to spontaneous HCV clearance in Caucasians and African Americans was not associated with spontaneous

HCV clearance in our study.[10–14]
Thomas et al. [14] studied 1008 subjects in six independent cohorts and found that rs12979860 CC genotype was predictive of spontaneous HCV clearance among individuals of both European and African ancestry. An association between rs12979860 CC genotype and spontaneous HCV clearance was also shown by Tillmann et al. [16] who studied 190 German women and by Montes-Cano et al. [18] in a study of 353 Spanish subjects. In all three studies, only one SNP (rs12979860) was tested. An association between rs8099917 TT genotype and response to pegylated interferon and ribavirin treatment had been reported in the studies of Caucasian patients and Japanese patients with chronic HCV infection.[11,12,17] An association between rs8099917 TT genotype and spontaneous clearance of HCV infection was also demonstrated in a study of 132 predominantly Caucasian patients in Australia and a study of 1362 Swiss and German patients.[12,15] Only two SNPs (rs8099917 and rs12980275) were tested in the study in Australia. The study in Switzerland tested more than 500 000 SNPs. Analysis of data from 1213 individuals with available data at both rs12979860 and rs8099917 found that rs12979860 genotype was highly associated with chronic HCV infection and was in strong linkage disequilibrium with rs8099917.[12]

In this study, we tested eight SNPs and found an association between spontaneous HCV clearance and four SNPs including rs8099917, rs8105790, rs12980275 and rs10853728 but not rs12979860. Ge et al. [10] had noted that the linkage between rs8099917 and rs12979860 is high among Caucasians, but low among African Americans. We found that rs8099917 was strongly linked to rs12979860 (r 2 = 1.00), rs12980275 (r 2 = 0.97) and rs8105790 (r 2 = 1.00) in our study. In our study, all donors with rs12979860 CC had rs8099917 TT genotype, but donors with rs12979860 CT could be rs8099917 TT or TG.

The rs12979860 C allele frequency in the Chinese Han population (83 subjects from Beijing, China) was reported to be 93.4% in HapMap and 94–98% in Thomas' study of 47 Chinese in Taiwan and 59 Chinese in San Francisco, but it was only 74% in our study. The rs8099917 T allele frequency in the Chinese Han population was reported to be 93.5% in HapMap and 93.3% in our study. The subjects in our study all came from one county, Hebei, in the northern part of China. So, the SNP allele frequencies in our study might be only representative of the northern local region. While most Chinese in the major cities of China are of Han ancestry, other ancestries predominate in some parts of China. Studies involving larger numbers of Chinese in different regions of China are necessary to determine the precise frequency of the favourable alleles at rs12979860 and rs8099917 among Chinese of various ancestries.

In this study, the SNP rs8099917 had the strongest association with spontaneous HCV clearance. Although three other SNPs (rs10853728, rs 12980275 and rs8105790) in the IL28B region were independently associated with spontaneous HCV clearance, inclusion of these three SNPs or the haplotype ATTC with favourable alleles at these three SNPs plus rs8099917 did not improve the prediction of spontaneous HCV clearance in the multivariate model compared with rs8099917 alone. Several studies showed that women were more likely to undergo spontaneous HCV clearance than men. One study of 67 persons with acute HCV infection, 66% of whom were injection drug users, found that HCV clearance occurred in 34% of women compared with 3% of men (P < 0.001).[20] Another study followed 135 injection drug users with incident HCV infection and found that the age-adjusted hazard ratio of spontaneous HCV clearance for women was 2.91 (95% CI: 1.68–5.03).[21] A systematic review of 31 longitudinal studies that included 314 subjects showed that the relative risk of spontaneous HCV clearance for men was 0.43 (95% CI: 0.36–0.53) (P = 0.00001).[22]

Two recent studies examined gender, IL28B genetic variants and spontaneous HCV clearance. In Grebely et al.'s[15] study of 132 Australians, rs8099917 TT genotype (adjusted hazard ratio 3.78, 95% CI: 1.04–13.76) was the only factor predicting spontaneous HCV clearance on multivariate analysis, but female gender and jaundice during the acute illness were not. In Montes-Cano et al.'s[18] study of 352 Spanish subjects, rs12979860 CC genotype was associated with a higher rate of spontaneous HCV clearance in both men (72.4%vs 27.6%) and women (72.5%vs 27.5%) compared with those with CT or TT genotype. In this study, we found that women had a higher rate of spontaneous HCV clearance than men, 26.3%vs 14.6%, and this difference persisted even after stratification for IL28B genotypes. Among those with rs8099917 TT genotype, women were twice as likely to have spontaneous HCV clearance as men. Female gender remained an independent predictor of spontaneous HCV clearance in the multivariate model, with OR of 1.95.

Some studies found that the presence of jaundice or symptoms during acute HCV infection was associated with a higher rate of spontaneous HCV clearance.[15,16,22] Tillmann et al. [16] found that jaundice during acute infection was associated with an increased chance of spontaneous HCV clearance (42.9%vs 13.7%) in persons with non-CC genotype at rs12979860, but not in those with CC genotype (56.3%vs 60.6%). In this study, spontaneous HCV clearance rate was similar in donors with and without documented ALT elevation during the outbreaks, but the donors were not regularly monitored, and it is possible that ALT was not tested at the time of acute infection. We were also not able to determine whether any of the donors had symptomatic illness or were jaundiced during the acute infection.

In summary, in this study of a large homogenous cohort of HCV-infected plasma donors, we found that 21.3% had spontaneous HCV clearance. We confirmed that IL28B genotype is associated with spontaneous HCV clearance with rs8099917 TT genotype showing the strongest association, while rs12979860 CC genotype had no association. Women had a higher rate of spontaneous HCV clearance regardless of IL28B genotype. Our results suggest that while IL28B genotype is associated with spontaneous HCV clearance in patients of diverse racial/ethnic background, the SNP with the strongest association may vary. Further studies are needed to confirm this observation and to clarify whether other factors such as gender and severity of the acute illness are independent predictors of spontaneous HCV clearance after correction for IL28B genotype. These results will help in determining which patients with acute HCV infection should start on antiviral therapy and which ones to be monitored.

Full Text Available At Medscape
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Insulin resistance and response to telaprevir plus peginterferon α and ribavirin in treatment-naïve patients infected with HCV genotype 1

Insulin resistance and response to telaprevir plus peginterferon α and ribavirin in treatment-naïve patients infected with HCV genotype 1

Source

Gut doi:10.1136/gutjnl-2011-300749
  • Viral hepatitis
  • Original article
  1. Patrick Marcellin11
+ Author Affiliations
  1. 1Service d'Hépatologie and INSERM UMRS 938, Hôpital Saint Antoine, Université Pierre&Marie Curie, Paris, France
  2. 2Liver Unit, Hospital Clinic, IDIBAPS, Ciberehd, University of Barcelona, Barcelona, Spain
  3. 3Klinikum der Universität zu Köln, Köln, Germany
  4. 4Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria
  5. 5Department of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium
  6. 6Clinic of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy
  7. 7Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
  8. 8Janssen Pharmaceuticals, Paris, France
  9. 9Tibotec Inc, Titusville, New Jersey, USA
  10. 10Tibotec BVBA, Beerse, Belgium
  11. 11Service d'Hépatologie and INSERM CRB3, Hôpital Beaujon, APHP, Université Paris-Diderot, Clichy, France
  1. Correspondence to Dr Lawrence Serfaty, Hôpital St Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France; lawrence.serfaty@sat.aphp.fr
  1. Contributors LS, XF, TG, PF, FN, GC, JPD and PM were study investigators and participated in the recruitment of patients and reporting of data for the patients they enrolled. IL-D, RDeM, GP and MB contributed to the design, conduct and analysis of the C208 clinical trial. LS wrote the first draft of the manuscript and had full access to the data. RDeM provided statistical analysis support. All authors were involved in the interpretation of the data, reviewed and revised the manuscript for intellectual content, and approved the final version for submission.
  • Revised 11 November 2011
  • Accepted 28 November 2011
  • Published Online First 2 March 2012
Abstract

Objective Insulin resistance is a predictor of poor response to peginterferon/ribavirin in patients infected with the chronic hepatitis C virus (HCV). There are no data on direct-acting antivirals. This exploratory analysis assessed the effect of metabolic factors and insulin resistance, measured by homoeostatic model assessment (HOMA), on virological response to telaprevir in Study C208.

Design Overall, 161 HCV genotype 1-infected, treatment-naïve patients received 12 weeks of telaprevir plus peginterferon/ribavirin, then 12/36 weeks of peginterferon/ribavirin depending on on-treatment response criteria. The prognostic significance of several factors, including HOMA-insulin resistance (HOMA-IR), on virological response at weeks 4 and 12, end of treatment and 24 weeks after treatment was explored by multiple regression analysis.

Results Baseline HOMA-IR data were available for 147 patients; baseline characteristics were consistent with the overall population. Baseline HOMA-IR <2, 2–4 and >4 was seen in 54%, 30% and 16% of patients, respectively. Neither response rates (any time point) nor week 4 viral load decline were significantly influenced by baseline HOMA-IR. In multivariate analyses, fibrosis stage and low-density lipoprotein cholesterol level were predictive of sustained virological response (OR 0.47 and 1.02, respectively). After the end of treatment, HOMA-IR was significantly lower in patients with sustained virological response than in those without (0.61 vs 1.34 for relapsers and 1.15 for non-responders; p<0.05).

Conclusion In this study, baseline HOMA-IR was not predictive of virological response to telaprevir in HCV genotype 1-infected, treatment-naïve patients, while sustained virological response was associated with improved HOMA-IR. These results suggest that metabolic factors and insulin resistance do not have a significant effect on telaprevir-based treatment efficacy.
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Gene expression profiling of HCV genotype 3a initial liver fibrosis and cirrhosis patients using microarray

Research

Gene expression profiling of HCV genotype 3a initial liver fibrosis and cirrhosis patients using microarray

Waqar Ahmad, Bushra Ijaz and Sajida Hassan
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Journal of Translational Medicine 2012, 10:41 doi:10.1186/1479-5876-10-41
Published: 7 March 2012

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Abstract (provisional)

Background
Hepatitis C virus (HCV) causes liver fibrosis that may lead to liver cirrhosis or hepatocellular carcinoma (HCC), and may partially depend on infecting viral genotype. HCV genotype 3a is being more common in Asian population, especially Pakistan; the detail mechanism of infection still needs to be explored. In this study, we investigated and compared the gene expression profile between initial fibrosis stage and cirrhotic 3a genotype patients.

Methods
Gene expression profiling of human liver tissues was performed containing more than 22000 known genes. Using Oparray protocol, preparation and hybridization of slides was carried out and followed by scanning with GeneTAC integrator 4.0 software. Normalization of the data was obtained using MIDAS software and Significant Microarray Analysis (SAM) was performed to obtain differentially expressed candidate genes.

Results
Out of 22000 genes studied, 219 differentially regulated genes found with P [less than or equal to] 0.05 between both groups; 107 among those were up-regulated and 112 were down-regulated. These genes were classified into 31 categories according to their biological functions. The main categories included: apoptosis, immune response, cell signaling, kinase activity, lipid metabolism, protein metabolism, protein modulation, metabolism, vision, cell structure, cytoskeleton, nervous system, protein metabolism, protein modulation, signal transduction, transcriptional regulation and transport activity.

Conclusion
This is the first study on gene expression profiling in patients associated with genotype 3a using microarray analysis. These findings represent a broad portrait of genomic changes in early HCV associated fibrosis and cirrhosis. We hope that identified genes in this study will help in future to act as prognostic and diagnostic markers to differentiate fibrotic patients from cirrhotic ones.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.
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Protease inhibitors: Silver bullets for chronic hepatitis C infection?

EDUCATIONAL OBJECTIVE: Readers will integrate protease inhibitors into the management of chronic hepatitis C virus infection

Protease inhibitors: Silver bullets for chronic hepatitis C infection?

NAIM ALKHOURI, MD
Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH
NIZAR N. ZEIN, MD*⇓

Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH
ADDRESS: Nizar N. Zein, MD, Department of Gastroenterology and Hepatology, A31, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail zeinn@ccf.org.

This Article
  1. doi: 10.3949/ccjm.79a.11082 Cleveland Clinic Journal of Medicinevol. 79 3 213-222
  1. Download Full Text (PDF)

Abstract
Recent trials evaluated the safety and efficacy of two protease inhibitors, boceprevir (Victrelis) and telaprevir (Incivek), added to standard care with pegylated interferon and ribavirin, in patients with chronic hepatitis C virus (HCV) infection. These drugs open the door for triple therapy and other new therapies involving combinations of other direct-acting antiviral agents to become the new standard of care for this population.

Key points
Standard care with the combination of pegylated interferon and ribavirin produces a sustained virologic response in about 40% of patients infected with HCV genotype 1, the most prevalent genotype in North America.

New phase 3 trials showed that the addition of an oral protease inhibitor (boceprevir or telaprevir) increased the sustained virologic response rates to 70% in patients infected with HCV genotype 1.
Boceprevir and telaprevir must be used in combination with pegylated interferon and ribavirin; they should not be used as monotherapy because of concern about the development of drug-resistant mutations.
The main side effects of boceprevir were anemia and dysgeusia. Adverse events associated with telaprevir included rash, pruritus, anemia, and diarrhea.

The treatment of hepatitis c virus (HCV) infection is on the brink of major changes with the recent approval of the first direct-acting antiviral agents, the protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek).
Both drugs were approved by the US Food and Drug Administration (FDA) Advisory Panel for Chronic Hepatitis C in May 2011 and are believed to significantly improve treatment outcomes for patients with HCV genotype 1 infection.

This review summarizes the results of recent phase 3 clinical trials that evaluated the safety and efficacy of these new agents (TABLE 1).1–5
 
Click To Enlarge TABLE 1
 
Phase III clinical trials of boceprevir and telaprevir


CURRENTLY, FEWER THAN 50% OF PATIENTS ARE CURED
The goal of HCV treatment is to eradicate the virus. However, most infected patients (especially in the United States and Europe) are infected with HCV genotype 1, which is the most difficult genotype to treat.
Successful treatment of HCV is defined as achieving a sustained virologic response—ie, the absence of detectable HCV RNA in the serum 24 weeks after completion of therapy. Once a sustained virologic response is achieved, lifetime “cure” of HCV infection is expected in more than 99% of patients.13
The current standard therapy for HCV, pegylated interferon plus ribavirin for 48 weeks, is effective in only 40% to 50% of patients with genotype 1 infection.14 Therefore, assessing predictors of response before starting treatment can help select patients who are most likely to benefit from therapy.
Viral factors associated with a sustained virologic response include HCV genotypes other than genotype 1 and a low baseline viral load.

Beneficial patient-related factors include younger age, nonblack ethnicity, low body weight (≤ 75 kg), low body mass index, absence of insulin resistance, and absence of advanced fibrosis or cirrhosis.
More recently, a single-nucleotide polymorphism near the interleukin 28B (IL28B) gene, coding for interferon lambda 3, was found to be associated with a twofold difference in the rates of sustained virologic response: patients with the favorable genotype CC were two times more likely to achieve a sustained virologic response than patients with the CT or TT genotypes.15–17


PROTEASE INHIBITORS: MECHANISM OF ACTION
HCV is a single-stranded RNA virus, and its genome encodes a single polyprotein of about 3,000 amino acids. This polyprotein is cleaved by proteases during and after translation into four structural and six nonstructural proteins. The NS3/4A protease plays an important role in viral replication by cleaving the HCV polyprotein and releasing most of the nonstructural proteins (FIGURE 1).18,19


Click To Enlarge (FIGURE 1).



Click To Enlarge TABLE 2
Adverse events reported in clinical trials of boceprevir and telaprevir


NS3/4A protease inhibitors rely on the principle of end-product inhibition, in which the cleavage product of the protease (a peptide) acts to inhibit the enzyme activity; this is why they are called peptidomimetics. The active site of the NS3/4A protease is a shallow groove composed of three highly conserved amino acid residues, which may explain why protease inhibitors display high antiviral efficacy but pose a low barrier to the development of resistance.20

Protease inhibitors are prone to resistance
The development of viral resistance to protease inhibitors has been a major drawback to their use in patients with chronic HCV infection.21
HCV is a highly variable virus with many genetically distinct but closely related quasispecies circulating in the blood at any given time. Drug-resistant, mutated variants preexist within the patient’s quasispecies, but only in small quantities because of their lesser replication fitness compared with the wild-type virus.22 When direct-acting antiviral therapy is started, the quantity of the wild-type virus decreases and the mutated virus gains replication fitness. Using protease inhibitors as monotherapy selects resistant viral populations rapidly within a few days or weeks.

HCV subtypes 1a and 1b may have different resistance profiles. With genotype 1a, some resistance-associated amino acid substitutions require only one nucleotide change, but with genotype 1b, two nucleotide changes are needed, making resistance less frequent in patients with HCV genotype 1b.23

Boceprevir
Boceprevir is a specific inhibitor of the HCV viral protease NS3/4A.
In phase 3 clinical trials, boceprevir 800 mg three times a day was used with pegylated interferon alfa-2b (PegIntron) 1.5 μg/kg/week and ribavirin (Rebetol) 600 to 1,400 mg daily according to body weight.
Before patients started taking boceprevir, they went through a 4-week lead-in phase, during which they received pegylated interferon and ribavirin. This schedule appeared to reduce the incidence of viral breakthrough in phase 2 trials, and it produced higher rates of sustained virologic response and lower relapse rates compared with triple therapy without a lead-in phase.
Rapid virologic response was defined as undetectable HCV RNA at week 4 of boceprevir therapy (week 8 of the whole regimen).

Boceprevir in previously untreated patients with HCV genotype 1: The SPRINT-2 trial
The Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial1 included more than 1,000 previously untreated adults with HCV genotype 1 infection (938 nonblack patients and 159 black patients; two other nonblack patients did not receive any study drug and were not included in the analysis). In this double-blind trial, patients were randomized into three groups:
  • The control group received the standard of care with pegylated interferon and ribavirin for 48 weeks
  • The response-guided therapy group received boceprevir plus pegylated interferon and ribavirin for 24 weeks after the 4-week lead-in phase; if HCV RNA was undetectable from week 8 to week 24, treatment was considered complete, but if HCV RNA was detectable at any point from week 8 to week 24, pegylated interferon and ribavirin were continued for a total of 48 weeks.
  • The fixed-duration therapy group received boceprevir, pegylated interferon, and ribavirin for 44 weeks after the lead-in period.
In the overall cohort, the rates of sustained virologic response were 63% in the response-guided therapy group and 66% in the fixed-duration therapy group compared with 38% in the control group (P < .001 for both) (TABLE 2 ). In the subgroup of patients who were black, the rates were 42%, 53%, and 23%, respectively. Overall, 44% of patients in the response-guided therapy group were able to stop all treatment at 28 weeks.

The rate of relapse was 8% and 9% in the boceprevir groups vs 23% in the control group. Patients in the boceprevir groups who had a decrease in HCV RNA of less than 1 log10 during the lead-in phase were found to have a significantly higher rate of boceprevirresistant variants than those who achieved a decrease of HCV RNA of 1 log10 or more.

Boceprevir in previously treated patients with HCV genotype 1: The RESPOND-2 trial
The Retreatment With HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) (RESPOND-2) trial2 was designed to assess the efficacy of combined boceprevir, pegylated interferon, and ribavirin for repeat treatment of patients with HCV genotype 1. These patients had previously undergone standard treatment and had a reduction of 2 log10 or more in HCV RNA after 12 weeks of therapy but with detectable HCV RNA during the therapy period or had had a relapse (defined as undetectable HCV RNA at the end of a previous course of therapy with HCV RNA positivity thereafter). Importantly, null-responders (those who had a reduction of less than 2 log10 in HCV RNA after 12 weeks of therapy) were excluded from this trial.
After a lead-in period of interferon-ribavirin treatment for 4 weeks, 403 patients were assigned to one of three treatment groups:
  • Pegylated interferon and ribavirin for 44 weeks (the control group)
  • Boceprevir, pegylated interferon, and ribavirin in a response-guided regimen
  • Boceprevir, pegylated interferon, and ribavirin for 44 weeks (the fixed-duration group).
Sustained virologic response was achieved in only 21% of patients in the control group. Adding boceprevir increased the rate to 59% in the response-guided therapy group and to 67% in the fixed-duration group. Previous relapsers had better rates than partial responders (69%–75% vs 40%–52%).
Importantly, patients who had a poor response to pegylated interferon and ribavirin during the lead-in phase (defined as having less than a 1-log decrease in the virus before starting boceprevir) had significantly lower rates of sustained virologic response and higher rates of resistance-associated virus variants.

Side effects of boceprevir
Overall, boceprevir is well tolerated. The most common side effects of triple therapy are those usually seen with pegylated interferon and ribavirin, such as flulike symptoms and fatigue (TABLE 2 ). However, anemia was more frequent in the boceprevir groups in both SPRINT-2 and RESPOND-2 (45%–50% compared with 20%–29% in the control groups). Erythropoietin was allowed in these studies and was used in about 40% of patients.

The other common side effect associated with boceprevir was dysgeusia (alteration of taste). Dysgeusia was reported by approximately 40% of patients; however, most dysgeusia events were mild to moderate in intensity and did not lead to treatment cessation.

In the SPRINT-2 trial,1 the study drugs had to be discontinued in 12% to 16% of patients in the boceprevir groups because of adverse events, which was similar to the rate (16%) in the control group. Erythropoietin was allowed in this trial, and it was used in 43% of patients in the boceprevir groups compared with 24% in the control group, with discontinuation owing to anemia occurring in 2% and 1% of cases, respectively.

Telaprevir, the other protease NS3/4A inhibitor, has also shown efficacy over current standard therapy in phase 3 clinical trials. It was used in a dose of 750 mg three times a day with pegylated interferon alfa-2a (Pegasys) 180 μg per week and ribavirin (Copegus) 1,000 to 1,200 mg daily according to body weight. A lead-in phase with pegylated interferon and ribavirin was not applied with telaprevir, as it was in the boceprevir trials. Extended rapid virologic response was defined as an undetectable HCV RNA at weeks 4 and 12 of therapy.

Telaprevir in previously untreated patients with HCV genotype 1
The ADVANCE study3 was a double-blind randomized trial assessing the efficacy and safety of telaprevir in combination with pegylated interferon and ribavirin in more than 1,000 previously untreated patients. The three treatment groups received:
  • Telaprevir, pegylated interferon, and ribavirin for 8 weeks, followed by pegylated interferon and ribavirin alone for 16 weeks in patients who achieved an extended rapid virologic response (total duration of 24 weeks) or 40 weeks in patients who did not (total duration of 48 weeks)
  • Telaprevir, pegylated interferon, and ribavirin for 12 weeks, followed by pegylated interferon-ribavirin alone for 12 (total of 24 weeks) or 36 weeks (total of 48 weeks) according to extended rapid virologic response
  • Standard care with pegylated interferon and ribavirin for 48 weeks.
The rate of sustained virologic response was 69% in the group that received telaprevir for 8 weeks and 75% in the group that received it for 12 weeks compared with 44% in the control group (P < .0001 for both) (TABLE 2 ). Patients infected with HCV genotype 1b had a higher sustained virologic response rate (79%) than those infected with HCV genotype 1a (71%).

Sustained virologic response rates were lower in black patients and patients with bridging fibrosis or cirrhosis, but were still significantly higher in the telaprevir groups than in the control group. The results of this subset analysis were limited by small numbers of patients in each category.
In total, 57% of those who received telaprevir for 8 weeks and 58% of those who received it for 12 weeks achieved an extended rapid virologic response and were able to cut the duration of their therapy in half (from 48 weeks to 24 weeks).

The relapse rates were 9% in the telaprevir groups and 28% in the control group.
The rate of virologic failure was lower in patients who received triple therapy than in those who received interferon-ribavirin alone (8% in the group that got telaprevir for 12 weeks and 13% in the group that got it for 8 weeks, vs 32% in the control group). The failure rate was also lower in patients with HCV genotype 1b infection than in those with genotype 1a.

The ILLUMINATE study4 (Illustrating the Effects of Combination Therapy With Telaprevir) investigated whether longer duration of treatment than that given in the ADVANCE trial increased the rate of sustained virologic response. Previously untreated patients received telaprevir, interferon, and ribavirin for 12 weeks, and those who achieved an extended rapid virologic response were randomized at week 20 to continue interferonribavirin treatment for 24 or 48 weeks of total treatment.

The sustained virologic response rates in patients who achieved an extended rapid virologic response were 92% in the group that received pegylated interferon and ribavirin for 12 weeks, and 88% in those who received it for 48 weeks. Thus, the results of this study support the use of response-guided therapy for telaprevir-based regimens.

Telaprevir in previously treated patients with HCV genotype 1: The REALIZE trial
In this phase 3 placebo-controlled trial,5 622 patients with prior relapse, partial response, or null response were randomly allocated into one of three groups:
  • Telaprevir for 12 weeks plus pegylated interferon and ribavirin for 48 weeks
  • Lead-in for 4 weeks followed by 12 weeks of triple therapy and another 32 weeks of pegylated interferon and ribavirin
  • Pegylated interferon and ribavirin for 48 weeks (the control group).
The overall sustained virologic response rates were 66% and 64%, respectively, in the telaprevir groups vs 17% in the control group (P < .0001). The sustained virologic response rates in the telaprevir groups were 83% to 88% in prior relapsers, 54% to 59% in partial responders, and 29% to 33% in null-responders. Of note, patients did not benefit from the lead-in phase.
This was the only trial to investigate the response to triple therapy in null-responders, a group in which treatment has been considered hopeless. A response rate of approximately 31% was encouraging, especially if we compare it with the 5% response rate achieved with the current standard of care with pegylated interferon and ribavirin.

Telaprevir side effects
As with boceprevir-based triple therapy, the most common adverse events were related to pegylated interferon (TABLE 2 ).

Nearly 50% of patients who receive telaprevir develop a skin rash that is primarily eczematous, can be managed with topical steroids, and usually resolves when telaprevir is discontinued. Severe rashes occurred in 3% to 6% of patients in the ADVANCE trial,3 and three suspected cases of Stevens-Johnson syndrome have been reported to the FDA.

Other side effects that were more frequent with telaprevir included pruritus, nausea, diarrhea, and anemia. On average, the hemoglobin level decreased by an additional 1 g/dL in the telaprevir treatment groups compared with the groups that received only pegylated interferon-ribavirin. Erythropoietin use was not allowed in the phase 3 telaprevir studies, and anemia was managed by ribavirin dose reduction.
In the ADVANCE trial,3 study drugs were discontinued owing to adverse events in 7% to 8% of the patients in the telaprevir groups compared with 4% in the control group. In the ILLUMINATE trial,4 17% of patients had to permanently discontinue all study drugs due to adverse events.

FDA-APPROVED TREATMENT REGIMENS FOR BOCEPREVIR AND TELAPREVIR
For treatment algorithms, see the eFIGURES that accompany this article online.

Boceprevir in previously untreated patients
  • Week 0—Start pegylated interferon and ribavirin
  • Week 4—Add boceprevir
  • Week 8—Measure HCV RNA
  • Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL
  • Week 24—Measure HCV RNA; stop treatment if it is detectable
  • Week 28—Stop all treatment if HCV RNA was undetectable at weeks 8 and 24
  • Week 36—Measure HCV RNA; stop boceprevir
  • Week 48—Stop all treatment (eFIGURE 1).

Boceprevir in previously treated patients

  • Week 0—Start pegylated interferon and ribavirin
  • Week 4—Add boceprevir
  • Week 8—Measure HCV RNA
  • Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL
  • Week 24—Measure HCV RNA; stop treatment if it is detectable
  • Week 36—if HCV RNA was not detectable at week 8, stop all treatment now; if HCV RNA was detectable at week 8, stop boceprevir now but continue pegylated interferon and ribavirin
  • Week 48—Stop all treatment (eFIGURE 2).

Telaprevir in previously untreated patients and prior relapsers

  • Week 0—start telaprevir, pegylated interferon, and ribavirin
  • Week 4—measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL
  • Week 12—Stop telaprevir; measure HCV RNA; stop all treatment if HCV RNA is more than 1,000 IU/mL
  • Week 24—Stop pegylated interferon and ribavirin if HCV RNA was undetectable at week 12; measure HCV RNA and stop treatment if it is detectable; otherwise, continue pegylated interferon and ribavirin
  • Week 48—Stop all treatment (eFIGURE 3).

Telaprevir in patients who previously achieved a partial or null response

  • Week 0—Start telaprevir, pegylated interferon, and ribavirin
  • Week 4—Measure HCV RNA; stop treatment if it is more than 1,000 IU/mL
  • Week 12—Measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL; if less than 1,000 IU/mL then stop telaprevir but continue pegylated interferon and ribavirin
  • Week 24—Measure HCV RNA; stop treatment if HCV RNA is detectable
  • Week 48—Stop all treatment (eFIGURE 4).
Drug interactions with boceprevir and telaprevir
Both boceprevir and telaprevir inhibit cytochrome P450 3A (CYP3A) and thus are contraindicated in combination with drugs highly dependent on CYP3A for clearance and with drugs for which elevated plasma concentrations are associated with serious adverse events, such as atorvastatin (Lipitor), simvastatin (Zocor), sildenafil (Viagra), midazolam (Versed), and St. John’s wort. Giving potent inducers of CYP3A with boceprevir or telaprevir may lead to lower exposure and loss of efficacy of both protease inhibitors.

EMERGING THERAPIES FOR HCV
Thanks to a better understanding of the biology of HCV infection, the effort to develop new therapeutic agents started to focus on targeting specific steps of the viral life cycle, including attachment, entry into cells, replication, and release.24

Currently, more than 50 clinical trials are evaluating new direct-acting antivirals to treat HCV infection.25 Monoclonal and polyclonal antibodies that target the molecular process involved in HCV attachment and entry are being developed.26 The nonstructural protein NS5B (RNA polymerase) is intimately involved in viral replication and represents a promising target.27 Several nucleosides and nonnucleoside protease inhibitors have already entered clinical trials.

The low fidelity of the HCV replication machinery leads to a very high mutation rate, thus enabling the virus to quickly develop mutations that resist agents targeting viral enzymes.28 Therefore, a novel approach is to target host cofactors that are essential for HCV replication. An intriguing study by Lanford et al29 demonstrated that antagonizing microRNA-122 (the most abundant microRNA in the liver and an essential cofactor for viral RNA replication) by the oligonucleotide SPC3649 caused marked and prolonged reduction of HCV viremia in chronically infected chimpanzees.29

Although we are still in the early stages of drug development, the future holds great promise for newer drugs to improve the sustained virologic response, shorten the duration of treatment, improve tolerability with interferon-sparing regimens, and decrease viral resistance.

FUTURE PERSPECTIVES
With the introduction of the first direct-acting antiviral medications for HCV (boceprevir and telaprevir), 2011 will be marked as the year that changed hepatitis C treatment for the better. Triple therapy with pegylated interferon, ribavirin, and either boceprevir or telaprevir has the potential for increasing the rate of sustained virologic response to around 70% in previously untreated patients and 65% in previously treated patients who are infected with HCV genotype 1. The IL28B polymorphisms appear to play a role in the rate of sustained virologic response achieved with triple therapy, with preliminary data showing a better response rate in patients who have the CC genotype.17

These drugs will add up to $50,000 to the cost of treating hepatitis C virus infection, depending on the drug used and the length of treatment. However, they may be well worth it if they prevent liver failure and the need for transplantation.

Many questions remain, such as how to use these new regimens to treat special patient populations—for example, those with a recurrence of HCV infection after liver transplantation, those co-infected with HCV and human immunodeficiency virus, and those infected with HCV genotypes other than genotype 1.
Other direct-acting antiviral agents that specifically target the replication cycle of HCV are currently in clinical development. In fact, the future has already started with the release of the Interferon-Free Regimen for the Management of HCV (INFORM-1) study results.30 This was the first trial to evaluate an interferon-free regimen for patients with chronic HCV infection using two direct-acting antiviral drugs (the protease inhibitor danoprevir and the polymerase inhibitor RG7128), with promising results. 

Footnotes
  • ↵* Dr. Zein has disclosed consulting, teaching, speaking, and receiving research funding from Merck (makers of boceprevir) and Vertex (makers of telaprevir).
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