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Telaprevir FDA Approved

FDA Approves Telaprevir/Incivek For Hepatitis C
Telaprevir/Incivek Prescribing Information
Medication Guide

Boceprevir FDA Approved

Vicrelis/Boceprevir IS NOW FDA Approved May 13 2011
VICTRELIS™- Boceprevir: Prescribing Information and Medication Guide

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INCIVEK/Telaprevir and VICTRELIS (Boceprevir) Patient Assistance Programs

Getting Ready; Telaprevir or Boceprevir ?
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Treating Hepatitis C In 2011; The Bible Of Links
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2011 EASL; Easy To Understand Summary of the investigational Hepatitis C drugs .
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Released On Feb 2010

AASLD 2010 Summary Of Hepatitis C Oral Inhibitors

Treatment of Hepatitis C in 2011: What Can We Expect?
Mitchell L. Shiffman1
(1)
Liver Institute of Virginia, Bon Secours Health System, Mary Immaculate Hospital Medical Pavilion suite 313, 12720 McManus Blvd, Newport News, VA 23602, USA

Mitchell L. ShiffmanEmail: mlshiffman@googlemail.com
Published online: 25 February 2010

Abstract
Treatment for chronic hepatitis C virus (HCV) infection is the combination of a peginterferon and ribavirin. Although a fixed duration of treatment (24 weeks for patients with genotypes 2 and 3 and 48 weeks for patients with all other genotypes) has been advocated, the best results are likely to be achieved when the duration of therapy is adjusted based on the time to response. According to the principles of response-guided therapy, patients with rapid virologic response have a high rate of sustained virologic response (SVR) and a low rate of relapse, and can be treated for 24 weeks regardless of genotype. gIn contrast, patients who become HCV RNA undetectable at a slower rate need a longer duration of therapy. Direct-acting antiviral agents are currently being developed to treat patients with HCV genotype 1. These agents will significantly increase rapid virologic response when used with peginterferon and ribavirin; according to the concepts of response-guided therapy, such treatment will yield high rates of SVR with 24 to 28 weeks of treatment.
Keywords HCV - Peginterferon - Ribavirin


Introduction
For the past decade, the combination of peginterferon and ribavirin has been used to treat chronic hepatitis C virus (HCV) infection [1–3]. These agents yield sustained virologic response (SVR) rates of about 40–45% in patients with genotype 1 and 75–80% in patients with genotypes 2 and 3. Patients with genotypes 4, 5, and 6 have SVR rates between these ranges [4, 5]. Although the prevalence of the various genotypes varies according to ethnicity, race, and geography [6], the vast majority of patients worldwide are infected with HCV genotype 1 and fail to achieve SVR with the currently available therapy.

The mechanisms by which peginterferon and ribavirin act to eradicate HCV remain speculative and somewhat obscure. Peginterferon has a direct antiviral effect, inhibiting both the entry of virus into cells and viral replication, and enhances the immune response [7]. Ribavirin, a guanosine analog, is believed to inhibit viral replication by interfering with viral RNA synthesis [8]. However, neither agent specifically targets HCV, at least in part explaining the low response rates with current treatment. The ideal treatment for a chronic viral infection is an antiviral agent specifically constructed to inhibit a step in the viral life cycle. Although the development of specifically targeted antiviral therapy against HCV (STAT-C) has evolved slowly over the past decade, two agents—telaprevir and boceprevir—are currently being evaluated in phase 3 clinical trials [9•, 10, 11]. Availability of these two protease inhibitors is anticipated for late 2011.

This article reviews recently learned important concepts regarding the treatment of chronic HCV with peginterferon and ribavirin. These concepts are critically important to understand, because they have a direct bearing on how direct-acting antiviral agents (DAA) will be used with peginterferon and ribavirin to treat chronic HCV in 2011.


Response-Guided Therapy
Traditionally, the combination of peginterferon and ribavirin is administered for 48 weeks in patients with HCV genotypes 1, 4, 5, and 6 and for 24 weeks in patients with genotypes 2 and 3. However, we now understand that a spectrum of virologic response patterns occurs when patients are treated with peginterferon and ribavirin, and fixed-duration therapy based on genotype is no longer appropriate (Fig. 1) [12]. It was demonstrated recently that the time when the patient first becomes HCV RNA undetectable is directly related to the relapse rate and is the single most important determinant of SVR [13, 14].

Fig. 1

Patterns of virologic response observed during treatment with peginterferon and ribavirin.
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cEVR—complete early virologic response;

The “best” viral response pattern is a rapid virologic response (RVR), defined as being HCV RNA undetectable within 4 weeks of initiating treatment. RVR is observed in about 15% of patients with HCV genotype 1 and 66% of patients with genotypes 2 and 3 [13, 14]. Patients with genotypes 2 and 3 who achieve RVR have SVR rates greater than 80%, and relapse rates less than 5%. Prospective and retrospective studies have demonstrated that patients with HCV genotype 1 who achieve RVR have SVR greater than 80% even when the duration of treatment is reduced from 48 weeks to only 24 weeks [15, 16]. These data support the concept that genotype 1 patients with RVR could be treated for 24 weeks, just like patients with genotypes 2 and 3 who achieve RVR. Measuring HCV RNA at treatment week 4 is therefore important in all patients undergoing HCV treatment so that patients with RVR can be recognized and treatment shortened to 24 weeks.

Patients who become HCV RNA undetectable between weeks 4 and 12 are referred to as having a complete early virologic response (cEVR), which is observed in about 35% of patients with HCV genotype 1 and 31% of patients with HCV genotypes 2 and 3.

Patients with genotype 1 and cEVR have SVR rates of about 66% and relapse rates of about 25% when treated for 48 weeks [13, 17]. Patients with genotypes 2 and 3 who achieve cEVR have SVR and relapse rates of about 45% and 31% retrospectively when treated for only 24 weeks [14]. However, the SVR rate increases to 72% and the relapse rate declines to 13% when treatment is prolonged to 48 weeks, and relapse declines even further, to less than 5%, when weight-based ribavirin (1,000–12,000 mg/d) is used [18, 19].

Thus, patients with cEVR have similar SVR rates (66–72%) regardless of genotype when treated for 48 weeks with weight-based ribavirin (1,000–1,200 mg/d). A randomized, prospective, controlled trial is currently evaluating the impact of extending therapy to 48 weeks in patients with genotypes 2 or 3 and cEVR. Measuring HCV RNA at treatment weeks 4 and12 is therefore important in all patients undergoing treatment for HCV infection so that those with cEVR can be recognized and treatment can be maintained for 48 weeks.

Patients who become HCV RNA undetectable between weeks 12 and 24 are referred to as “slow to respond” (STR).

This virologic response pattern is observed in about 15% of patients with HCV genotype 1 but in less than 3% of patients with HCV genotypes 2 and 3. Patients with genotype 1 and the STR virologic response pattern have SVR rates of only 33–45% and relapse rates of more than 50% when treated for 48 weeks [13, 17]. Several studies have demonstrated that extending the duration of therapy from 48 to 72 weeks in these STR patients will reduce relapse and lead to a significant increase in SVR [20–22]. Measuring HCV RNA at treatment weeks 12 and 24 is therefore important in all patients undergoing treatment for HCV infection so that patients with the STR pattern can be recognized and therapy extended to 72 weeks in select patients who can tolerate a prolonged course.

Response-guided therapy is a powerful concept in the treatment of HCV infection, and allows each patient to receive the optimal duration of treatment based on their specific virologic response pattern.

The SVR rates that could be expected with the fixed duration of treatment according to genotype and response-guided therapy are summarized in Table 1. Two basic principles are necessary to understand when using response-guided therapy to treat HCV infection: 1) the faster a patient becomes HCV RNA undetectable during treatment, the higher the SVR rate and lower the relapse rate; and 2) SVR can be increased and relapse reduced in patients who respond slower simply by prolonging the duration of therapy. These principles will become paramount to understanding the role of a DAA when treating chronic HCV in 2011.

Table 1

Sustained virologic response rates with durations of therapy based on genotype and on response

(Data represent average values obtained and estimated from Shiffman et al. [14], Ferenci et al. [15], Jensen et al. [16], Shiffman et al. [17], Hadziyannis et al. [18], Willems et al. [19], Berg et al. [20], Sánchez-Tapias et al. [21], Pearlman et al. [22], Asselah Pearlman et al. [23].)
'

cEVR complete early virologic response:

HCV RNA undetectable between treatment weeks 4 and 12, NA not available, RVR rapid virologic response: HCV RNA undetectable by treatment week 4, STR slow to respond: HCV RNA undetectable between treatment weeks 12 and 24
aThe duration of treatment for patients with response-guided therapy is based on using a sensitive polymerase chain reaction (PCR) assay, either TaqMan PCR (Applied Biosystems, Foster City, CA), Amplicor PCR (Roche Diagnostic Systems, Nutley, NJ), or Transmission mediated amplification (TMA; Gen-Probe, San Diego, CA)


Development and Limitations of Direct-Acting Antiviral Agents for HCV

Three enzymes to which specific STAT-C agents could be targeted are involved in the replication of HCV: the HCV protease, polymerase, and helicase.

Numerous protease and polymerase inhibitors have been synthesized and tested against HCV replicons in vitro. At the time of this writing, two protease inhibitors are being evaluated in phase 3 clinical trials and numerous other protease and polymerase inhibitors are in phase 2 trials. The development of these agents has been specifically targeted for HCV genotype 1, although some compounds appear to have variable effects on genotypes 2 and 3.

Protease inhibitors are highly potent, reducing HCV RNA by 3 to 6 logs, but have a high rate of resistance. In contrast, polymerase inhibitors are less potent and in general lower HCV RNA levels by 2 to 4 logs [23]. However, they are far less prone to resistance when used as monotherapy. Both protease and polymerase inhibitors also have side effects. These include cardiac toxicity with prolonged QT interval, dysgeusia, nausea, vomiting, diarrhea, rashes, anemia, indirect hyperbilirubinemia, hepatotoxicity, neutropenia, lymphopenia, and generalized bone marrow suppression. Some adverse events have halted the development of specific compounds despite having excellent viral suppression. The two protease inhibitors currently in phase 3 clinical testing also have adverse effects but appear to provide an acceptable balance between efficacy and safety [9•, 10, 11].


Treatment of HCV with Protease Inhibitors

The PROVE 1 and 2 studies were double-blind, randomized, placebo-controlled phase 2 trials [9•, 10]. Both compared three treatment regimens with the peginterferon and ribavirin standard of care. In the experimental groups, patients were treated with telaprevir, peginterferon, and ribavirin triple therapy for 12 weeks followed by various durations of peginterferon and ribavirin alone, for either 0, 12, or 36 weeks. Total duration of therapy was either 12, 24, or 48 weeks. In PROVE 2, one group was treated with telaprevir and peginterferon alone, without ribavirin, for 12 weeks (Fig. 2). About 80–85% of patients achieved RVR. However, by the end of treatment, the percentage of patients who were HCV RNA undetectable had declined to 65–70%. This result was secondary to adverse events of peginterferon, ribavirin, and telaprevir, which led to dose modification, premature discontinuation, and viral recurrence. SVR was achieved in 62–65% of patients treated for a total of 24 and 48 weeks.

Fig. 2

Summary of results from the two treatment-naïve studies using peginterferon, telaprevir, and ribavirin (PEGIFN+TPV+RVN) for treatment of chronic hepatitis C virus (HCV) infection. Data using the same treatment regimens from the two studies were combined. Significantly higher relapse rates were observed in the group treated without ribavirin and in the group treated for less than 24 weeks. SVR—sustained virologic response.

(Data from McHutchison et al. [9•] and Hézode et al. [10].)

The SPRINT-1 study was a double-blind, randomized, placebo-controlled phase 2 trial that compared four treatment regimens with the peginterferon and ribavirin standard of care [11]. In the experimental groups, patients were treated with boceprevir, peginterferon, and ribavirin triple therapy for either 28 or 48 weeks, with or without a 4-week lead-in with peginterferon and ribavirin. An additional arm of the study evaluated a lower dose of ribavirin. Of patients with RVR, SVR was achieved in about 78% of patients treated for 28 weeks and 89% of patients treated for 48 weeks. Overall SVR was achieved in 55% of patients treated for 24 weeks and in 67–75% of patients treated for 48 weeks.

The results of data from these two trials fit nicely into the concept of response-guided therapy. Patients treated for less than 24 weeks had higher rates of relapse and lower SVR. In addition, the rates of SVR appeared to be similar for patients with RVR, whether treated for 24 or 48 weeks. Patients treated without or with lower doses of ribavirin also had lower rates of SVR.

Retreatment of Patients Who Failed to Achieve SVR with Peginterferon and Ribavirin with

Protease Inhibitors

'In the SPRINT-1 study, data on the efficacy of adding boceprevir to peginterferon and ribavirin at week 4 were obtained from the lead-in arms. Patients who had a decline in HCV RNA by at least 1.5 log from the pretreatment baseline after 4 weeks of peginterferon and ribavirin had SVR rates greater than 75% with the addition of boceprevir whether treated for 24 or 48 weeks. In contrast, those patients who had a less than 1.5-log decline in HCV RNA with peginterferon and ribavirin at week 4 had lower RVR rates and lower SVR rates following the addition of boceprevir, particularly when treated for only 24 weeks. '
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The Impact of Adding a DAA to Peginterferon and Ribavirin

Figure 3 illustrates the percentage of patients who are HCV RNA negative over time with the current standard of care compared with peginterferon, ribavirin, and a DAA. With peginterferon and ribavirin, the percentage of patients who become HCV RNA undetectable increases stepwise with duration of treatment up to 24 weeks. A significant fraction of patients then relapse; this percentage varies considerably, from less than 5% to more than 50% based on when patients first become HCV RNA undetectable. In contrast, all patients who are at least somewhat sensitive to peginterferon (≈85%) achieve RVR with triple therapy, and the percentage of patients who remain HCV RNA undetectable declines slightly between weeks 4 and 24 because of side effects, dose reduction, and premature discontinuation of treatment. However, relapse occurs in only a minority of patients who remain on treatment for 24 weeks because of the very high rate of RVR.

Thus, retreatment of patients with prior partial response and relapse is anticipated to also yield high rates of RVR and SVR. In contrast, retreatment of prior null responders with triple therapy is likely to yield lower rates of RVR and a lower SVR.

The ultimate SVR rates achieved in patients with prior null response and identification of patients who would be acceptable candidates for retreatment with DAA, peginterferon, and ribavirin will likely be defined within the next 2 years.

Fig. 3

Percentage of patients who are HCV RNA undetectable at various time points after the initiation of treatment with or without a direct-acting antiviral agent (DAA) plus peginterferon and ribavirin (PEGIFN+RBV+DAA).

When treated with peginterferon and ribavirin (PEGIFN+RVN), an increasing percentage of patients become HCV RNA undetectable over time and a certain percentage of patients relapse after treatment is discontinued. When a DAA is added to peginterferon and ribavirin, maximal virologic response is achieved within a few weeks and relapse is very low.

EOT—end of treatment; SVR—sustained virologic response.

(Data are estimated based on results from McHutchison et al. [9•], Hézode et al. [10], Kwo et al. [11], Shiffman [12], Ferenci et al. [13], and Shiffman et al. [14].)



Interleukin-28B Haplotype

It has long been hypothesized that host genetics play an important role in the ability to achieve SVR. This hypothesis was recently confirmed with the identification of a single nucleotide polymorphism (SNP) that has a high positive predictive value for SVR. This SNP is located near the gene that codes for interleukin (IL)-28B and is associated with a twofold increased likelihood of achieving SVR in patients infected with HCV genotype 1 regardless of race, sex, or other baseline factors [27 •].

The SNP that favors SVR is the CC haplotype, which is observed most frequently in the Asian population and least frequently in African Americans.

The frequency of the CC haplotype in various racial/ethic populations is directly related to the rate of SVR. Being either TT or a TC heterozygote at this locus is associated with a significant reduction in SVR.

It is already envisioned that all patients will have IL-28B testing performed before initiating peginterferon and ribavirin once such a test is commercially available. Patients with the CC haplotype have a high likelihood to achieve SVR and should be encouraged to remain on treatment. In contrast, patients with either the TC or TT haplotype have a low likelihood for SVR and probably will be taken off treatment early if they do not exhibit RVR or cEVR. Whether this gene will be useful in predicted SVR to triple combination therapy with a DAA, peginterferon, and ribavirin remains to be determined.

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*Update See Below:
IL28B Genomic-Based Treatment Paradigms for Patients With Chronic Hepatitis C Infection: The Future of Personalized HCV Therapies

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Jul 12, 2010
(IL28B) Genotype Test to Support Individualized Treatment.

Decisions for Patients with Hepatitis C Viral Infection. ...

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Treatment of HCV Infection in 2011

Based on current data and ongoing clinical trials using DAA, I have attempted to speculate about the treatment of chronic HCV infection in 2011.

The year 2011 will open with our current standard of care: peginterferon and ribavirin. Between now and 2011, a declining number of patients will likely be treated with peginterferon and ribavirin because of the desire to delay treatment until a DAA is available.

Futhermore, patients will likely be tested for the IL-28B haplotype; only those with the CC allele, and a high chance to achieve SVR, are likely to be treated with peginterferon and ribavirin. Patients with mild fibrosis may also opt to defer therapy because they have a low likelihood of developing significant fibrosis over the next several years. During this time, I anticipate more uniform application of the concepts of response-guided therapy. Patients who achieve RVR will be treated for 24 weeks, patients with cEVR will be treated for 48 weeks, and STR patients will be treated for 72 weeks. We will be more prepared to modify the doses of peginterferon and ribavirin to limit adverse events in patients who have already become HCV RNA undetectable. The use of epoetin-α will be limited to only those patients who become anemic very rapidly (within the first 1 to 2 months of treatment). This limitation will be especially true if IL-28B testing determines that the patient has a high chance for SVR.

It is anticipated that the first DAA will be approved by the US Food and Drug Administration by mid-late 2011. At that time, patients will be treated with triple therapy: peginterferon, ribavirin, and a DAA. About 80% of patients will achieve RVR and SVR of 70% is anticipated. The treatment duration will be reduced for all patients with RVR to 24 to 28 weeks, depending on whether a “lead-in” strategy using peginterferon and ribavirin is adopted. Relapse will be less than 5%; the remaining 10% of patients will simply be unable to tolerate the side effects of one or more of these three medications and will prematurely discontinue treatment. Patients who become HCV RNA undetectable after week 4 will be treated for 48 weeks. Patients who do not become HCV RNA undetectable by treatment week 8 to 12 will likely stop treatment. It remains to be determined if patients who do not achieve SVR with triple therapy could be more effectively treated after 2011 with a combination of DAAs.


Conclusions
The principles of response-guided therapy can help predict how DAA will be used in the future. Preliminary data suggest that the combination of a DAA, peginterferon, and ribavirin will yield high rates of RVR and therefore high rates of SVR with a limited duration of treatment. Patients who do not achieve RVR with a DAA, peginterferon, and ribavirin will require 48 weeks of treatment and will have a lower SVR.

Disclosure
Dr. Shiffman has served as a consultant, speaker, and/or on advisory boards for, and/or has received grant support from, Anadys, Biolex, Bristol-Myers Squibb, Conatus, GlaxoSmithKline, Globeimmune, Human Genome Sciences, Idenix, Johnson & Johnson/Tibotec, Novartis, Pfizer, Roche, Romark, Schering-Plough, Valeant, Vertex, Wyeth, and Zymogenetics. These companies have products for treatment of HCV infection.

References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

1Fried MW, Shiffman ML, Reddy KR, et al.: Combination of peginterferon alfa-2a (40 kd) plus ribavirin in patients with chronic hepatitis C virus infection. N Engl J Med 2002, 347:975–982.
2.Manns MP, McHutchinson JG, Gordon SC, et al.: Peginterferon-alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001, 358:958–965.
3.McHutchison JG, Lawitz EJ, Shiffman ML, et al., for the IDEAL study team: Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009, 361:580–593.
4.El Makhzangy H, Esmat G, Said M, et al.: Response to pegylated interferon alfa-2a and ribavirin in chronic hepatitis C genotype 4. J Med Virol 2009, 81:1576–1583.
5.Yu ML, Chuang WL: Treatment of chronic hepatitis C in Asia: when East meets West. J Gastroenterol Hepatol 2009, 24:336–345.
6.Wasley A, Alter MJ: Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis 2000, 20:1–16.
7.Fensterl V, Sen GC: Interferons and viral infections. Biofactors 2009, 35:14–20.
8.Martin P, Jensen DM: Ribavirin in the treatment of chronic hepatitis C. J Gastroenterol Hepatol 2008, 23:844–855.
9.• McHutchison JG, Everson GT, Gordon SC, et al.: Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009, 360:1827–1838. The combination of telaprevir, peginterferon, and ribavirin yields high rates of RVR and SVR with just 24 weeks’ total duration of therapy.
10.Hézode C, Forestier N, Dusheiko G, et al.: Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009, 360:1839–1850.
11.Kwo P, Lawitz EJ, McCone J, et al.: HCV sprint-1: boceprevir plus peginterferon alfa-2b/ribavirin for treatment of genotype 1 chronic hepatitis C in previously untreated patients. Hepatology 2008, 48(Suppl 4):1027A. 12.Shiffman ML: Optimizing the current therapy for chronic hepatitis C virus. Peginterferon and ribavirin dosing and the utility of growth factors. Clin Liver Dis 2008, 12:487–505.
13.Ferenci P, Fried MW, Shiffman ML, et al.: Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD)/ribavirin. J Hepatol 2005, 43:453–471.
14.Shiffman ML, Suter F, Bacon BR, et al.: Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007, 357:124–134. 15.Ferenci P, Laferl H, Scherzer TM, et al.: Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 2008, 135:451–458.
16.Jensen DM, Morgan TR, Marcellin P, et al.: Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006, 43:954–960. 7.Shiffman ML, Hamzeh FM, Chung RT: Effect of time to response on viral breakthrough and relapse rates in patients infected with HCV genotype 1 and treated with peginterferon alfa-2a plus ribavirin. Hepatology 2008, 48(Suppl):862A. 18.Hadziyannis SJ, Sette H Jr, Morgan TR, et al.: Peginterferon-alfa 2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004, 140:346–355.
19.Willems B, Hadziyannis SJ, Morgan TR, et al.: Should treatment with peginterferon plus ribavirin be intensified in patients with HCV genotype 2/3 without a rapid virological response? J Hepatol 2007, 46:S6.
20.Berg T, von Wagner M, Nasser S, et al.: Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 2006, 130:1086–1097.
21.

Also See : AASLD 2010 Summary Of Hepatitis C Oral Inhibitors

Telaprevir
Telaprevir is an investigational oral protease inhibitor used in combination with pegylated interferon plus ribavirin and is being developed by Vertex in collaboration with Johnson & Johnson.
.The two trials named "ADVANCE and ILLUMINATE" were for patients with genotype 1 who have not previously treated.

Response-guided therapy (Response guided therapy is intended to enable the physician to determine the duration of combination therapy based on a patient's viral response during treatment) was used in ADVANCE, whereby patients whose virus was undetectable at weeks 4 and 12 of treatment with telaprevir-based therapy were eligible to reduce their treatment from 48 weeks to 24 weeks.

The Phase 3 ILLUMINATE trial was designed to confirm both the use of *response-guided therapy and to evaluate whether there was any benefit to extending total treatment duration from 24 to 48 weeks."

In ADVANCE and ILLUMINATE, 58% and 65% of people, respectively, met these criteria for 24-week total treatment. In ILLUMINATE there was no benefit in extending therapy to 48 weeks.

Phase 3 REALIZE
Trial REALIZE was the second pivotal Phase 3 trial and was designed to evaluate telaprevir-based regimens in people who had received pegylated-interferon-based therapy but did not achieve a cure. REALIZE is the only Phase 3 clinical trial to date of an investigational direct-acting antiviral to include all major subgroups of difficult-to-treat patients including null responders, who were defined as people who had a less than a 2 log10 reduction in viral load by week 12 of a prior course of therapy.

The Results.

ADVANCE
Overall in ADVANCE, 75% of people treated with a telaprevir-based combination regimen for 12 weeks, followed by an additional 12 or 36 weeks of pegylated-interferon and ribavirin alone, achieved SVR, compared to 44% of people treated with 48 weeks of pegylated-interferon and ribavirin alone.

ILLUMINATE
In ILLUMINATE, 72% of people overall achieved SVR with telaprevir-based therapy. New data from this study showed that 60% of African Americans/Blacks and 63% of people with advanced liver fibrosis or cirrhosis achieved SVR with telaprevir-based therapy in the overall study analysis. Of African Americans/Blacks whose virus was undetectable at weeks 4 and 12, 88% of people achieved SVR in both the 24-week and 48-week randomized treatment arms. There was no control arm of pegylated-interferon and ribavirin alone in ILLUMINATE.

REALIZE
Results of the REALIZE trial showed that 65 percent of patients treated with telaprevir plus the standard of care were cured, or sustained viral response compared to 17 percent of patients in the control group who were re-treated with just the standard of care.

SVR In The Three Different Groups Were As Follows:
86 percent of re-lapsers were cured after telaprevir treatment compared to 24 percent in the control arm.
Among the second group, the cure rate for the telaprevir-treated patients was 57 percent compared to 15 percent for the control arm.

Control Arm = *SOC pegylated interferon plus ribavirin

Finally, in the last group which consisted of the most difficult to treat patients, telaprevir achieved a 31 percent cure rate compared to 5 percent for the control arm. Results across all three patients types were statistically significant in favor of telaprevir over standard of care, officials report.

Complete Information

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Side Effects :

In ADVANCE, discontinuation of telaprevir or placebo only due to adverse events during the telaprevir treatment phase occurred in 11% of people in the 12-week telaprevir arm, 7% of people in the 8-week telaprevir arm and 1% of people in the control arm. In ILLUMINATE, 12% of people overall discontinued telaprevir only due to adverse events during the telaprevir treatment phase.

Discontinuation of all drugs due to either rash or anemia was low in both studies (1% to 3%). Rash was primarily characterized as eczema-like, manageable and resolved upon stopping telaprevir. Ninety-two percent and 95% of rash was mild to moderate in ADVANCE and ILLUMINATE, respectively. Rash was managed with the use of topical corticosteroids and antihistamines, and anemia was primarily managed by reducing the dose of ribavirin. The use of erythropoiesis-stimulating agents (ESAs) were not allowed in any of the Phase 3 clinical studies.

Discontinuation (%) of all drugs during the telaprevir treatment phase

ADVANCE

12-week telaprevir arm ..................................7%
8-week telaprevir arm......................................8%
Control Arm.................................... 4%

ILLUMINATE*
Total .................................................7%*

There was no control arm in ILLUMINATE

Telaprevir may have * fewer side effects (like anemia) than boceprevir.Vertex announced a new trial which will be called the "OPTIMIZE" and is for genotype 1 patients who have not previously treated.

AASLD/2010 Telaprevir 3 Studies Showed Superior SVR (Viral Cure)Regardless of Race/Stage Of Liver Disease
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Boceprevir

Boceprevir is also an investigational oral HCV protease inhibitor used in combination with pegylated interferon plus ribavirin and is being developed by Merck.

*Excerpt:
The two trials were the SPRINT-2 trial which enrolled genotype 1 patients who have never treated previously. The RESPOND-2 trial enrolled genotype 1 patients who previously treated but did not respond to or relapsed after treatment.

Merck released final results from two phase-3 studies of boceprevir, saying it produced “significantly higher” results compared with patients in the control group.

In the "RESPOND 2" trial at 24 weeks after conclusion of treatment, the patients treating in the *control arm with "no telaprevir" or with only *SOC achieved a SVR of 21 percent.

Adding Boceprevir to the treatment increased SVR to 59 percent for the second arm *(Second arm received 4 weeks of lead-in therapy of peginterferon alpha 2b and ribavirin followed by response-guided therapy of peginterferon alpha 2b and ribavirin combined with 800 mg of Boceprevir three times a day) and 67 percent for the third arm *(Third arm received 4 weeks of lead-in therapy of peginterferon alpha 2b and ribavirin followed by 44 weeks of peginterferon alpha 2b and ribavirin combined with 800 mg of Boceprevir).

It was noted that previous relapsers fared better than nonresponders in all arms. The therapy was well-tolerated, and the most common reason for discontinuing treatment was for patients who still had detectable HCV-RNA at week 12.

From HCV Advocate

SPRINT-2

The SPRINT-2 study included 1,097 HCV genotype 1
treatment-naïve patients (never been treated). The treatment
protocol consisted of a 4 week lead-in phase of
PegIntron plus ribavirin (without boceprevir), followed
by the triple combination of boceprevir, PegIntron
and ribavirin. Duration and continuation of treatment
was guided by the type of on-treatment response to the
medications.*
.
The SVR or sustained virological response rates (HCVRNA negative 24 weeks after the last dose of medicine is taken) by different treatment arms are listed below:
.a. If HCV RNA (viral load) negative at week 8 through week 24,
triple therapy was continued for a total treatment duration of 28 weeks;
sustained virological response (SVR) = 63%
a. If HCV RNA positive at week 8 but undetectable at week 24, boceprevir was stopped at week 28 and PegIntron/ribavirin combination therapy (without boceprevir) was continued for a total treatment duration of 48 weeks;SVR = 66%
a. The control arm was standard of care – PegIntron plus ribavirin—with a treatment duration of 48weeks;SVR = 38%
.African Americans/Blacks—Treatment Response
There were also 159 African American/Black patients in the study—
African Americans/Blacks comprised 15% of the patient population in this trial.
The SVR rates by different treatment arms are listed below:
.a. If HCV RNA negative at week 8 through week 24,triple therapy was continued for a total treatment duration of 28 weeks: SVR = 42%
a.If HCV RNA positive at week 8 but undetectable at week 24, boceprevir was stopped at week 28 andPegIntron/ribavirin combo therapy without boceprevir) was continued for a total treatment duration of 48weeks; SVR = 53%
a. The control arm was standard of care – PegIntron plus ribavirin—with a treatment duration of 48weeks; SVR = 23%
.*If any patients were HCV RNA positive at week 24 all treatment was stopped.


HCV RESPOND 2
The RESPOND 2 study included 403 HCV genotype 1
“treatment-failure” patients. The study included a 4
week lead-in phase of PegIntron plus ribavirin
(without boceprevir), followed by the triple combination
of boceprevir, PegIntron and ribavirin1 and treatment
duration was based on type of on-treatment response.
.The SVR rates and duration of treatment periods for all
patients are listed below.
a. If HCV RNA negative at week 8 and at week 12 the total
treatment duration was 36 weeks; SVR = 59%
a. IF HCV RNA positive at week 8, but undetectable at
week 12, boceprevir was stopped at week 36 and the
combination of PegIntron/ribavirin was continued for a
total treatment duration of 48 weeks; SVR = 66%
a. Control arm was standard of care – combination of
PegIntron plus ribavirin—for a total treatment duration
of 48 weeks; SVR = 21%
*If any patients were HCV RNA positive at week 12 all
treatment was stopped.
.It is important to know that the treatment duration in the
boceprevir containing arms were 28, 36 or 48 weeks
depending on the type of on-treatment response.

Side Effects: Treatment appeared to be associated with two side effects compared with placebo -- anemia and a distorted sense of taste, or disgeusia. Overall, patients on treatment had greater use of erythropoietin "Note (rescue drugs)" to treat anemia compared with controls (43% for short- and full-course, versus 24% of those on placebo). More boceprevir patients also had to reduce their treatment dose due to anemia (20% and 21% versus 13%). Other adverse events included nausea, headache, and fatigue, at similar rates across all three groups".

Merck began submission of a new drug application for boceprevir on a rolling basis and expects to complete that process by the end of the year.

IL28B Genomic-Based Treatment Paradigms for Patients With Chronic Hepatitis C Infection: The Future of Personalized HCV Therapies
.

Am J Gastroenterol advance online publication

doi: 10.1038/ajg.2010.370Paul J Clark MD 1, Alex J Thompson MD, PhD 1 and John G McHutchison MD 11 Duke Clinical Research Institute and Division of Gastroenterology, Duke University Medical Center, School of Medicine, Duke University, Durham, North Carolina, USACorrespondence: Paul J. Clark, MD, Division of Gastroenterology, Duke Clinical Research Institute, Duke University Medical Center, PO Box 17969, Durham, North Carolina 27715, USA.

E-mail: paul.clark@duke.edu Received 5 April 2010;

Accepted 16 August 2010; Published online 5 October 2010.

Abstract

Genome-wide association studies (GWAS) have recently identified host genetic variation to be critical for predicting treatment response and spontaneous clearance in patients infected with hepatitis C virus (HCV). These important new studies are reviewed and their future clinical implications discussed. Single-nucleotide polymorphisms in the region of the IL28B gene on chromosome 19, coding for the interferon (IFN)-λ-3 or IL28B gene, are strongly associated with treatment response to pegylated IFN and ribavirin in patients infected with genotype 1 HCV.

The good response variant is associated with a twofold increase in the rate of cure.

Allele frequencies differ between ethnic groups, largely explaining the observed differences in response rates between Caucasians, African Americans and Asians. IL28B polymorphism is also strongly associated with spontaneous clearance of HCV.

The biological mechanisms responsible for these genetic associations remain unknown and are the focus of ongoing research. Knowledge of a patient's IL28B genotype is likely to aid in clinical decision making with standard of care regimens. Future studies will investigate the possibility of individualizing treatment duration and novel regimens according to IL28B type.

Source

AASLD Presented Nov 2/Final Results of Clinical Trial on Boceprevir