biopsy

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what is the take on biopsy to the blood hcv fibrosoe panel. My gastro said it is acurate and safer. What has anyone else heard

From: Christ <ludichrist2000@...>009 - VCHepC <VCHepC >; Hepatitis C <Hepatitis C >; WebWarriors grp < >Sent: Tue, May 4, 2010 6:49:37 PMSubject: [ ] New Therapies in Hepatitis C Virus/Protease Inhibitors

New Therapies in Hepatitis C Virus/Protease Inhibitors

New Medication to Treat Hepatitis C / ann GromischHepatitis C is a contagious liver disease which is spread by contact with blood that is contaminated with the hepatitis C virus. Most cases of acute hepatitis C or HCV advance to chronic HCV. This increases the risk of developing advanced liver disease which is the leading cause of liver cancer. People with HCV are grouped into genotypes, which are subgroups of the virus and are determined by duration of infection, age, viral load, and degree of liver inflammation and tissue scarring. The current standard treatment for HCV is pegylated interferon (PEG-IFN) in combination with ribavirin (RBV). This treatment is effective in about 40 to 50 percent of people with genotype-1 and 80

percent of individuals classified as genotype-2 and 3. In the United States, most people with HCV are genotype-1. An article in the May 2010 issue of Current Opinions in Gastroenterology announces the current trial of new medication which promise higher cure rates for HCV genotype-1 patients.The introduction of a first generation protease inhibitor is hoped to have a higher response rate in new HCV patients as well as HCV patients who have received prior treatment. This new type of medication, STAT-C, or specifically targeted antiviral therapy, would be added to the combination therapy of PEG-IFN and RBV. STAT-C targets the enzymes which cause the replication of the hepatitis C virus. The hope is for higher cure rates and reduced time of treatment. There is concern regarding relapse rates and side effects. In clinical trials, the relapse rate was the lowest for patients who received 24 weeks of treatment with the three drugs followed by 24 weeks of

treatment with the current standard treatment.Additional clinical trials are investigating the combination of oral antiviral drugs, protease inhibitors, and polymerase inhibitors. The aim is to develop an effective interferon free regime. About 50 to 60 percent of HIV-infected individuals cannot tolerate interferon.Approval of the first generation protease inhibitor and testing of interferon free treatments is expected in 2011.Sources: Current Opinion in Gastroenterology, May 2010- volume 26- issue 3

Article In Full

From Current Opinion in GastroenterologyNew Therapies in the Management of Hepatitis C Virus J. s; R.

Authors and DisclosuresAbstract and IntroductionAbstractPurpose of review The present review discusses recent developments in drug discovery for hepatitis C. We are on the verge of a new era with the introduction of direct acting oral agents that will transform the treatment landscape. Both healthcare providers and patients need to stay abreast of these changes that will influence decisions to treat. This article will discuss the most promising up-to-date hepatitis C virus antiviral therapies in clinical investigation as well as the associated clinical trial results.Recent findings First generation protease inhibitors will offer higher sustained viral response rates for both naive (70–80%) and treatment-experienc ed (40–50%) populations when added to standard pegylated interferon and ribavirin. However, these dramatic gains will be partially offset by new challenges

with viral resistance and increased adverse events.Summary There are currently a number of drugs under investigation that target the enzymes involved in hepatitis C virus replication. Year 2011 should bring the approval of the first generation of protease inhibitors that will offer higher cure rates for genotype 1 patients and open the door for the eventual testing of interferon-free regimens.IntroductionHepatitis C virus (HCV) infection is a global problem with an estimated prevalence of 1.6% in the United States.[1,2] The majority of patients acutely infected with HCV become chronically infected, which increases the risk of developing further complications associated with advanced liver disease. HCV-related end-stage liver disease is a leading cause of hepatocellular carcinoma and the most common indication for liver transplantation in the United States.[3] Current standard therapy

for HCV includes pegylated interferon (PEG-IFN) in combination with ribavirin (RBV), and this combination is effective in approximately 40–50% of genotype 1-infected patients and 80% of genotype 2-infected and 3-infected patients.[4, 5] Unfortunately, the majority of HCV patients in the United States are infected with genotype 1.[6] The relatively low response rate in treating genotype 1-infected patients, in combination with the long treatment durations and adverse side effect profile has led to a relatively small minority of patients opting for treatment. However, the introduction of specifically targeted antiviral therapy (STAT-C) is now on the horizon with anticipated higher cure rates and the potential for shorter treatment duration. Approval of the first STAT-C compounds is expected by mid-2011 and many patients are being 'warehoused' in anticipation.

Protease Inhibitors: Higher Sustained Viral Response, Shorter Duration, Resistance EmergenceGiven the advancement of our understanding of the HCV life cycle over the past decade, there are a number of drugs under investigation that target the enzymes involved in HCV replication. The class of drugs furthest along in development is the inhibitors of the HCV serine protease NS3-NS4A.[7] Two protease inhibitors have now completed phase II testing and have yielded some consistent early lessons. For naive, genotype 1 patients, higher cure rates and shorter duration of therapy can be expected, but partially offset by new issues of resistance and increased adverse events. The recently published Protease Inhibition for Viral Evaluation (PROVE 1 and 2, evaluating telaprevir, TVR)[8••,9••] and Serine Protease Inhibitor Therapy (SPRINT-1,

evaluating boceprevir, BOC)[10••] studies evaluated protease inhibitors in combination with PEG-IFN/RBV in genotype 1, naive patients. In PROVE 1, TVR was dosed at 750 mg every 8 h for 12 weeks in combination with PEG-IFN and RBV followed by an additional 12 weeks, or 36 weeks of standard of care (SOC). The sustained viral response (SVR) rate in SOC was 41%, compared with 61% (P = 0.02) in the 24 week treatment group and 67% (P = 0.002) in the 48 week treatment group. Relapse rates were highest in the control group (23%) compared with the 24 week (2%) and 48 week TVR treatment group (6%). However, more patients discontinued therapy in the TVR treatment groups secondary to adverse side effects, with rash being the most common reason for discontinuation.[8••] In the PROVE 2 trial, shorter duration treatment was explored with treatment groups receiving

triple therapy (TVR + PEG-IFN/RBV) for only 12 weeks (with and without RBV) compared with an additional 12 weeks of SOC. SVR was 46% in the control group, compared with 36% in the non-RBV group (P = 0.20), 60% in the 12 week triple therapy TVR group (P = 0.12) and 69% in the 24 week triple therapy TVR group (P = 0.004). Relapse rates were highest in the non-RBV-treated group (48%) compared with the control group (22%), 12 week triple therapy group (30%) and 24 week triple therapy group (14%). Rash again occurred more commonly in the TVR treatment groups than in the control group[9••] (Fig. 1).Figure 1.Sustained viral response data in naive patients treated with telaprevirPROVE, Protease Inhibition for Viral Evaluation; SVR, sustained viral response

From PROVE 1 and 2, it appears that TVR has the ability to help overcome negative host and viral factors. A recent pooled analysis[11•] looked at a subgroup of patients with characteristics associated with low virologic response. The overall SVR for the pooled TVR treatment groups was 65 vs. 44% in the control group (P < href="javascript: newshowcontent( ">[12•] treatment-naive, genotype 1 patients (N = 161) were administered triple therapy for 12 weeks with the subsequent PEG-IFN/RBV treatment duration determined using a response-guided strategy. Patients who achieved rapid virologic response (RVR) received a total of 24 weeks of therapy and those who did not have an RVR continued PEG-IFN/RBV to week 48. The SVR rates in this study ranged from 81 to 85%, higher than those observed in the phase II PROVE trials. This study clearly suggests that response-guided therapy based on RVR

at week 4 may optimize SVR and provides a useful guide for determining which patients should be treated for 24 vs. 48 weeks.

BOC is another oral NS3-NS4A protease inhibitor with potent antiviral activity. The final results from the HCV SPRINT-1 study have been reported in which HCV genotype 1 patients were randomly assigned to receive different combinations of PEG-IFN, RBV (400–1400 mg/day) and BOC (800 mg three times daily). The treatment regimens included a control group treated with 48 weeks of SOC compared to five BOC treatment regimens (4 weeks of PEG-IFN/RBV lead-in followed by triple therapy for 24 or 44 weeks; triple therapy for 28 or 48 weeks; triple therapy, but with low-dose RBV for 48 weeks). The following SVR rates were reported: control group, 38%; triple therapy 28 weeks, 55%; triple therapy 48 weeks, 67%; lead-in group 28 weeks, 56%; lead-in group 48 weeks, 75%; and low-dose RBV group, 36%. It should be noted that up to 50% of patients were treated with erythropoietin in this trial, highlighting the increased rates of anemia with BOC.

Higher rates of discontinuation secondary to adverse side effects and viral breakthrough occurred in the BOC treatment groups compared with the control group. Of note, the highest reported viral breakthrough was seen in the low-dose RBV group.[10••]

Ribavirin is Required to Maximize Sustained Viral Response with Protease Inhibitors and Limit Resistance

As highlighted above, early phase II studies show strong evidence for the need of RBV in STAT-C drug regimens. Patients who did not receive RBV in the PROVE trials and those with low-dose RBV (400–1000 mg) in the SPRINT-1 trial had increased viral breakthrough, higher relapse and lower SVR. These data strongly indicate that standard-dose RBV is required to optimize response to these first generation protease inhibitors via a reduction in the development of resistance/breakthr ough (Fig. 2).

Figure 2.Importance of ribavirin in combination with protease inhibitors PROVE, Protease Inhibition for Viral Evaluation; SVR, sustained viral response.

It is also clear that the initial rapid drop in HCV viral levels on protease combination therapy is due to inhibition of wild-type virus that then leads to the 'uncovering' of preexisting resistant variants. The continued replication of these variants can then lead to a virologic breakthrough. Resistant variants are present in most patients at very low frequencies (<1%)>

Protease Inhibitors: Hope for NonrespondersAn initial phase II trial with BOC-containing regimens in previous HCV genotype 1 nonresponders to SOC was not encouraging (SVR 14%), though in retrospect inadequate BOC dosing regimens were being used.[13] Since this early experience, a number of studies are starting to suggest reasonable response rates for the treatment-experienc ed population. In PROVE 3,[14••] treatment-experienc ed patients were randomized to one of four treatment arms (SOC for 48 weeks; TVR + PEG-IFN/RBV for 12 weeks, then SOC for an additional 12 weeks; TVR + PEG-IFN/RBV for 24 weeks, then SOC for an additional 24 weeks; or TVR + PEG-IFN for 24 weeks). SVR rates were 38–39% among previous nonresponders who received TVR-based triple therapy. Relapse rates were

lowest among patients who received 24 weeks of triple therapy followed by 24 weeks of standard therapy (13 vs. 30–53% for other treatment arms). An important factor to consider in interpreting the results of the PROVE 3 trial is the stringent stopping rule established for TVR therapy. Because of concerns for high rates of resistance with incomplete viral suppression, patients in PROVE 3 discontinued TVR if HCV RNA remained detectable (>30 IU/ml) at week 4. It is now apparent that patients with declining but detectable HCV RNA at week 4 continue to experience HCV RNA reductions during treatment with TVR-containing regimens and have a high likelihood of achieving SVR with a total of 48 weeks of therapy. A hint of anticipated SVR with this response-guided approach to retreatment has now been reported from study 107 (patients in PROVE studies who did not achieve SVR in control group were retreated with triple therapy for 12 weeks followed by either 12

or 36 weeks of consolidation PEG-IFN/RBV) . SVR rate for this well characterized population was 57% among prior nonresponders.[15]

Of interest, a similar SVR rate was seen in 'lead-in, null responders' from the SPRINT-1 trial. Kwo et al. conducted a retrospective analysis of SVR rates among patients who received 24 or 44 weeks of BOC and PEG-IFN/RBV following a 4-week lead-in period of PEG-IFN/RBV therapy. Among patients with a null response to the 4-week lead-in treatment period (<>

Lead-in viral decline and relationship to sustained viral response HCV, hepatitis C virus.

Polymerase Inhibitors: Unique Genetic Barrier to Resistance for NucleosidesMultiple agents targeting the HCV RNA-dependent polymerase inhibitor, which is critical for viral replication, are also currently in trials. One of the most advanced of these polymerase inhibitors is RG7128, a nucleoside analogue. RG7128 showed potent antiviral activity as monotherapy in HCV genotype 1 patients who had failed prior standard therapy,[16] as well as in combination with PEG-IFN/RBV. [17,18] It also has been shown to have a similar safety profile as standard therapy with PEG-IFN/RBV and has demonstrated significant antiviral potency regardless of race, ethnicity or genotype.[17–19] Thus far, viral resistance has not been seen in any clinical trials with RG7128,[16,18] which suggests that the nucleoside class may offer a higher genetic barrier to viral resistance than the protease class of inhibitors.[ 20•]Another

nucleoside polymerase inhibitor, R1626, also showed potent HCV antiviral activity (virus negative at 48 weeks) when combined with PEG-IFN/RBV compared with the control group (84 vs. 65%, respectively) . This trial also showed the importance of RBV in combination therapy as the end of treatment responses were less in the non-RBV groups compared with the control group. However, the development of this drug has been halted due to unacceptable rates of hematologic abnormalities, highlighted by lymphopenia. [21] Other second generation nucleotide polymerase inhibitors are in the early stages of development, such as PSI-7851 and IDX184, and have shown encouraging antiviral activity.[22, 23] PSI-7851 has demonstrated dose-dependent HCV RNA reductions over 3 days of dosing, and patients receiving the 400-mg dose achieved a mean HCV RNA decrease of 1.95 log10 IU/ml. Population sequencing did not identify any evidence of treatment-emergent drug resistance and no

patients discontinued treatment early.[22] Dose-dependent decreases in HCV RNA were also observed during the 3-day IDX184 dosing period with mean reductions ranging from 0.47 to 0.74 log10 IU/ml.[23]In addition to the nucleoside RNA-polymerase inhibitors, nonnucleoside HCV RNA-polymerase inhibitors are also showing promise in early HCV trials. Nonnucleoside inhibitors such as GS-9190, filibuvir, BI207127, VCH-916, VCH-222, MK-3281 and ABT-333 have shown potent antiviral activity for patients with genotype 1 HCV infections and generally have been well tolerated in early clinical studies.[24–31] Even though the early results have shown promise, the genetic barrier to resistance for this class appears to be low, similar to the protease class.Interferon-free Regimens

Given the continued need for PEG-IFN and full-dose RBV, there are many HCV-infected groups that may not benefit from the initial approval of STAT-C agents, including decompensated cirrhosis, renal failure, posttransplant and the IFN-intolerant group (which may consist of as many as 50–60% of all HCV-infected patients). Thus, what is desperately needed is the development of IFN-free regimens, that is, combination of small molecules similar to HIV therapy. A novel study called INFORM-1, the first dual combination clinical trial with oral antivirals in HCV patients, is ongoing and evaluates the safety and combined antiviral activity of RG7227, a protease inhibitor and RG7128, a polymerase inhibitor, in 14 days of combination therapy in treatment-naive patients infected with HCV genotype 1. The initial cohorts of this study were reported and appear to lay the foundation for more aggressive and prolonged non-IFN trial designs. Patients

receiving this combination for 14 days experienced a median reduction in viral levels of 4.8–5.2 log IU in the higher doses tested and this combination was equally effective in both naive and previous nonresponder patients. No treatment-related serious adverse events, dose reductions, drug–drug interactions or discontinuations were reported.[32••] Given these encouraging data, many other trials are now beginning to explore combinations of STAT-C agents in the absence of PEG-IFN and/or RBV. Lastly, other strategies to improve the tolerability of IFN and RBV with new analogues of IFN and RBV are also being investigated. [33•,34•,35•,36]Conclusion

In summary, potent viral suppression and shortened duration of therapy have been shown in clinical trials with the addition of protease inhibitors to standard therapy. Although there is optimism surrounding the new STAT-C agents in the treatment of HCV, there is also a concern on how resistance and new adverse events will impact future therapy. It also appears that the platform exists to begin to explore non-IFN-containing regimens, which would be an enormous step forward to accessing a large proportion of infected patients. The future looks encouraging for the clinician treating HCV, and more importantly, for the patients infected with HCV.http://www.medscape .com/viewarticle /720695_7

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