June 23, 2010

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.


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).


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)

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

Release Date:


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.


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.

Cedars-Sinai Medical Center
New York Organ Donor Network Donate Life
Organ Procurement and Transplantation Network

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.

  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.



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).

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.


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’.


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."