New Therapies in the Management of Hepatitis C Virus

Anthony J. Michaels; David R. Nelson

Posted: 04/30/2010; Curr Opin Gastroenterol. 2010;26(3):196-201.
© 2010 Lippincott Williams & Wilkins

Abstract and Introduction

Abstract

Purpose 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-experienced (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.

Introduction

Hepatitis 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 Emergence

Given 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 telaprevir

PROVE, 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 < 0.001). SVR rates were significantly higher with TVR-based vs. control treatment among patients with baseline HCV RNA at least 800 000 IU/ml (P < 0.05), patients with genotype 1a HCV infection (P < 0.05), patients with genotype 1b HCV infection (P < 0.05), men (P < 0.05), patients more than 50 years of age (P < 0.05) and those with bridging fibrosis (P < 0.05). The conclusion from this analysis is that TVR is effective across all subgroups of patients who have been traditionally considered to be difficult to treat. Another phase II trial with TVR was recently released that suggests SVR rates in naive patients may be higher than previously reported, especially when a response-guided duration is followed. In study C208,[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/breakthrough (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%) and are usually detected after near complete suppression of the dominant, wild-type virus. Another important finding from the PROVE trials is the different rates of breakthrough detected between genotype 1a and 1b (much higher for 1a). The explanation for these observations is a difference in the genetic barrier to resistance between subtypes. For example, the V36M or R155K mutation that can confer drug resistance to TVR requires only one nucleotide change from genotype 1a sequence, whereas two substitutions are required in genotype 1b. Thus, it appears that HCV subtyping may play an important role in helping to select future treatment regimens and predict resistance development.

Protease Inhibitors: Hope for Nonresponders

An 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-experienced population. In PROVE 3,[14••] treatment-experienced 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 (< 1.0 log10 IU/ml HCV RNA reduction), the SVR rate was 25% for patients who continued 24 weeks of triple therapy and 55% for those who received 44 weeks of triple therapy. Thus, PROVE 3 suggests that prior nonresponders may be able to achieve at least a 39% SVR with retreatment with triple therapy-containing regimens, whereas these other emerging datasets suggest SVR rates of 55–57% with a response-guided approach may be obtainable (Fig. 3).

Figure 3. Lead-in viral decline and relationship to sustained viral response

HCV, hepatitis C virus.

Polymerase Inhibitors: Unique Genetic Barrier to Resistance for Nucleosides

Multiple 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.

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•• This is one of the key studies showing that the addition of TVR to current SOC with PEG-IFN and RBV in treatment-naive hepatitis C patients significantly improves SVR and may allow for shorter treatment durations.

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•• This study is similar to the PROVE1 study, but shorter treatment durations were used. This important study shows that shorter treatment durations can be used with the addition of TVR to SOC in treating patients with chronic hepatitis C, and higher SVRs can be achieved compared with SOC.

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•• This study highlights the final results of the addition of BOC to SOC in treatmentnaive hepatitis C patients and shows that improved SVR rates are achieved with triple therapy compared with SOC.

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• This study shows that TVR in addition to SOC is effective across all subgroups of hepatitis C patients who have been traditionally difficult to treat.

Marcellin P, Forns X, Goeser T, et al. Virologic analysis of patients receiving telaprevir administered q8 h or q12 h with peginterferon-alfa-2a or -alfa-2b and ribavirin in treatment-naïve patients with genotype 1 hepatitis: study C208 [abstract 194]. Hepatology 2009; 50:395A.

• This study clearly suggests that response-guided therapy may optimize SVR and provides a useful guide for determining which patients should be treated for 24 vs. 48 weeks.

Schiff E, Poordad F, Jacobson I, et al. Boceprevir (B) combination therapy in null responders (NR): response dependent on interferon responsiveness [abstract 104]. J Hepatol 2008; 48:S46.

McHutchison JG, Manns MP, Muir A, et al. PROVE3 final results and 1-year durability of SVR with telaprevir-based regimen in hepatitis C genotype 1-infected patients with prior nonresponse, viral breakthrough or relapse to peginterferon-alfa-2a/b and ribavirin therapy [abstract 66]. Hepatology 2009; 50:334A–335A.

•• Unlike with PROVE 1 and PROVE 2, this study looks at previous nonresponders to SOC and continues to show improved SVR rates when TVR is added to SOC in this patient population.

Shiffman ML, Berg T, Poordad F, et al. A study of telaprevir combined with peginterferon-alfa-2a and ribavirin in subjects with well documented nonresponse or relapse after previous peginterferon-alfa-2a and ribavirin treatment: interim analysis [abstract 1852]. Hepatology 2008; 48:1135A–1136A.

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Gane EJ, Rodriguez-Torres M, Nelson DR, et al. Antiviral activity of the HCV nucleoside polymerase inhibitor R7128 in HCV genotype 2 and 3 prior nonresponders: interim results of R7128 1,500 mg bid with PEG-IFN and ribavirin for 28 days [abstract LB10]. Hepatology 2008; 48:1024A.

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• This study highlights the concept that nucleoside polymerase inhibitors may present a higher barrier of viral resistance compared to nonnucleoside polymerase inhibitors or protease inhibitors.

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Bavisotto L, Wang CC, Jacobson IR, et al. Antiviral, pharmacokinetic and safety data for GS 9190, a nonnucleoside HCV NS5b polymerase inhibitor, in a phase-1 trial in HCV genotype 1 infected subjects [abstract 49]. Hepatology 2007; 46 (Suppl 1):255A.

Jacobson I, Pockros P, Lalezari J, et al. Antiviral activity of filibuvir in combination with pegylated interferon alfa-2a and ribavirin for 28 days in treatment naïve patients chronically infected with HCV genotype 1 [abstract 1052]. J Hepatol 2009; 50 (Suppl 1):S382.

Larrey D, Benhamou Y, Lohse AW, et al. Safety, pharmacokinetics and antiviral effect of BI 207127, a novel HCV RNA polymerase inhibitor, after 5 days oral treatment in patients with chronic hepatitis C [abstract 1054]. J Hepatol 2009; 50 (Suppl 1):S383.

Lawitz E, Cooper C, Rodriguez-Torres M, et al. Safety, tolerability and antiviral activity of VCH-916, a novel nonnucleoside HCV polymerase inhibitor in patients with chronic HCV genotype-1 infection [abstract 92]. J Hepatol 2009; 50 (Suppl 1):S37.

Bedard J, Nicolas O, Bilimoria D, et al. Identification and characterization of VCH-222, a novel potent and selective nonnucleoside HCV polymerase inhibitor [abstract 935]. J Hepatol 2009; 50 (Suppl 1):S340.

Cooper C, Larouche R, Bourgault B, et al. Safety, tolerability and pharmacokinetics of the HCV polymerase inhibitor VCH-222 following single dose administration in healthy volunteers and antiviral activity in HCV-infected individuals [abstract 935]. J Hepatol 2009; 50 (Suppl 1):S342.

Brainard D, Wright DH, Sneddon K, et al. Safety, tolerability, and pharmacokinetics after single and multiple doses of MK-3281 in healthy subjects [abstract 935]. J Hepatol 2009; 50 (Suppl 1):S341.

Rodriguez-Torres M, Lawitz E, Cohen D, et al. Treatment-naive, HCV genotype 1-infected subjects show significantly greater HCV RNA decreases when treated with 28 days of ABT-333 plus peginterferon and ribavirin compared to peginterferon and ribavirin alone [abstract 935]. Hepatology 2009; 50:5A.

Gane EJ, Roberts SK, Stedman C, et al. First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: safety, pharmacokinetics, and virologic results from INFORM-1 [abstract 935]. J Hepatol 2009; 50 (Suppl 1):S380.

•• This key study of the first dual combination clinical trial with oral antivirals in hepatitis C patients shows that interferon-free regimens may be a future possibility in treatment.

Zeuzem S, Sulkowski M, Lawitz E, et al. Efficacy and safety of albinterferon alfa-2B in combination with ribavirin in treatment-naive, chronic hepatitis C genotype 1 (CHC G1) patients [abstract 1041]. J Hepatol 2009; 50 (Suppl 1): S377.

• This study reports on a newer interferon agent that allows for less frequent dosing intervals compared with current therapy while still achieving comparable SVRs in the genotype 1 hepatitis C patient population.

Nelson D, Benhamou Y, Chuang WL, et al. Efficacy and safety results of albinterferon alfa-2B in combination with ribavirin in interferon-alfa treatment naive patients with genotype 2 or 3 chronic hepatitis C [abstract 1042]. J Hepatol 2009; 50 (Suppl 1):S378.

• This study reports on a newer interferon agent that allows for less frequent dosing intervals compared with current therapy while still achieving comparable SVRs in the genotype 2/3 hepatitis C patient population.

Lawitz E, Muir AJ, Poordad F, et al. Treatment week 24 results of weight-based taribavirin versus weight-based ribavirin, both with peginterferon alfa-2b, in naive chronic hepatitis C, genotype 1 patients [abstract 272]. Hepatology 2008; 48:433A.

• This study reports on an improved RBV agent with comparable SVR rates, but fewer cases of anemia compared with standard RBV.

Poordad F, Lawitz E, Hassanein T, et al. Sustained virologic response (SVR) results for weight-based-taribavirin versus weight-based-ribavirin, in naive chronic hepatitis C, genotype 1 patients [abstract 65]. Hepatology 2009; 50:334A.

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 290).

Curr Opin Gastroenterol. 2010;26(3):196-201. © 2010 Lippincott Williams & Wilkins

http://www.medscape.com/viewarticle/720695

Ribavirin Causing Mitochondrial Toxicity in Patients With HIV/HCV Is a Good Sign: Study

From Reuters Health Information

By Will Boggs, MD

NEW YORK (Reuters Health) Jun 23 - In HIV patients being treated with ribavirin for hepatitis C, mitochondrial toxicity might actually be a good sign. It's associated with higher rates of sustained virologic response, say researchers from Austria.

"Mitochondrial toxicity is not necessarily a bad thing to happen during antiviral therapy for hepatitis C since it was not detrimental to our patients in any way," said senior author Dr. Markus Peck-Radosavljevic from Medical University of Vienna in e-mail to Reuters Health. Instead, he said, it could be a marker of adequate exposure to ribavirin.

In 48 patients infected with both viruses, Dr. Peck-Radosavljevic and colleagues studied the incidence of mitochondrial toxicity and hemolytic anemia during concomitant therapy with HAART and pegylated-interferon alpha (PEG-IFN) plus ribavirin. They also studied another 16 coinfected patients who were not receiving HAART.

During anti-HCV therapy with PEG-IFN plus ribavirin, patients with and without HAART had higher venous lactate levels (a marker of mitochondrial toxicity), although the increases were greater in patients with concomitant HAART, the authors report in a study published online May 20th in The Journal of Infectious Diseases.

By week 4, there was a significant correlation of higher doses of ribavirin and greater increases in venous lactate levels, but this association disappeared after week 24, when there was a dosage reduction of ribavirin for patients with HCV genotypes 1 and 4.

Fourteen patients developed asymptomatic hyperlactatemia. Lactate acidosis developed in only 1 patient who was treated with HAART and high-dose ribavirin. Nine patients who received high-dose ribavirin had severe weight loss.

Rates of hepatic steatosis tended to decrease among patients who received HAART and low-dose ribavirin (from 67% at baseline to 40% after treatment) and to increase in patients who received HAART and high-dose ribavirin (from 36% to 56%).

Patients who developed mitochondrial toxicity during treatment with PEG-IFN plus ribavirin had significantly higher ribavirin response rates at week 4 (51%) compared to patients without mitochondrial toxicity (21%; p = 0.015). Also, sustained virologic responses were more common in patients who had mitochondrial toxicity events than in those who didn't (73% vs 44%; p = 0.031).

"This has the potential to become an interesting tool for tailoring ribavirin dosages," the investigators say. Mitochondrial toxicity might eventually be used to titrate the dose of ribavirin prospectively.

"Adjusting the ribavirin-dose according to plasma levels has already been shown to be an effective means of getting optimal response, but this is technically demanding and not widely available," Dr. Peck-Radosavljevic said. "Instead, ribavirin dose could be titrated according to lactate levels, which are much easier to obtain."

As for treatment, he advises: "Do not be afraid of treating HIV-HCV coinfected patients under HAART with full-dose PEG-IFN/ribavirin just like you would treat any HCV-monoinfected patient."

The study was supported by Roche, which markets ribavirin. Dr. Peck-Radosavljevic and 2 of the other 8 authors reported having received research support, speaker fees, and/or travel grants from Roche.

J Infect Dis 2010;202:156-160.

http://www.medscape.com/viewarticle/724075

FDA Approves Rapid Test for Antibodies to Hepatitis C Virus

FDA NEWS RELEASE

For Immediate Release: June 25, 2010
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

The U.S. Food and Drug Administration today announced approval of the first rapid blood test for antibodies to the hepatitis C virus (HCV) for individuals 15 years and older.

The OraQuick HCV Rapid Antibody Test is used to test individuals who are at risk for infection with HCV and people with signs or symptoms of hepatitis. HCV is transmitted through exposure to infected blood, which, for example, can occur during intravenous drug use. The virus can also be transferred from an infected mother to her child. Hepatitis C can lead to liver inflammation and dysfunction and, over time, to liver disease and liver cancer.

OraQuick is a test strip and does not require an instrument for diagnosis. It takes about 20 minutes to obtain results from the test.

“Approval of OraQuick means that more patients can be notified of their HCV infection faster so that they can consult with their physicians for appropriate health measures,” said Jeffrey Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health. “Getting faster treatment is an important public health step to control this dangerous disease.”

OraQuick is not approved for HCV screening of the general population.

According to the U.S. Centers for Disease Control and Prevention, there are approximately 3.2 million people in the United States chronically infected with HCV and each year, about 17,000 people are newly infected. Chronic HCV infection is a leading reason for a liver transplants in the United States and HCV is associated with an estimated 12,000 deaths annually. Approximately 75 to 85 percent of people who become infected with the hepatitis C virus develop chronic infection.

OraQuick is manufactured by Bethlehem, Penn.-based OraSure Technologies Inc.

For more information:

FDA: Medical Devices
NIH: Hepatitis C
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm217318.htm

Growing New Livers

Published by Steven Novella under General Science, Science and Medicine
June 15, 2010

A team as Mass General has published the results of their preliminary research into growing new livers from hepatocyte stem cells. The work is encouraging – but to put it into perspective, it is still a long way away from growing fully functional transplantable organs.

What the team did was take rat livers and wash away all of the liver cells leaving behind just the connective tissue. They used this connective tissue as a scaffold on which to grow a new liver with hepatocytes. They then transplanted the new liver into rats. They report that the artificial livers survived for a few hours.

This is obviously a long way away from an artificial liver. First, the new livers had only hepatocytes, but not the other kinds of cells that make up a normal liver. So even if this technique worked completely, it would only create a partially functioning liver.

Another obstacle to overcome is creating a liver that has something approaching a normal infrastructure, including blood vessels and bile ducts. It’s not enough to have a mass of cells, they have to have the proper structure to function. This is not a trivial obstacle.

In fact the liver may be a deceptively difficult organ to grow in this manner. Other teams have had success using essentially the same technique with hearts – using a scaffold on which to grow new heart cells. Heart cells have the advantage of synchronizing themselves as they grow, so they beat together. The challenge is growing the internal electrical system of the heart, but this can be bypassed by using a pacemaker.

Other organs will be of varying complexity. A pancreas doesn’t seem as difficult as a lung or liver, while kidneys have a complex internal structure.

The questions is – how much potential is there in the scaffolding approach to growing organs? This seems like a stop-gap measure – a partial solution to the problem of how to grow organs. It may be useful for a couple of different kinds of organs, likes hearts, and for some other body parts – a trachea was transplanted using this method. But it seems unlikely, without further major breakthroughs, that this approach will be the ultimate solution to growing organs.

Growing new organs from scratch – from an embryonic state – may be the only way to get the full infrastructure and cellular organization. The problem here is that it takes time. An adult organ may take a decade to grow. For some organs an adult organ, or close to it, would be necessary – like heart and lungs. For others, even a several year old organ may suffice. A small liver or kidney would still provide significant function, and may continue to grow as the recipient ages.

There is also the question of what to grow the new organs in. Ideally we would grow them in vats – some completely artificial environment. But this will likely be a huge technological hurdle. There are insurmountable ethical problems to growing them in people – clones that would serve as organ banks (like in the movie, The Island). It is interesting to consider the public reaction to other human options, such as growing them in headless torsos – just a formless mass of cloned human tissue full of organs being fed intravenously.

There is also the option of genetically engineering animals to grow cloned human organs, and then sacrificing them when the organs are needed. Perhaps they can be engineered to be immunologically naked, and then matched to the recipient when it comes time to harvest the organ.

There are two significant advantages to growing organs. The first is that we have a shortage of donated organs – people die waiting for organs to be transplanted. The second is the issue of tissue rejection. Getting a transplant even from a compatible donor requires a lifetime of immunosuppressant drugs and the risk of rejection. A transplant of your own cloned tissue, however, would be 100% compatible and therefore not require drugs or risk rejection. This is a huge advantage, which would revolutionize organ transplants.

Conclusion

This latest study is a baby step forward in one technique which is likely to be very useful, but ultimately limited, in terms of a final solution for organ transplants. But it’s a step. We need another 50 baby steps or so before we reach our goal, but there are useful milestone along the way. I think we will see in the next decade grown hearts for transplant, and maybe even grown livers and pancreases. Skin is another organ that will likely occur sooner than later. But such predictions are inherently unreliable – there remains major obstacles to overcome and they cannot be predicted in the short term.

http://www.theness.com/neurologicablog/?p=2052

Higher Cancer Rates Found in Liver Transplant Recipients Receiving Cyclosporine

HOBOKEN, NJ -- June 24, 2010 -- A study published in the July issue of [Liver Transplantation shows that cyclosporine treatment is a significant risk factor for the development of de novo cancer in liver transplant recipients.

Several studies have yielded conflicting results about the incidence of de novo cancer between cyclosporine-based and tacrolimus-based regimens. Elucidating the role of different calcineurin inhibitor (CNI) regimens in the occurrence of de novo cancer after liver transplant was the goal of this study.

Herold Metselaar, MD, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands, and colleagues performed retrospective analyses in 385 liver transplant recipients who underwent surgery between 1986 and 2007.

They analysed data included age of recipient at time of transplantation, gender of recipient, primary liver transplant indication, type of primary immunosuppressive therapy, de novo malignancy post transplantation, interval from liver transplant to diagnosis of malignancy, interval from liver transplant or diagnosis of cancer to death, and interval from liver transplant to diagnosis of the first acute rejection.

All patients were followed until December 2008. The primary endpoint was de novo malignancy, which was defined as the development of cancer other than recurrent primary liver cancer. Of the 385 study participants, 50 (13.0%) patients developed at least 1 de novo cancer.

The researchers observed that cyclosporine, in comparison with tacrolimus, is the most important risk factor for de novo malignancy after liver transplant.

This higher cancer risk was not, however, found in all cyclosporine treated patients, but cyclosporine specifically enhanced development of de novo cancer in patients transplanted in more recent years (2005-2007), and in younger patients (age, <50 y). In addition, cyclosporine treatment particularly resulted in more aggressive types of cancer compared with tacrolimus, with a 1-year survival rate of <30%.

The reason for the increased cancer rates among cyclosporine recipients is believed to be the fact that from January 2005, cyclosporine dosing based on the conventional C0 level monitoring was replaced by dosing based on C2 level monitoring in all liver transplant recipients. As this was the only major change in the cyclosporine treatment in the recent study period, the team concluded that the C2 monitoring strategy was the reason for the increased early de novo cancer risk.

"Strikingly, cyclosporine treated patients transplanted from 2005 on showed a 9.9-fold higher de novo cancer risk in the early phase after liver transplant compared with patients treated with tacrolimus, said Dr. Metselaar. "These data indicate that only the specific cyclosporine treatment used in recent years was associated with a higher risk for early development of de novo cancer."

"We also observed that, compared with tacrolimus-treated patients, cyclosporine-treated patients had a 2.5-times higher risk to develop more aggressive cancer types that do not belong to the non-melanoma skin cancer and post-transplant lymphoproliferative disorder categories, indicating that cyclosporine is not only associated with a higher early de novo cancer risk, but also with cancer types having a worse prognosis," he added.

http://www.docguide.com/news/content.nsf/news/852576140048867C8525774C007A0833

Dr. Melissa Palmer: Which Doctors Treat Liver Disease?

There are many different kinds of doctors who evaluate and treat people with liver disorders. First, there is the family physician or internist. These doctors are also referred to as primary care physicians (PCPs). They are often the first ones to discover that something is wrong with the liver. From there, the patient is customarily referred to a specialist—either a gastroenterologist, hepatologist, or infectious disease specialist—for further evaluation and treatment. This specialist may be in a practice located at an academic institution or in a private practice located in a community setting. The difference between the various types of doctors a patient with liver disease encounters may sometimes be confusing. Hopefully, this section will clarify these differences in order to eliminate any future confusion.

Vitals.com can help you find a doctor in your area. You can search for doctors by name, city, zip code and medical condition.

The Medical Doctor (MD)

Medical Doctors (MDs) are physicians who have successfully completed four years of medical school training. After graduating from medical school, these doctors must complete a minimum of one additional year of training in a hospital in what is known as an internship. They must then pass a state-licensing exam in order to practice medicine in that state. After obtaining their license, they have the right to practice medicine in that state. However, many doctors choose to continue their training in a hospital by undergoing a residency—typically an additional two years.

After completing their residency, these doctors must take an exam in order to become board certified in a specialty, such as family medicine or internal medicine. Doctors may practice medicine whether or not they pass this exam. Doctors who become family doctors or internists have general knowledge in all areas of medicine including the heart, lungs, kidneys, stomach, intestines, and liver. At this time, a doctor may decide to undergo additional specialty training, known as a fellowship, in a specific area of internal medicine, such as gastroenterology, hepatology, or infectious diseases, in order to become an expert in these areas.

The Doctor of Osteopathy (DO)

Doctors of osteopathy (DOs) are commonly referred to as osteopaths. These are doctors who graduated from a four-year osteopathic school. They must also complete a one-year internship in a hospital in order to be eligible to obtain a license to practice medicine. Osteopaths can also choose to undergo an additional two-year residency, and may thereafter undergo specialty training in a specific area of medicine.

Osteopaths tend to focus on treating “the body as a whole,” particularly on the body’s ability to heal itself. Osteopaths typically center their treatment on the musculoskeletal system, the muscles and bones, often using techniques such as bone manipulation and a form of massage.

The Family Physician

A family physician is a doctor—either an MD or a DO—who has been trained to prevent, diagnose, and treat medical conditions in people of all ages. The family physician takes care of the general health of the patient and his entire family. Their training is not limited to internal medicine, but includes some training in psychiatry, obstetrics, gynecology, and surgery. These are the “Marcus Welby” doctors, seemingly able to handle almost any general problem.

There is a separate board certification examination specifically for family practitioners. This is known as the family practice boards. Specializing in family practice medicine requires an additional three years’ training beyond medical school. The amount of exposure to, and degree of expertise in liver disease varies among family practitioners. However, family physicians have not undergone additional specialized training in liver disease.

The Internist

An internist is a doctor—an MD or a DO—who is trained to prevent, diagnose, and treat medical conditions in adolescents and adults, including the elderly. Internists have received some basic training in subspecialty areas of internal medicine, including gastroenterology, hepatology, and infectious diseases. Internists are trained to treat both straightforward and complex problems of the internal organs. They are also trained in emergency medicine and critical care medicine. There is a separate board certification examination specifically for internists. It is known as the internal medicine boards. Specializing in internal medicine requires an additional three years’ training beyond medical school.

The amount of exposure to, and degree of expertise in liver disease varies among internists. Internists have the option of continuing their training in a subspecialty of internal medicine. This requires applying for, and being accepted into, a fellowship in the subspecialty of their choice. gastroenterology, hepatology, and infectious diseases are among the many subspecialties of internal medicine.

The Gastroenterologist

A gastroenterologist is an internist who has completed specialty training in the treatment of digestive disorders. Digestive disorders include disorders of the esophagus, stomach, small and large intestines, pancreas, gallbladder, and liver. In order to become board certified in gastroenterology, the doctor must first become board certified in internal medicine. In order to become eligible to even take the examination for board certification in gastroenterology, a gastrointestinal (GI) fellowship lasting an additional two to three years beyond an internal medicine residency must be completed.

During the course of their two to three years of training in gastroenterology, some gastroenterologists have little exposure to patients with liver disease. On the other hand, some gastroenterologists have a great deal of exposure to patients with liver disease during the course of their gastroenterology specialty training. Thus, the level of experience and expertise among gastroenterologists in diagnosing and treating liver disease varies greatly. It is important for the patient to determine the gastroenterologist’s level of expertise in liver disease prior to establishing a long-term medical relationship with this type of doctor.

The Hepatologist

A hepatologist is the most experienced and qualified type of doctor to treat people with liver disease. Since there is currently no separate board certification examination in the field of hepatology, there is no official definition of a hepatologist. However, there are specialized training programs for doctors who are focused solely on liver disease. These are known as hepatology fellowships and typically last from one to two years. Over the course of a hepatology fellowship, a doctor receives comprehensive training in the diagnosis and treatment of liver disease. This specialty training typically includes extensive exposure to all liver diseases, including those that are rare and infrequently seen. This intense training in liver disease is rarely matched in a gastroenterology fellowship.

A physician who successfully completes a hepatology fellowship is considered a hepatologist. Most hepatologists, although not all, are also gastroenterologists. These doctors have successfully completed both a hepatology and a gastroenterology fellowship. Occasionally, gastroenterologists who have not completed a fellowship in hepatology nonetheless focus their medical practice primarily on the diagnosis and treatment of people with liver disease. While these physicians do not have a separate diploma in the field of liver disease, they may also be considered hepatologists.

For many reasons, it is to the patient’s advantage to choose a hepatologist to treat his liver disease. The patient can be virtually assured that the hepatologist will have substantial experience in the diagnosis and treatment of the full range of liver diseases. Furthermore, hepatologists are likely to be the first to learn about the most up-to-date therapies—both FDA-approved and experimental—and to incorporate them into their practices. However, whether someone chooses to see a gastroenterologist or a hepatologist, it is important to find a doctor who is willing to work with him as an equal partner in the healing process.

Infectious Disease Specialists

An infectious disease specialist is an internist who has completed a specialty fellowship in infectious diseases of all types. Many infectious disease specialists treat people with liver disease caused by infectious – such as hepatitis B and C (both of which are caused by viruses). During the course of their two years of training in infectious diseases, some infectious disease specialists have little exposure to patients with viral hepatitis. On the other hand, some infectious disease specialists receive a great deal of exposure to patients with viral hepatitis during the course of their specialty training. Thus, the level of expertise among infectious disease specialists in diagnosing and treating viral hepatitis varies greatly. It is important for the patient to determine the infectious disease specialist’s level of expertise in treating hepatitis B or C prior to establishing a long-term medical relationship with this type of doctor. It should be stressed that infectious disease doctors have no special expertise treating liver diseases that are not caused by infections – such as alcoholic liver disease or autoimmune hepatitis.

All contents of this article are Copyright © Melissa Palmer, MD

Dr. Palmer is an internationally renowned hepatologist who has been practicing medicine since 1985. She maintains the largest private medical practice devoted to liver disease in the United States. Dr. Palmer was trained in hepatology (as well as medical school) at the Mount Sinai School of Medicine in New York City. She lectures frequently on liver disease-related topics to her medical peers and to the general public. She has appeared on television many times and is often quoted in magazines and newspapers. Dr. Palmer is a board member of the New York chapter of the American Liver Foundation, and she sits on the nutrition subcommittee of the national chapter of the American Liver Foundation, the advisory board of the Latino Organization for Liver Awareness (LOLA) and the Primary Biliary Cirrhosis Organization (PBCers).
 
http://spotlight.vitals.com/2009/12/dr-melissa-palmer-which-doctors-treat-liver-disease/

Bayer’s Liver Cancer Drug to Be Tested Against Sirtex

June 24, 2010, 2:21 AM EDT
By Simeon Bennett

June 24 (Bloomberg) -- Bayer AG’s Nexavar treatment for advanced liver cancer will be tested against a radiotherapy made by Sirtex Medical Ltd. in a final-stage study of patients in the Asia-Pacific region.

A total of 360 patients with inoperable liver cancer in 13 countries will receive either Nexavar or Sydney-based Sirtex’s SIR-Spheres, Singapore’s National Cancer Centre, the trial organizer, said in an e-mailed statement today.

“We hope to conclude which therapy is more beneficial to patients in terms of better survival, tumor shrinkage and quality of life,” Pierce Chow, who will lead the study, said in the statement. “This therapy will then serve as first line and the other as second-line treatment.”

About 80 percent of liver cancer cases occur in the Asia- Pacific region, and most people are diagnosed too late for surgery, according to the World Health Organization. The cancer kills about 610,000 people worldwide each year, making it the fourth most-deadly tumor, the United Nations agency said.

A previous trial that combined the two treatments extended patients’ lives by almost a year, a result that was better than either product on its own, according to the statement. The results were first presented at the American Society of Clinical Oncology’s conference in Chicago last month.

Liver cancer is caused mainly by the hepatitis B and C viruses, which are transmitted through blood or sexual contact and attack the organ, according to the U.S. National Cancer Institute. Left untreated, patients with advanced liver cancer have a median survival of about three months, the Singapore Cancer Centre said in the statement.

Microscopic Beads

SIR-Spheres are injectable microscopic polymer beads designed to shrink tumors by carrying a radiotherapy drug directly to them, avoiding the damage to healthy tissue that’s caused by conventional radiotherapy.

Bayer, of Leverkusen, Germany, co-markets Nexavar with New York-based Onyx Pharmaceuticals Inc.

Sirtex fell 4.3 percent to A$5.08 in Australian trading. The stock has lost 33 percent this year after surging more than fourfold in 2009.

--Editors: Lena Lee, Suresh Seshadri.

To contact the reporter on this story: Simeon Bennett in Singapore at sbennett9@bloomberg.net

To contact the editor responsible for this story: Jason Gale at j.gale@bloomberg.net .

http://www.businessweek.com/news/2010-06-24/bayer-s-liver-cancer-drug-to-be-tested-against-sirtex.html

Small Molecule Anti-virals with Optimized Efficacy and Fewer Side Effects Fuel Growth in the Hepatitis C Therapeutics Market in Indonesia, Finds Frost & Sullivan

Posted on : 2010-06-24

Author : Frost & Sullivan

News Category : PressRelease

SINGAPORE, June 24 /PRNewswire/ -- Regular blood screening conducted in hospitals for at-risk patients, particularly injecting drug users (IDUs), has expanded the patient base and enhanced prospects for the hepatitis C therapeutics market in Indonesia. Moreover, increasing health awareness in Indonesia has encouraged the population (mostly urban) to opt for annual physical examinations and regular blood screening that enable the detection of Hepatitis C.

New analysis from Frost & Sullivan (http://www.pharma.frost.com/), Multi Client Study: Opportunities Assessment for the Hepatitis C Therapeutics Market in Indonesia, finds that the global hepatitis C treatment market earned revenues of $2.3 billion in 2007, and is expected to increase to approximately $4.5 billion by 2017 due to new drug launches occurring after 2010.

"Small molecule anti-virals with improved efficacy are poised to take the market forward," says Frost & Sullivan Vice President, Rhenu Bhuller. "Several strategies are being explored in clinical trials, including add-on therapy to the current standard of care, interferon replacement, and ribavirin replacement."

Refined versions of interferons, oral formulations of small molecule inhibitors, and the new drug class known as protease inhibitors are in the pipeline and represent the future of hepatitis C virus (HCV) treatment. Despite the initiatives undertaken, only 2 percent of those diagnosed are placed under treatment, primarily because of the lack of government reimbursement.

Treatment of hepatitis C is restrained by the high cost of medication for patients who do not have health insurance. While Indonesia offers healthcare coverage to its population, many of the poor people are unable to apply for the insurance. Those not entitled are expected to bear the cost themselves, which is approximately $1,000 per month.

The low rate of treatment and compliance is also caused by patients' fear of side effects associated with treatment. These include bone marrow depression, flu-like symptoms, neuropsychiatric disorders, and autoimmune syndromes. Besides, limited efficacy for those infected with genotype-1 strain and an inconvenient mode of administration has contributed to non-compliance.

Studies have shown that patients treated with combination therapy of the two drugs are more likely to reach sustained virological response than those treated with monotherapy. With this, more patients are likely to accept treatment, as there is a better chance for them to completely recover from Hepatitis C. In Indonesia, the standard treatment for HCV is Peg intron; Peg intron + Ribavirin; Pegasys; and Pegasys + Ribavirin.

Physicians interviewed agreed that patients respond better to combination therapy and recovery rates are higher for patients on Pegylated interferon (Peg intron or Pegasys) + Ribavirin. Additionally, most patients are HIV positive, making treatment more difficult, as the possibility of co-infection is higher among these patients.

Companies that offer treatments with improved efficacy and fewer side effects, combined with disease education can help overcome the challenges clouding the market landscape. Encouraging better compliance now will enhance the likelihood of future compliance, especially for improved treatments. Creating incentives for patients to stay on HCV treatment will improve the chances of patient compliance. In order to increase their HCV market share with newer drugs, companies must make sure that patients are aware of their disease status.

"Awareness programs are mostly centered in urban areas, with the aid of media such as television and internet as a source of information delivery," says Bhuller. "Outreach programs must target rural areas to stop the onslaught of the disease."

Creating marketing campaigns that highlight better efficacy, partnerships with governments to lower costs, but increase distribution, and broadening diagnosis efforts will increase market presence.

If you are interested in more information on this study, please send an e-mail to Nicklaus Au, Corporate Communications, at nicklaus.au@frost.com ,with your full name, company name, title, telephone number, company e-mail address, company website, city, state and country.

Multi Client Study: Opportunities Assessment for the Hepatitis C Therapeutics Market in Indonesia is part of the Pharmaceuticals & Biotechnology Growth Partnership Services program, which also includes research in the following markets: Global Pharmaceuticals & Biotechnology and Global Healthcare. All research services included in subscriptions provide detailed market opportunities and industry trends that have been evaluated following extensive interviews with market participants.

About Frost & Sullivan

Frost & Sullivan, the Growth Partnership Company, enables clients to accelerate growth and achieve best-in-class positions in growth, innovation and leadership. The company's Growth Partnership Service provides the CEO and the CEO's Growth Team with disciplined research and best-practice models to drive the generation, evaluation, and implementation of powerful growth strategies. Frost & Sullivan leverages over 45 years of experience in partnering with Global 1000 companies, emerging businesses and the investment community from 40 offices on six continents. To join our Growth Partnership, please visit http://www.frost.com/.

Multi Client Study: Opportunities Assessment for the Hepatitis C Therapeutics Market in Indonesia

P387

SOURCE Frost & Sullivan

http://www.earthtimes.org/articles/press/finds-frost--sullivan,1358261.html#

New HCV Antivirals in the Pipeline

excertped from new Hepatology textbook recently published.

From Jules: there are over 25 orally administered HCV antiviral drugs in development at this time that have been publicly presented at conferences. Many companies have multiple drugs in development. There are many potential combinations for regimens. Therapy for HCV will be like HIV consisting of a combination of the oral drugs. For now peginterferon plus ribavirin will be included in therapy until and if researchers can prove that an SVR, a cure, can be achieved without using peginterferon and ribavirin. Plus, there are a few new interferons in development that appear to be easier to tolerate. The first 2 HCV protease inhibitors telaprevir & boceprevir are now in the last stage of clinical studies in patients, phase 3, before FDA approval, which is expected next around Summer 2011, so they are expected to be available in the pharmacy by the Fall of 2011.

Table 1. Antivirals in the pipeline.

HCV life cycle and targets for STAT-C

HCV is a positive-sense single-stranded RNA virus of approximately 9600 nucleotides. The HCV genome contains a single large open reading frame encoding for a polyprotein of about 3100 amino acids. From this initially translated polyprotein, the structural HCV protein core (C) and envelope 1 and 2 (E1, E2); p7; and the six non-structural HCV proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B, are processed by both viral and host proteases. The core protein forms the viral nucleocapsid carrying E1 and E2, which are receptors for viral attachment and host cell entry. The non-structural proteins are mainly enzymes essential for the HCV life cycle (Bartenschlager 2004; Pawlotsky 2007). P7 is a small hydrophobic protein that oligomerises into a circular hexamer, most likely serving as an ion channel through the viral lipid membrane (Carrere-Kremer 2002; Clarke 2006). The large translated section of the HCV genome is flanked by the strongly conserved HCV 3' and 5' untranslated regions (UTR). The 5' UTR is comprised of four highly structured domains forming the internal ribosome entry site (IRES), which plays an important role in HCV replication (Figure 2).

Figure 9. Antiviral activity of NS3/4A protease inhibitors.

Resistance to NS3/4A inhibitors Because of the high replication rate of HCV and the poor fidelity of its RNA-dependent RNA polymerase, numerous variants (quasispecies) are continuously produced during HCV replication. Among them, variants carrying mutations altering the conformation of the binding sites of STAT-C compounds can develop. During treatment with specific antivirals, these drug-resistant variants have a fitness advantage and can be selected to become the dominant viral quasispecies. Many of these resistant mutants exhibit an attenuated replication with the result that, after stopping exposure to specific antivirals, the wild type may displace the resistant variants (Tong 2006; Sarrazin 2007). Nevertheless, HCV quasispecies resistant to NS3/4A protease inhibitors or non-nucleoside polymerase inhibitors can be detected at low levels in some patients who were never treated with specific antivirals before (Gaudieri 2009; Kuntzen 2008; Rodriguez-Frias 2009; Le Pogam 2008). The clinical relevance of these pre-existing mutants is not completely understood, although there is evidence that they may reduce the chance of achieving an SVR after treatment with STAT-C compounds.

Table 5. Resistance mutations to HCV NS3 protease inhibitors.

* mutations associated with resistance in vitro but not described in patients.

Telaprevir

To date, mutations conferring telaprevir-resistance have been identified at four positions, V36A/M/L, T54A, R155K/M/S/T and A156S//T (Lin 2005; Lin 2007; Sarrazin 2007; Welsch 2008; Zhou 2008) (Table 5). The A156 mutation was revealed by in vitro analyses in the replicon while the other mutations were detected in vivo by a clonal sequencing approach during telaprevir administration in patients with chronic hepatitis C. A detailed kinetic analysis of telaprevir-resistant variants was performed in genotype 1 patients during 14 days of telaprevir monotherapy and combination therapy with PEG-IFN a-2a (Sarrazin 2007). Telaprevir monotherapy initially led to a rapid HCV RNA decline in all patients due to a strong reduction in wild type virus. In patients who developed a viral rebound during telaprevir monotherapy, mainly the single mutation variants R155K/T and A156T were uncovered by wild type reduction and became dominant after day 8. These single mutant variants were selected from preexisting quasispecies. During the viral rebound phase these variants typically were replaced by highly resistant double-mutation variants (e.g., V36M/A +R155K/T). The combination of telaprevir and PEG-IFN a-2a was sufficient to inhibit the breakthrough of resistant mutations in a 14-day study (Forestier 2007). It is important to note that after up to 3 years of telaprevir treatment low to medium levels of V36 and R155 variants were observed in single patients (Forestier 2008).

As shown also for other NS3/4A protease inhibitors (e.g., ITMN-191), the genetic barrier to telaprevir resistance differs significantly between HCV subtypes. In all clinical studies of telaprevir alone or in combination with PEG-IFN a and ribavirin, viral resistance and breakthrough occurred much more frequently in patients infected with HCV genotype 1a compared to genotype 1b. This difference was shown to result from nucleotide differences at position 155 in HCV subtype 1a (aga, encodes R) versus 1b (cga, also encodes R). The mutation most frequently associated with resistance to telaprevir is R155K; changing R to K at position 155 requires 1 nucleotide change in HCV subtype 1a and 2 nucleotide changes in subtype 1b isolates (McCown 2009).

Boceprevir

In the replicon system, mutations have been seen at three positions that confer boceprevir resistance (Table 5). T54A, A156S and V170A confer low level resistance to boceprevir whereas A156T, which also confers telaprevir and ciluprevir resistance, exhibits greater levels of resistance (Tong 2006). In patients with chronic hepatitis C three additional mutations were detected during boceprevir monotherapy (V36G/ M/A, V55A, R155K) (Susser 2009). In a number of these patients at one year and in single patients at even 4 years after stopping boceprevir treatment resistant variants could still be detected in the HCV quasispecies by clonal sequence analysis (Susser 2009). However, another study revealed that the antiviral activity of boceprevir was not different in people whether they had or had not been previously treated with PEG-IFN a (Vermehren 2009).

Compounds targeting HCV replication

NS5B polymerase inhibitors

NS5B RNA polymerase inhibitors can be divided into two distinct categories. Nucleoside analogue inhibitors (NIs) like valopicitabine (NM283), R7128, R1626, PSI-7851 or IDX184 mimic the natural substrates of the polymerase and are incorporated into the growing RNA chain, thus causing direct chain termination by blocking the active site of NS5B (Koch 2006; Koch 2007). Because the active centre of NS5B is a highly conserved region of the HCV genome, NIs are potentially effective against different genotypes. Single amino acid substitutions in every position of the active centre may result in loss of function. Thus, there is a relatively high genetic barrier in the development of resistances to NIs.

In contrast to NIs, the heterogeneous class of non-nucleoside inhibitors (NNIs) achieves NS5B inhibition by binding to different allosteric enzyme sites, which results in conformational protein change before the elongation complex is formed (Beaulieu 2007). For allosteric NS5B inhibition high chemical affinity is required. NS5B is structurally organized in a characteristic Òright hand motifÓ, containing finger, palm and thumb domains, and offers at least four NNI binding sites, a benzimidazole-(thumb 1)-, thiophene-(thumb 2)-, benzothiadiazine-(palm 1)- and benzofuran-(palm 2)-binding site (Lesburg 1999; Beaulieu 2007) (Figure 12). Because of their distinct binding sites, different polymerase inhibitors can theoretically be used in combination or in sequence to manage the development of resistance. Because NNIs bind distantly to the active centre of NS5B, their application may rapidly lead to the development of resistant mutants in vitro and in vivo. Moreover, mutations at the NNI binding sites do not necessarily lead to impaired function of the enzyme.

Figure 13. Antiviral activity of nucleoside analogue NS5B polymerase inhibitors.

Non-nucleoside analogs

At least 4 different allosteric binding sites have been identified for the inhibition of the NS5B polymerase by non-nucleoside inhibitors. An overview of the antiviral activities of non-nucleoside polymerase inhibitors in monotherapy studies is shown in Figure 14.

NNI site 1 inhibitors (thumb 1 / benzimidazole site)

BILB1941, BI207127 and MK-3281 are NNI site 1 inhibitors investigated in phase I clinical trials and have shown little to modest antiviral activity (Erhard 2009; Shi 2009; Sarrazin 2009). No viral breakthrough via selection of resistant variants was seen after 5 days of treatment with BILB1941 or BI207127.

NNI site 2 inhibitors (thumb 2 / thiophene site)

Filibuvir (PF-00868554) is a NNI site 2 inhibitor with modest antiviral activity in a phase I study. In a subsequent triple therapy trial with filibuvir, pegylated interferon a-2a and ribavirin for 4 weeks viral breakthrough was observed in 5/26 patients.

VCH-759, VCH-916 and VCH-222 are three other NNI site 2 inhibitors with antiviral activity in monotherapy studies (Cooper 2009; Sarrazin 2009). For VCH-759 as well as VCH-916 viral breakthroughs via selection of resistant variants were observed.

NNI site 3 inhibitors (palm 1 / benzothiadiazine site)

ANA598 is a NNI site 3 inhibitor that displayed antiviral activity during treatment of genotype 1 infected patients. Viral breakthrough was not observed during this short monotherapy trial.

NNI site 4 inhibitors (palm 2 / benzofuran site)

Monotherapy with the NNI site 4 inhibitor HCV-796 showed low antiviral activity in genotype 1 infected patients (Kneteman 2009; Villano 2007). Viral breakthrough was associated with selection of resistant variants conferring a medium to high level of phenotypic resistance. For GS-9190 low antiviral activity was observed in a clinical study and variants conferring resistance were identified in the beta-hairpin of the polymerase. ABT-333, another palm site inhibitor, demonstrated antiviral activity in patients with genotype 1 infection and from in vitro replicon as well as clinical studies specific variants were observed as main resistance mutations.

Figure 14. Antiviral activity of non-nucleoside analogue NS5B polymerase inhibitors.

NS5A inhibitor

In a single ascending dose study it was shown that inhibition of the NS5A protein with BMS-790052 leads to a sharp initial decline of HCV RNA concentrations (Nettles 2008). BMS-790052 is the first NS5A inhibitor binding to domain I of the NS5A protein, which was shown to be important for regulation of HCV replication. No clinical data on resistance to this class of drugs have been presented yet and results of multiple dose studies are eagerly anticipated. (from Jules: clinical data, in patients was presented at the EASL meeting in April 2010 and previously at AASLD 2 years ago)

links:
 
Once-daily NS5A Inhibitor (BMS-790052) Plus Peginterferon-alpha-2a And Ribavirin Produces High Rates Of Extended Rapid Virologic Response In Treatment-naïve HCV-genotype 1 Subjects: Phase 2a Trial - Bristol-Myers Squibb Study AI444014 - (04/20/10)

BMS-790052 is a First-in-class Potent Hepatitis C Virus (HCV) NS5A ... Nov 1, 2008 ... This new class of drug, the BMS NS5A inhibitor, attracted quite a lot of discussion because of it potent viral load reduction of -3.6 logs, ... www.natap.org/2008/AASLD/AASLD_06.htm

The Most recent data updates on new HCV antivirals and new interferons were reported at the recent EASL:

EASL 45th Annual Meeting
(European Association for the Study of the Liver)
April 14-18, 2010
Vienna, Austria

http://www.natap.org/2010/HCV/062310_01.htm

OPTN Statement Regarding Liver Transplant Waiting Times and Allocation

Release Date:

06/24/2009

Recent news regarding liver transplantation has raised public questions regarding how donated livers are allocated and potential variation in transplant waiting times. The national Organ Procurement and Transplantation Network (OPTN), operated by United Network for Organ Sharing (UNOS) under federal contract, cannot discuss details of individual transplant candidates subject to federal laws and regulations regarding patient confidentiality. The OPTN can address general questions about policy and process.

Whenever a person known to the public receives a transplant, it is tempting to compare that person's waiting time to national averages. Any comparison of one person's experience to that of thousands of others can be misleading.

Liver waiting time is greatly influenced by a formula that assigns priority for organ offers based on the candidate's risk of dying within three months without a transplant. For candidates 12 or older, this formula is called a MELD score. (Younger candidates are prioritized by a companion system known as PELD).

MELD uses objective calculations of common laboratory tests of liver and kidney function. MELD scores can range from 6 (least urgent) to 40 (most urgent); candidates with a score of 15 or higher are at considerable risk of dying in the short term without a transplant.

OPTN policy prioritizes liver candidates local to the organ donor with a MELD or PELD score of 15 or higher, then those candidates within the region of the donor who have scores of 15 and higher, before any less urgent candidates may be considered.

Of candidates listed in the United States with an initial MELD or PELD score between 19 and 24, half receive a liver transplant within approximately 15 weeks of being listed. Of those listed with an initial MELD or PELD score of 25 or higher, half receive a transplant within 20 days of listing. Candidates with lower MELD/PELD priority may often wait months to years for a transplant opportunity.

Other factors may further affect waiting time, such as whether the candidate is generally compatible or incompatible with many donor offers based on blood type or body size. Waiting time in a given local area may reflect particular characteristics in that area's recipient population that are not common to other areas. The national allocation system cannot and does not make any distinction of candidate priority based on wealth, celebrity or other purely social characteristics.

In recent years, approximately 6,500 liver transplants have been performed annually in the United States. Today more than 15,000 men, women and children continue to await this lifesaving gift. We hope the current attention generated by news reports will remind the public of the continuing need of all transplant candidates, and of the opportunity to end their wait through making a positive commitment to organ donation.

http://www.unos.org/news/newsDetail.asp?id=1265

Organ Donations Decline as Need Increases

Submitted by Deborah Mitchell on 2010-03-22

More than 100,000 people need life-saving organ transplants in the United States, and an additional million need life-saving and life-improving tissues, eyes, and corneas. Yet every day, an average of 18 people die because there are not enough organ donations to meet the need, according to the Organ Procurement and Transplantation Network. The seriousness of the lack of organ donations has been highlighted in a new study conducted by investigators at Cedars-Sinai Medical Center.

The study’s authors found that the gap between the number of organs available for transplant and the number of patients waiting for a donor organ is widening. The number of organs from living donors has declined progressively since 2004, and for the first time, the number of organs from deceased donors has declined.

Members of the research team, led by Andrew S. Klein, MD, director of Cedars-Sinai Medical Center’s Comprehensive Transplant Center, found that the number of living donors increased yearly from 1999 to 2004, but has been declining since then. Although the number of organ donations from deceased individuals risen each year between 1999 and 2007, the increase was not sufficient to offset the decline in living donor donations.

The fact that transplantation of solid organs is now so successful has actually made getting an organ more difficult. “Improved survival rates and the expectation that organ replacement will enhance quality of life have encouraged more doctors and their patients with organ failure to opt for transplantation,” explains Klein.

One example is Kurt Penner. As a prelude to the past winter Olympics, double-lung transplant recipient Penner carried the Olympic torch in Ontario to highlight the need for organ and tissue donations. Penner received his double-lung transplant through the Trillium Gift of Life Network within days of dying of emphysema.

Recently, Apple CEO Steve Jobs, who had a life-saving liver transplant last year, joined forces with governor Arnold Schwarzenegger to help push through new legislation in California to expand the number of organ donors in that state.

Convincing individuals to be an organ donor is a challenge. Although about 90 percent of Americans say they support organ donation, only 30 percent know the steps that need to be taken to become a donor. Several factors contribute to the public’s lack of awareness of the issue and to organ shortage itself, as the Cedars-Sinai researchers note.

Some of those factors include disincentives for living organ donors (e.g., loss of income while taking off work, transplant-related medical expenses may not be covered by the recipient’s insurance), lack of understanding by the public about organ donation policies, poor training of medical personnel who request consent for donations, and an inability to accurately evaluate the quality of donated organs based on currently available procurement testing.

Klein notes that their study showed that the public needs to be educated about organ donation and that the transplantation process and organ procurement facilities need to be more transparent if we hope to turn around the decline in organ donations as the need increases. For more information about organ donation, the Mayo Clinic discusses 10 myths about the topic, and OrganDonor.gov discusses how to be an organ donor.

SOURCES:
Cedars-Sinai Medical Center
New York Organ Donor Network Donate Life
OrganDonor.gov
Organ Procurement and Transplantation Network

http://www.emaxhealth.com/1275/24/36134/organ-donations-decline-need-increases.html

Physicians Test for Hepatitis C Based on Risk Factors but Should Expand Screening for High-Prevalence Age Group

SUMMARY: Medical providers seeing patients in a high-risk urban setting tend to recommend hepatitis C virus (HCV) testing based on known risk factors such as drug or alcohol use and having symptoms of liver disease such as cirrhosis or elevated ALT, according to an analysis published in the May 20, 2010 advance online edition of the Journal of Viral Hepatitis. Overall prevalence was high, however, and the investigators suggested that broader HCV screening might be useful for people born between 1945 and 1964, even if they do not have other risk factors.

By Liz Highleyman

W.N. Southern from Albert Einstein College of Medicine and colleagues examined HCV testing practices to determine which patient characteristics are associated with getting tested and with testing HCV positive. They also sought to determine the prevalence of HCV infection in a high-risk urban population.

Approximately 3.2 million people in the U.S. have chronic hepatitis C, the study authors noted as background, but many are not aware of their infection.

The researchers analyzed all patients seen at the ambulatory care clinic at Montefiore Medical Center in the Bronx, New York City, between January 1 and February 29, 2008. In addition, they extracted demographic information, laboratory data, and ICD-9 diagnostic codes from electronic medical records of patients seen between March 1, 1997 and February 29, 2008. All participants were included in the baseline phase of the Hepatitis C Assessment and Testing Project (HepCAT), a serial cross-sectional study of HCV screening strategies.

Results 

1. Among the 9579 participants analyzed, 3803 (39.7%) had been tested for HCV.
2. Of these, 438 (11.5%) were HCV positive.
3. The overall prevalence of HCV infection was estimated to be 7.7%, assuming that untested participants would test positive at the same rate as tested subjects, based on risk-factors.
4. The following risk factors were associated with being tested for HCV, and with being HCV positive: 

          *Being in the high-prevalence birth cohort born during 1945-1964

            (roughly age 45 to 65);

          *History of drug or alcohol abuse; Being HIV positive;

          *Diagnosis of cirrhosis; Diagnosis of end-stage renal (kidney) disease; 

          *Elevated alanine transaminase (ALT).

"In a high-risk urban population, a significant proportion of patients were tested for HCV and the prevalence of HCV infection was high," the study authors concluded. The estimated 7.7% prevalence in this group of patients is several times higher than the 1.6% rate for the U.S. general population.

"We found strong evidence that physicians are using a risk-based screening strategy to identify patients with HCV infection, using known risk factors and other conditions associated with HCV to guide testing," they continued in their discussion. However, they added, broader screening may be indicated for people in the high-prevalence birth cohort, even those without behavioral or clinical risk factors.

Expanded testing might be useful given that a considerable proportion of people with HCV do not know how they became infected. Furthermore, sexual transmission of HCV is a growing concern among HIV positive gay men, but sexual behavior is not commonly regarded as a hepatitis C risk factor. At a recent hepatitis C forum attended by gay men in San Francisco, several participants said their providers had refused to test them for HCV because they did not have a history of injection drug use or other traditional risk factors.

Investigator affiliations: Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY; School of Public Health, Boston University, Boston, MA; VA QUERI-HIV/Hepatitis Program, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA; Division of Viral Hepatitis, Centers for Disease Control and Prevention, National Center for HIV/Viral Hepatitis/STD/TB Prevention, Atlanta, GA.

6/22/10

Reference

WN Southern, M-L Drainoni, BD Smith, and others. Hepatitis C testing practices and prevalence in a high-risk urban ambulatory care setting. Journal of Viral Hepatitis (Abstract). May 20, 2010 (Epub ahead of print).

http://www.hivandhepatitis.com/hep_c/news/2010/0622_2010_b.html

The Life Cycle of Hepatitis C

Liver cells infected with the hepatitis C virus

The hepatitis C virus must attach to and infect liver cells in order to carry out its life cycle and reproduce - this is why it is associated with liver disease. While little is known about the exact natural processes of hepatitis C, like other viruses, it must complete eight key steps to carry out its life cycle:

1. The virus locates and attaches itself to a liver cell. Hepatitis C uses particular proteins present on its protective lipid coat to attach to a receptor site (a recognizable structure on the surface of the liver cell).

2. The virus's protein core penetrates the plasma membrane and enters the cell. To accomplish this, hepatitis C utlilizes its protective lipid (fatty) coat, merging its lipid coat with the cellÕs outer membrane (the coat is in fact composed of a fragment of another liver cell's plasma membrane). Once the lipid coat has successfully fused to the plasma membrane, the membrane engulfs the virus - and the viral core is inside the cell.

3. The protein coat dissolves to release the viral RNA in the cell. This may be accomplished during penetration of the cell membrane (it is broken open when it is released into the cytoplasm), or special enzymes present in liver cells may be used to dissolve the casing.

4. The viral RNA then coopts the cell's ribosomes, and begins the production of materials necessary for viral reproduction. Because hepatitis C stores its information in a "sense" strand of RNA, the viral RNA itself can be directly read by the host cell's ribosomes, functioning like the normal mRNA present in the cell. As it begins producing the materials coded in its RNA, the virus also probably shuts down most of the normal functions of the cell, conserving its energy for the production of viral material, although it occasionally appears that hepatitis C will stimulate the cell to reproduce (presumably to create more cells that can produce viruses), which is why hepatitis C is often associated with liver cancer. The viral RNA first synthesizes the RNA transcriptase it will need for reproduction.

5. Once there is adequate RNA transcriptase, the viral RNA creates an antisense version (the paired opposite) of itself as a template for the creation of new viral RNA. The viral RNA is now copied hundreds or thousands of times, making the genetic material for new viruses. Some of this new RNA will contain mutations.

6. Viral RNA then directs the production of protein-based capsomeres (the building blocks for the virus's protective protein coat). Ribosomes create the proteins and release them for use.

7. The completed capsomeres assemble around the new viral RNA into new viral particles. The capsomeres are designed to attract each other and fit together in a certain way. When enough capsomeres are brought together, they self-assemble to form a spherical shell, called a capsid, that fully encapsulates the virus's RNA. The completed particle is called a nucleocapsid.

8. The newly formed viruses travel to the inside portion of the plasma membrane and attach to it, creating a bud. The plasma membrane encircles the virus and then releases it - providing the virus with its protective lipid coat, which it will later use to attach to another liver cell. This process of budding and release of new viruses continues for hours at the cell surface until the cell dies from exhaustion.

Each surviving virus - those which are not destroyed by the immune system or other environmental factors - can produce hundreds or thousands of offspring. Over time, this endless cycle of reproduction results in significant damage to the liver, as millions upon millions of cells are destroyed by viral reproduction or by the immune system's attacks on infected cells.

http://www.epidemic.org/theFacts/hepatitisC/lifeCycle/

Study busts liver disease myth

Sumati Yengkhom, TNN, Jun 23, 2010, 05.48am IST

KOLKATA: If you had the idea that alcohol and obesity were primarily responsible for fatty liver and other liver diseases, here is a report that turns this theory on its head. Non-obese and non alcoholic people also fall prey to liver diseases, including the cirrhosis of the liver.

A study by a team of Kolkata doctors has revealed a high prevalence rate of non-alcoholic fatty liver (NAFL) and other liver diseases among the non-obese, non-alcoholic people from poor families. The remarkable findings by the team of doctors from SSKM’s School of Digestive & Liver Diseases (SDLD) breaks the myth that NAFL is particular to developed countries that are associated with industrialisation, sedentary lifestyle and obesity.

A sample size of 1,911 adults from Nagari panchayat in Birbhum district were chosen for the study. A majority of them belonged to the below poverty line category and are either agricultural workers or labourers. People from this region and economic background were chosen so that they can be taken as representatives of those living in less developed regions across the country.

None had either hepatitis B or C that can trigger liver ailment. And despite the fact that about 47% of them were malnourished, the most remarkable finding of the study is that about 9% of this sample — who did not consume alcohol and were not obese — had fatty liver.

“Confirmation for NAFL was done by dual radiological screening consisting of ultra sonography and CT scan in order to double check for an absolutely error free result. The study was conducted over a period of two years,” said gasteroenterologist Dr Khaunish Das, who was a part of the team.

Because of the significant prevalence of NAFL and higher risks of liver diseases — including cryptogenic cirrhosis — in this non-obese, non-alcoholic, non-affluent population, the researchers believe NAFL will be a major determinant for future liver disease burden in developing economies.

Cirrhosis of the liver is considered the thirteenth most common cause for mortality. So far, chronic viral hepatitis due to hepatitis B and C was known as the most common cause for cirrhosis of the liver.

The study highlights two issues. First, NAFL is prevalent among individuals in developing countries who many not have the typical metabolic risk factors for NAFL and therefore, perceived to be not in the risk category for the condition. Secondly, NAFL in this Birbhum population could be similar to NAFL in other population from similar backgrounds.

“The study has shown that non-obese people who are physically active and without a bulging waistline can also have fatty liver. In fact, this study provides evidence for the first time that NAFL will be an important determinant of liver disease burden even in poor and emerging economies,” said Dr Abhijit Chowdhury who heads SDLD.

The findings of the study have been published recently in two reputable journals — ‘Hepatology, the journal of American Association for the study of liver’ and ‘Nature Reviews’.

http://timesofindia.indiatimes.com/city/kolkata-/Study-busts-liver-disease-myth/articleshow/6080741.cms

Gregg Allman feeling 'pretty good' after liver transplant

By Rick Diamond, Getty Images

Just in: Rocker Gregg Allman has undergone a successful liver transplant operation at the Mayo Clinic in Jacksonville, Fla.

"I feel pretty good, considering everything that's happened," Allman said in a statement after having surgery this morning. "Everybody involved here, my doctors and nurses in the hospital and all the Allman Brothers fans, they've just all been great."

In late 2007, The singer, keyboardist, songwriter and guitarist began a series of treatments for his Hepatitis C, but chronic damage of his liver led to doctors recommending a transplant. Now he's looking forward to a speedy recovery, say his publicists. Adds Allman, "Every day is a gift, and I can't wait to get back on the road making music with my friends."

http://content.usatoday.com/communities/entertainment/post/2010/06/gregg-allman-feeling-pretty-good-after-liver-transplant-/1