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HepDART 2009
06-10 December 2009
Kohala Coast, Hawaii, USA Back grey_arrow_rt.gif
Longitudinal clonal resistance analysis of treatment-naïve patients with chronic Hepatitis C (CHC) genotype 1 infection treated with MK-7009, a Novel NS3/4a Protease Inhibitor, in combination with Pegylated Interferon Alfa-2a and Ribavirin for 28 day
Reported by Jules Levin
HepDart Dec 6-10 2009 Hawaii
Richard J.O. Barnard1, Adetoun Adeniji-Adele1, Amy Himmelberger1, Richard Wiedmann2, Peggy M. Hwang3, Erin Quirk2, Nicholas Kartsonis2, Andrew W. Lee2, Robert Tipping3, Michael D. Miller1, Daria Hazuda1 1Antiviral Research, 2ID/Vaccines Clinical Research, 3Biostatistics, Merck Research Laboratories, West Point, PA, USA
Copyright © 2009 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. All Rights Reserved
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ABSTRACT
Background: MK-7009 is a noncovalent competitive inhibitor of HCV NS3/4A protease which significantly improved rapid viral response (RVR) rates in CHC patients when administered in combination with pegylated interferon (peg-IFN) and ribavirin (RBV) for 28 days (i.e., "triple therapy"). We now report updated efficacy and resistance studies for patients treated with continued peg-IFN/RBV for 12 weeks total.
Methods: This is a randomized, placebo-controlled, double-blind study of MK-7009 in treatment-naïve CHC patients. MK-7009 was administered for 28 days with peg-IFN/RBV in 1 of 5 regimens: placebo, 300 mg BID, 600 mg BID, 600 mg QD, or 800 mg QD; all patients subsequently continue peg-IFN/RBV for an additional 44 weeks. HCV RNA was determined by Roche Cobas Taqman PCR with a lower limit of detection (LLOD) ∼ 10 IU/mL. RVR and complete Early Viral Response (EVR) are defined as the percentage of treated patients below LLOD at 4 and 12 weeks, respectively. For resistance studies, the NS3 region of the HCV genome was amplified by RT-PCR from RNA purified from patient plasma. Both population and clonal sequencing was performed on the resultant NS3 amplicons.
Results: 94 subjects (mean age 46.1 years, 59% male, mean baseline HCV RNA 6.70 log10 IU/mL) were randomized and treated.
The proportion of subjects who achieved RVR in the MK-7009-containing arms ranged from 69% to 82%, vs. 6% of the control (p < 0.0001 for each MK-7009 dose group, per-protocol analysis).
Preliminary data for 81 patients through Week 12 indicate continued viral suppression on peg-IFN/RBV only treatment, as 77 to 89% of subjects originally treated with triple therapy achieved EVR vs. 60% of control (per-protocol analysis).
4 patients had viral breakthrough at levels sufficient to perform resistance testing by week 12. Resistant HCV variants in the NS3/4a region of the HCV genome were detected in the three viral breakthrough patients randomized to receive MK-7009 by day 42 of the study.
Three patients had viruses that exhibited the R155K variant by week 12 of the study. The virus from one of these patients also exhibited low levels of the D168V variant. One patient exhibited a mixture of D168V/A/T by day 42 of the study. Clonal and population sequencing analysis was performed at multiple time points through week 12 from these patients where samples were available.
Conclusions: In this first study of MK-7009 in combination with peg-IFN/RBV, MK-7009 is a well-tolerated and potent inhibitor of HCV. This interim analysis indicates high rates of viral suppression to undetectable levels through 12 weeks in subjects treated with MK-7009 in combination with standard therapy for the initial 28 days. The results support further development of MK-7009 for HCV treatment. Resistance variants identified in this study were at positions 155 and 168 of the NS3/4a region.
Methods
Viral Resistance
Resistance sequencing was performed only for patients who met virological failure in Protocol 007, defined as:
· If the patient did not achieve at least 2 log10 decline in HCV viral RNA by week 4.
· If the patient has evidence of breakthrough viremia as defined by >1-log10 increase from nadir RNA (from two consecutive HCV RNA measurements)
· Plasma viral RNA of >100IU/ml in two consecutive visits after becoming undetectable
Due to the sensitivity of resistance assays, resistance analysis was performed on patient samples with HCV viral loads of >1000 IU/ml. Resistance analysis was performed at baseline, week 12 and intermediate time points based on sample availability.
Clonal Sequencing: DNA Amplicons obtained at baseline and the indicated time points were purified and cloned into a bacterial plasmid. ∼40 independent clones from each time point were sequenced
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Figure 2. MK-7009 Protocol 007 Study Design. Patients were randomized into several MK-7009 with doses groups. Patients were dosed with MK-7009 or placebo and pegylated interferon 2α (Peg-IFN) and ribavirin (RBV) for 28 days. Patients were then continued on Peg-IFN and RBV for an additional 44 weeks. Primary hypothesis: RVR rates for at least 1 MK-7009-treated group superior to placebo.
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Figure 5. Patient 1 (Genotype 1B). MK-7009 dose; 300mg b.i.d. Clonal resistance analysis (pie charts) was performed at the indicated time points. The red line denotes the limit of detection for the resistance sequencing assay
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Figure 6. Patient 2 (Genotype 1A). MK-7009 dose; 300mg b.i.d. Clonal resistance analysis (pie charts) was performed at the indicated time points. The red line denotes the limit of detection for the resistance sequencing assay. *D168V was also observed at in 1/4 amplicons by population sequencing at day 28. Clonal sequencing utilizes a different amplicon. As D168V was not amplified in the clonal analysis at day 28 (near the limit of detection of the assay), it is likely that D168V exists at very low levels at this time point.
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Figure 7. Patient 3 (Genotype 1A). MK-7009 dose; 600mg q.d. Clonal resistance analysis (pie charts) was performed at the indicated time points. The red line denotes the limit of detection for the resistance sequencing assay.
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Figure 8. Patient 4 (Genotype 1A). MK-7009 dose; 800mg b.i.d. Clonal resistance analysis (pie charts) was performed at the indicated time points. The red line denotes the limit of detection for the resistance sequencing assay.
Friday, December 18, 2009
Scripps Research Scientists Identify Novel Hepatitis C Inhibitors
_______________________________________________
Scripps Research Scientists Identify Novel Hepatitis C Inhibitors
December 16th, 2009
Scientists from the Scripps Florida campus of The Scripps Research Institute and their colleagues at Boston University have described their discovery of several novel drug-like inhibitors of the hepatitis C virus (HCV). These new inhibitors have the potential to substantially widen the current options to treat HCV infection.
The research, from the laboratory of Professor Donny Strosberg, Ph.D., of Scripps Florida, supported by members of the Scripps Florida Lead Discovery Division directed by Peter Hodder, Ph.D., and colleagues from Boston University, was published in the December 2009 edition of the journal ASSAY and Drug Development Technologies and appears in the December 15, 2009 print edition of the journal Bioorganic & Medicinal Chemistry Letters.
With more than 130 million people infected worldwide by HCV, new therapeutic strategies are urgently needed for this blood-borne disease, which is the main cause, with hepatitis B, of liver cancer, according to the National Cancer Institute.
Using a new fluorescence-based assay, the scientists were able to identify four small-molecule inhibitors of dimerization of the viral core protein. In this process, which is essential to the survival of the virus, the core protein binds to itself and related proteins to form the viral capsid, the outer lipid-encapsulated protein shell that protects the virus’s genetic material like an eggshell protects its yolk sack.
“The fact that is so exciting is that no one has really considered the core protein as a viable target in HCV—in HIV, yes, but not HCV,” said Strosberg. “With this study, there is now no good reason why researchers shouldn’t go after the HCV core protein.”
One of the problems in developing drugs for HCV is that it mutates at such prodigious rates; mutations in viral enzymes tend to lead to increased drug resistance.
By targeting the interactions of the core protein with itself and with other proteins, Strosberg and his colleagues have sought to reduce the problem of rapid mutation—because the core protein mutates much less than the other HCV proteins, and because mutations that affect the interface between core and itself or other proteins would be more likely to deactivate the virus anyway. Core proteins orchestrate the assembly and release of the infectious virus, as well as the disassembly of viral particles upon entering host cells.
Significantly, the new compounds not only inhibited dimerization of the core but also inhibited propagation of HCV in isolated hepatoma cells.
The New Assay
In a study that appeared in the Journal of General Virology earlier this year, Strosberg and his colleague described how peptides (molecules of two or more amino acids that are the building blocks of proteins) derived from the HCV core protein also inhibited its dimerization. Peptides however, are difficult to administer orally, unstable in the blood circulation, and are therefore difficult to use therapeutically.
The new assay goes one step further, allowing Strosberg and his colleagues to identify the three times smaller molecules with potential to interfere with the core protein function in the virus.
“While there is no similarity structurally between these new small molecule inhibitors and the peptides, functionally they behave precisely the same way,” Strosberg said. “We developed an assay to screen small molecules that is robust and capable of revealing useful compounds that block protein-protein interactions and production of the virus.”
Protein-protein interactions, which involve such key physiological actions as signal transduction and protein assembly, are highly desirable drug discovery targets, not only for HCV, but also for other viral infections because inhibitors of these protein associations have been shown to lack many clinical complications, such as the adverse side effects of recombinant therapeutic proteins. However, designing small molecules that inhibit protein-protein interaction remains problematic for a number of reasons, primarily because proteins are so large—interactions are thought to often take place over a wide area and conformation/site-selectivity is difficult to engineer.
“We always look for the simplest solution,” Strosberg said. “We knew from our peptide study that we could split the core protein and use only one part that we knew still allowed the dimerization process. That simplified the process because the core protein is sometimes difficult to work with.”
Next, Strosberg and his team uncovered a domain on the core protein—what they call “a hot spot”—that was essential for the interaction that creates the capsid and allows the virus to function.
“Since we had already established a proof-of-concept that certain peptides could disrupt capsid formation, we left the peptide world and moved into the small-molecule world,” he said. “We developed the high-throughput version of the assay. That’s what the industry always wants to know first—can you move from a peptide to a small-molecule and can you find inhibitors among screen large collections?”
From there, the team screened small-molecule compounds that could potentially disrupt the protein-protein gears that create the viral capsid, using the protein library and high-throughput screening technology available at Scripps Florida. For initial screening, Strosberg and his colleagues used a relatively small library containing nearly 2,250 indoline alkaloid-type compounds, produced by their colleagues at Boston University.
These studies revealed the four promising compounds described in the study.
“These new compounds definitely put us closer to the ‘El Dorado’ of finding viable protein-protein inhibitors for HCV,” said Strosberg.
The small molecule inhibitor study made clear that three of the newly discovered inhibitors are relatively non-toxic compounds that could be the basis for the development of new anti-HCV drugs or could be used in combination with other compounds such as interferon on HCV targets other than the virus’s core protein.
“These small-molecule candidates are quite promising,” Strosberg said. “We continue to study the binding of these compounds with the HCV core protein and hope to design even more potent inhibitors based on their structures.”
The first author of the ASSAY and Drug Development Technologies study, “A Time-Resolved Fluorescence-Resonance Energy Transfer Assay for Identifying Inhibitors of Hepatitis C Virus Core Dimerization,” is Smitha Kota of The Scripps Research Institute. In addition to Strosberg, others authors include, Louis Scampavia, Timothy Spicer, Virginia Takahashi, and Peter Hodder of The Scripps Research Institute, and Aaron Beeler, John Snyder and John Porco of The Center for Chemical Methodology and Library Development, Boston University.
The first author of the Bioorganic & Medicinal Chemistry Letters study, “New Small Molecule Inhibitors of Hepatitis C Virus,” is Wanguo Wei of The Center for Chemical Methodology and Library Development, Boston University; the corresponding author is John K. Snyder, also of Boston University. In addition to Strosberg, other authors include Smitha Kota and Virginia Takahashi of The Scripps Research Institute; and Cuifang Cai of Boston University.
Both studies were supported by The Scripps Research Institute, the Factor Foundation of America, the National Institute of General Medical Sciences, and other funding from the National Institutes of Health.
Scripps Research Scientists Identify Novel Hepatitis C Inhibitors
December 16th, 2009
Scientists from the Scripps Florida campus of The Scripps Research Institute and their colleagues at Boston University have described their discovery of several novel drug-like inhibitors of the hepatitis C virus (HCV). These new inhibitors have the potential to substantially widen the current options to treat HCV infection.
The research, from the laboratory of Professor Donny Strosberg, Ph.D., of Scripps Florida, supported by members of the Scripps Florida Lead Discovery Division directed by Peter Hodder, Ph.D., and colleagues from Boston University, was published in the December 2009 edition of the journal ASSAY and Drug Development Technologies and appears in the December 15, 2009 print edition of the journal Bioorganic & Medicinal Chemistry Letters.
With more than 130 million people infected worldwide by HCV, new therapeutic strategies are urgently needed for this blood-borne disease, which is the main cause, with hepatitis B, of liver cancer, according to the National Cancer Institute.
Using a new fluorescence-based assay, the scientists were able to identify four small-molecule inhibitors of dimerization of the viral core protein. In this process, which is essential to the survival of the virus, the core protein binds to itself and related proteins to form the viral capsid, the outer lipid-encapsulated protein shell that protects the virus’s genetic material like an eggshell protects its yolk sack.
“The fact that is so exciting is that no one has really considered the core protein as a viable target in HCV—in HIV, yes, but not HCV,” said Strosberg. “With this study, there is now no good reason why researchers shouldn’t go after the HCV core protein.”
One of the problems in developing drugs for HCV is that it mutates at such prodigious rates; mutations in viral enzymes tend to lead to increased drug resistance.
By targeting the interactions of the core protein with itself and with other proteins, Strosberg and his colleagues have sought to reduce the problem of rapid mutation—because the core protein mutates much less than the other HCV proteins, and because mutations that affect the interface between core and itself or other proteins would be more likely to deactivate the virus anyway. Core proteins orchestrate the assembly and release of the infectious virus, as well as the disassembly of viral particles upon entering host cells.
Significantly, the new compounds not only inhibited dimerization of the core but also inhibited propagation of HCV in isolated hepatoma cells.
The New Assay
In a study that appeared in the Journal of General Virology earlier this year, Strosberg and his colleague described how peptides (molecules of two or more amino acids that are the building blocks of proteins) derived from the HCV core protein also inhibited its dimerization. Peptides however, are difficult to administer orally, unstable in the blood circulation, and are therefore difficult to use therapeutically.
The new assay goes one step further, allowing Strosberg and his colleagues to identify the three times smaller molecules with potential to interfere with the core protein function in the virus.
“While there is no similarity structurally between these new small molecule inhibitors and the peptides, functionally they behave precisely the same way,” Strosberg said. “We developed an assay to screen small molecules that is robust and capable of revealing useful compounds that block protein-protein interactions and production of the virus.”
Protein-protein interactions, which involve such key physiological actions as signal transduction and protein assembly, are highly desirable drug discovery targets, not only for HCV, but also for other viral infections because inhibitors of these protein associations have been shown to lack many clinical complications, such as the adverse side effects of recombinant therapeutic proteins. However, designing small molecules that inhibit protein-protein interaction remains problematic for a number of reasons, primarily because proteins are so large—interactions are thought to often take place over a wide area and conformation/site-selectivity is difficult to engineer.
“We always look for the simplest solution,” Strosberg said. “We knew from our peptide study that we could split the core protein and use only one part that we knew still allowed the dimerization process. That simplified the process because the core protein is sometimes difficult to work with.”
Next, Strosberg and his team uncovered a domain on the core protein—what they call “a hot spot”—that was essential for the interaction that creates the capsid and allows the virus to function.
“Since we had already established a proof-of-concept that certain peptides could disrupt capsid formation, we left the peptide world and moved into the small-molecule world,” he said. “We developed the high-throughput version of the assay. That’s what the industry always wants to know first—can you move from a peptide to a small-molecule and can you find inhibitors among screen large collections?”
From there, the team screened small-molecule compounds that could potentially disrupt the protein-protein gears that create the viral capsid, using the protein library and high-throughput screening technology available at Scripps Florida. For initial screening, Strosberg and his colleagues used a relatively small library containing nearly 2,250 indoline alkaloid-type compounds, produced by their colleagues at Boston University.
These studies revealed the four promising compounds described in the study.
“These new compounds definitely put us closer to the ‘El Dorado’ of finding viable protein-protein inhibitors for HCV,” said Strosberg.
The small molecule inhibitor study made clear that three of the newly discovered inhibitors are relatively non-toxic compounds that could be the basis for the development of new anti-HCV drugs or could be used in combination with other compounds such as interferon on HCV targets other than the virus’s core protein.
“These small-molecule candidates are quite promising,” Strosberg said. “We continue to study the binding of these compounds with the HCV core protein and hope to design even more potent inhibitors based on their structures.”
The first author of the ASSAY and Drug Development Technologies study, “A Time-Resolved Fluorescence-Resonance Energy Transfer Assay for Identifying Inhibitors of Hepatitis C Virus Core Dimerization,” is Smitha Kota of The Scripps Research Institute. In addition to Strosberg, others authors include, Louis Scampavia, Timothy Spicer, Virginia Takahashi, and Peter Hodder of The Scripps Research Institute, and Aaron Beeler, John Snyder and John Porco of The Center for Chemical Methodology and Library Development, Boston University.
The first author of the Bioorganic & Medicinal Chemistry Letters study, “New Small Molecule Inhibitors of Hepatitis C Virus,” is Wanguo Wei of The Center for Chemical Methodology and Library Development, Boston University; the corresponding author is John K. Snyder, also of Boston University. In addition to Strosberg, other authors include Smitha Kota and Virginia Takahashi of The Scripps Research Institute; and Cuifang Cai of Boston University.
Both studies were supported by The Scripps Research Institute, the Factor Foundation of America, the National Institute of General Medical Sciences, and other funding from the National Institutes of Health.
Preliminary Phase 1b Proof of Concept Data With ACH-1625 to Treat Hepatitis C
Achillion Announces Positive Preliminary Phase 1b Proof of Concept Data With ACH-1625 to Treat Hepatitis C
Achieves 3.94 log10 Reduction in HCV RNA With Continued Safety and Tolerability
NEW HAVEN, Conn., Dec 15, 2009 -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today reported proof of concept data from the preliminary results of its phase 1b clinical trial of ACH-1625, demonstrating that treatment with ACH-1625 achieved a mean 3.94 log10 reduction in HCV RNA after five-day monotherapy, with continued good safety and tolerability in patients with hepatitis C (HCV). ACH-1625 is an inhibitor of HCV NS3 protease that was discovered and is being developed by Achillion.
The Phase 1 Program
In June 2009, Achillion initiated dosing in a randomized, double-blind, placebo-controlled phase 1a/1b clinical trial to investigate the safety, tolerability, pharmacokinetic profile and antiviral activity of ACH-1625 after single and multiple ascending oral doses in healthy volunteers and oral repeat doses for 5 days in subjects with hepatitis C infection. The trial is taking place in Europe and will enroll at least 54 subjects, including both healthy volunteers and HCV-infected patients.
In September 2009, Achillion announced positive results from the phase 1a segment of the study. Subjects in the phase 1a single ascending dose (SAD) segment of the study received single doses of ACH-1625 ranging from 50 mg to 2000 mg. Subjects in the phase 1a multiple ascending dose (MAD) segment of the study received 5 days of ACH-1625 up to a maximal dose of 2000 mg per day.
Preliminary data from the SAD and MAD trial segments demonstrated ACH-1625 was well tolerated at all doses and there were no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. All reported adverse events were classified as mild or moderate, were transient and showed no apparent dose relationship.
Proof-of-Concept Results
Today, Achillion announced proof of concept data from the preliminary results of the phase 1b segment of the study. Subjects in this first dosing cohort of HCV-infected patients received doses of 600 mg BID (n=9, randomized to 6 active drug, 3 placebo). Preliminary results showed that a mean reduction in viral load of 3.94 log10 was achieved in the treatment group, as compared to a mean reduction of 0.22 log10 in the placebo group. All subjects in the treatment group had viral load decline between 3.0 and 4.5 log10, and two subjects reached undetectable levels of HCV RNA. Safety results from this dosing group were similar to those observed in the phase 1a segment of the trial. There were no serious adverse events, no clinically significant changes in vital signs, ECGs, or laboratory evaluations. All reported adverse events were classified as mild or moderate, were transient and showed no apparent dose relationship.
Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 2.0 log10 from baseline through day 12, the last day of viral load measurement in the study.
Preliminary analysis of viral dynamics of ACH-1625 demonstrates a very rapid reduction in HCV RNA levels after the first dose. ACH-1625 displays high efficiency for inhibition of viral production, with mean efficiency of 0.9994 out of maximal efficiency of 1.0000.
"In addition to the dramatic reduction in viral load after 5 days of monotherapy, ACH-1625 demonstrates slow viral rebound, which is an important differentiating characteristic, as this continued suppression of viral load after discontinuation of the drug may translate into a more durable antiviral response," noted Dr. Elizabeth Olek, Chief Medical Officer at Achillion. "These positive proof-of-concept results corroborate our findings from pre-clinical studies with ACH-1625, which demonstrated high potency, unique pharmacokinetic properties, and an excellent safety profile."
Michael Kishbauch, President and Chief Executive Officer of Achillion, commented on the positive results, "These compelling interim results are very encouraging as we continue to advance the clinical development of this compound for the treatment of HCV. Not only are the results especially robust, but they give us proof-of-concept ahead of schedule. This is a credit to our top-notch research and development team, which deserves recognition for its scientific excellence and tireless efforts."
"We look forward to sharing additional data from the next cohort of the phase 1b study in early January 2010, when we plan to host an investor conference call to review both segments of the phase 1 trial, in addition to updates on other Achillion progress. In addition, we expect to present the full data set from the phase 1a and phase 1b study at the upcoming EASL (European Association for the Study of Liver Disease) meeting in April 2010 in Vienna," concluded Mr. Kishbauch.
About ACH-1625
ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50 ~1nM.
About HCV
The hepatitis C virus (HCV) is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease -- hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration; Achillion's expectations regarding timing and duration of other clinical trials, including cohort 6. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are: uncertainties relating to results of clinical trials, unexpected regulatory actions or delays, and Achillion's ability to obtain additional funding required to conduct its research, development and commercialization activities. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2008.
All forward-looking statements reflect Achillion's expectations only as of the date of this release and should not be relied upon as reflecting Achillion's views, expectations or beliefs at any date subsequent to the date of this release. Achillion anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Achillion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.
ACHN-G
This news release was distributed by GlobeNewswire, www.globenewswire.com
SOURCE: Achillion Pharmaceuticals, Inc.
CONTACT: Achillion Pharmaceuticals, Inc.
Mary Kay Fenton
(203) 624-7000
mfenton@achillion.com
Lippert/Heilshorn & Associates, Inc.
Investors:
Anne Marie Fields
(212) 838-3777
afields@lhai.com
Bruce Voss
(310) 691-7100
bvoss@lhai.com
Media:
Megan Rusnack
(212) 838-3777
mrusnack@lhai.com
Achieves 3.94 log10 Reduction in HCV RNA With Continued Safety and Tolerability
NEW HAVEN, Conn., Dec 15, 2009 -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today reported proof of concept data from the preliminary results of its phase 1b clinical trial of ACH-1625, demonstrating that treatment with ACH-1625 achieved a mean 3.94 log10 reduction in HCV RNA after five-day monotherapy, with continued good safety and tolerability in patients with hepatitis C (HCV). ACH-1625 is an inhibitor of HCV NS3 protease that was discovered and is being developed by Achillion.
The Phase 1 Program
In June 2009, Achillion initiated dosing in a randomized, double-blind, placebo-controlled phase 1a/1b clinical trial to investigate the safety, tolerability, pharmacokinetic profile and antiviral activity of ACH-1625 after single and multiple ascending oral doses in healthy volunteers and oral repeat doses for 5 days in subjects with hepatitis C infection. The trial is taking place in Europe and will enroll at least 54 subjects, including both healthy volunteers and HCV-infected patients.
In September 2009, Achillion announced positive results from the phase 1a segment of the study. Subjects in the phase 1a single ascending dose (SAD) segment of the study received single doses of ACH-1625 ranging from 50 mg to 2000 mg. Subjects in the phase 1a multiple ascending dose (MAD) segment of the study received 5 days of ACH-1625 up to a maximal dose of 2000 mg per day.
Preliminary data from the SAD and MAD trial segments demonstrated ACH-1625 was well tolerated at all doses and there were no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. All reported adverse events were classified as mild or moderate, were transient and showed no apparent dose relationship.
Proof-of-Concept Results
Today, Achillion announced proof of concept data from the preliminary results of the phase 1b segment of the study. Subjects in this first dosing cohort of HCV-infected patients received doses of 600 mg BID (n=9, randomized to 6 active drug, 3 placebo). Preliminary results showed that a mean reduction in viral load of 3.94 log10 was achieved in the treatment group, as compared to a mean reduction of 0.22 log10 in the placebo group. All subjects in the treatment group had viral load decline between 3.0 and 4.5 log10, and two subjects reached undetectable levels of HCV RNA. Safety results from this dosing group were similar to those observed in the phase 1a segment of the trial. There were no serious adverse events, no clinically significant changes in vital signs, ECGs, or laboratory evaluations. All reported adverse events were classified as mild or moderate, were transient and showed no apparent dose relationship.
Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 2.0 log10 from baseline through day 12, the last day of viral load measurement in the study.
Preliminary analysis of viral dynamics of ACH-1625 demonstrates a very rapid reduction in HCV RNA levels after the first dose. ACH-1625 displays high efficiency for inhibition of viral production, with mean efficiency of 0.9994 out of maximal efficiency of 1.0000.
"In addition to the dramatic reduction in viral load after 5 days of monotherapy, ACH-1625 demonstrates slow viral rebound, which is an important differentiating characteristic, as this continued suppression of viral load after discontinuation of the drug may translate into a more durable antiviral response," noted Dr. Elizabeth Olek, Chief Medical Officer at Achillion. "These positive proof-of-concept results corroborate our findings from pre-clinical studies with ACH-1625, which demonstrated high potency, unique pharmacokinetic properties, and an excellent safety profile."
Michael Kishbauch, President and Chief Executive Officer of Achillion, commented on the positive results, "These compelling interim results are very encouraging as we continue to advance the clinical development of this compound for the treatment of HCV. Not only are the results especially robust, but they give us proof-of-concept ahead of schedule. This is a credit to our top-notch research and development team, which deserves recognition for its scientific excellence and tireless efforts."
"We look forward to sharing additional data from the next cohort of the phase 1b study in early January 2010, when we plan to host an investor conference call to review both segments of the phase 1 trial, in addition to updates on other Achillion progress. In addition, we expect to present the full data set from the phase 1a and phase 1b study at the upcoming EASL (European Association for the Study of Liver Disease) meeting in April 2010 in Vienna," concluded Mr. Kishbauch.
About ACH-1625
ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50 ~1nM.
About HCV
The hepatitis C virus (HCV) is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease -- hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
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Maintenance Therapy
Hepatitis C Articles (HCV)
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Effect of HCV RNA Suppression During Peginterferon Alfa-2a Maintenance Therapy on Clinical Outcomes in the HALT-C Trial -- full text pdf of published study attached
Download the PDF here
Gastroenterology Dec 2009
from Jules: I know of some patients who achieved undetectable HCV RNA, had an end of treatment response but relapsed or had breakthrough. These patients could have cirrhosis, advanced disease or coinfection making them more suscetible to progression to decompensation or increased risk for developing cancer one day, so should they consider maintenance full-dose peg/rbv therapy now or are they better off waiting until the first oral HCV protease comes out in 2011 to use in triple therapy. The data is I recall once a patient has compensated cirrhosis there is a 1-3 or 4% risk of progressing to decompensation per year, so a consideration I guess is how long the patient has had cirrhosis and is it worth just waiting until 2011 mid-2011 I think, or is the risk of progression over the next 1.5 years too great to wait. Or one could use full dose peg/rbv therapy now and then restart therapy again in 2011 with triple therapy, but as some would say is it worth going through the difficulties of peg/rbv therapy for another year until triple is available, and a number of clinicians would say NO, wait for triple. The authors raise the idea that for patients that are unable to achieve cure with future therapy of only oral drugs perhaps maintenance therapy may have application.
"Our results demonstrate that viral suppression with standard doses of peginterferon and ribavirin during the 24-week lead-in phase was associated with a significant reduction in clinical outcomes during the ensuing 3.5 years regardless of whether patients received maintenance peginterferon therapy or not. Several previous studies have suggested that patients who are treated with even a single, brief course of interferon-based therapy have a reduction in HCC and improved mortality.10, 11 The present study also suggests that profound viral suppression, even for a relatively brief period of time, is associated with clinical benefit."....."Data from the HALT-C trial suggest that, if such patients could be kept HCV RNA undetectable on half-dose peginterferon maintenance therapy for 3.5 years, an SVR of approximately 52% could be achieved."......."The results of this analysis lay the foundation for future studies of maintenance therapy, not with peginterferon, but with potent oral protease and polymerase inhibitors of HCV"
"this analysis has demonstrated that profound viral suppression by more than 4 logs10 with full-dose peginterferon and ribavirin was associated with a significant decline in clinical outcomes over the next 3.5 years. Continuing half-dose peginterferon-alfa 2a as maintenance therapy did not affect the development of clinical outcomes regardless of the degree of viral suppression achieved during the lead-in phase. This analysis confirms that no rationale exists for maintenance peginterferon therapy among patients in whom HCV RNA cannot be suppressed to undetectable levels. Our data did show, however, that an SVR of approximately 50% was achieved in the few patients who became HCV RNA undetectable during the lead-in phase, experienced breakthrough or relapse, and then remained persistently HCV RNA negative during maintenance peginterferon for 3.5 years."
from Jules: As I have previously reported, these results were presented at AASLD Nov 2009, wherein I discussed that 2 yrs ago HALT-C investigators reported at AASLD maintenance therapy did not improve outcomes, I asked but they would not share the sklides, they published. Then at EASL they reported a 4 log viral load reduction may have benefit but data was early, I took pics of slides and reported it. Now at this recent AASLD they reported this data in the link, and subsequently publish this report in Gastroenterology. I reported from the beginning that the initial HALT-C data finding no benefit to maintenance therapy did not appear believable and there were problems with the study design, but they had told the world after AASLD 2 yrs ago that maintenance therapy did not work, so many patients and clinicians stopped using it, although not all. They misled the community, the study was not well designed so as to be able to properly explore the potential benefits of maintenance therapy, as I reported 2 yrs ago, and now they report this, I still maintain the study design may not have been able to identify other benefits from maintenance therapy, you can't find what you don't study!
AASLD: SVR Improves Survival, Risk for Liver Cancer, Decompensated Liver Disease and Liver Transplant/Death - Also, Transient Viral Suppression (breakthroughs/relapsers) Improves Clinical Outcomes Too - (11/09/09)
HALT-C Trial GroupMitchell L. ShiffmanCorresponding Author Informationemail address, Chihiro Morishima, Jules L. Dienstag¤, Karen L. Lindsay, John C. Hoefs, William M. Lee, Elizabeth C. Wright, Deepa Naishadham, Gregory T. Everson, Anna S. Lok, Adrian M. Di Bisceglie, Herbert L. Bonkovsky##, Marc G. Ghany
Received 15 April 2009; accepted 31 August 2009. published online 11 September 2009.
ABSTRACT
Background & Aims
The Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial demonstrated that low-dose peginterferon maintenance therapy was ineffective in preventing clinical outcomes in patients with chronic hepatitis C, advanced fibrosis, and failure to achieve a sustained virologic response during lead-in phase treatment with standard dose peginterferon/ribavirin. This analysis was performed to determine whether suppressing HCV RNA during the trial was associated with a reduction in clinical outcomes.
Methods
Seven hundred sixty-four patients treated during the lead-in phase of HALT-C trial were randomized to either peginterferon alfa-2a (90 µg/week) maintenance therapy or no treatment (control) for 3.5 years. Clinical outcomes included an increase in Child-Turcotte-Pugh score, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, hepatocellular carcinoma, and mortality.
Results
During the lead-in, ≥4-log10 decline in serum HCV RNA occurred in 178 patients; 82% of whom lost detectable HCV RNA and later broke through or relapsed. These patients had significantly (P = .003) fewer clinical outcomes whether randomized to maintenance therapy or control. Following randomization, serum HCV RNA increased significantly in all 90 control patients and in 58 of 88 receiving maintenance therapy. Only 30 patients had persistent suppression of HCV RNA by ≥4 log10 during maintenance therapy. No significant reduction in clinical outcomes was observed in these patients.
Conclusions
Viral suppression by ≥4 log10 with full-dose peginterferon/ribavirin is associated with a significant reduction in clinical outcomes. Continuing low-dose peginterferon maintenance therapy, even in patients with persistent viral suppression, does not lead to a further decline in clinical outcomes.
Discussion
The HALT-C trial was a prospective, randomized controlled study designed to determine whether continuing peginterferon alfa-2a at a dose of 90 µg/week over 3.5 years could reduce complications of cirrhosis, HCC, and mortality in patients with chronic hepatitis C and advanced bridging fibrosis or cirrhosis who had failed to achieve an SVR following treatment with peginterferon and ribavirin. Unfortunately, no overall reduction in any of these clinical end points was achieved.14 The results of 2 similar studies, Colchicine Versus Pegintron Long-term Therapy (CO-PILOT) and Evaluation of Pegintron in Control of Hepatitis C Cirrhosis (EPIC),3 were also reported recently.18, 19 In the CO-PILOT trial, no lead-in treatment phase preceded randomization; patients with advanced fibrosis or cirrhosis who were nonresponders to either standard or peginterferon with or without ribavirin were randomized to receive either peginterferon alfa-2b at a dose of 0.5 µg/kg/week or colchicine for 4 years. The study design of the EPIC3 trial was similar to that of the HALT-C trial; subjects entered a lead-in treatment phase of peginterferon alfa-2b and weight-based ribavirin after which nonresponders were randomized to receive either peginterferon alfa-2b at a dose of 0.5 µg/kg/week or no treatment for up to 3 years. Despite differences in study design, the results of the CO-PILOT and EPIC3 trials were very similar to those observed in the HALT-C trial; no overall benefit of peginterferon maintenance therapy was observed. In EPIC,3 a significant reduction in variceal bleeding was observed in the subset of patients with esophageal varices suggesting that peginterferon may affect portal pressure. A recent substudy of the HALT-C trial has demonstrated that peginterferon alfa-2a 90 µg/week lowers portal pressure in patients with a baseline portal hypertension and esophageal varices.20 However, maintenance therapy in the HALT-C trial was not associated with a reduction in variceal hemorrhage.
Before these 3 large trials of maintenance therapy were initiated, a preliminary study of maintenance therapy with standard interferon alfa-2b (3 mU 3 times weekly) did suggest that a maintenance approach might be effective.12 In that study, however, only patients who achieved a histologic response (defined as a 50% decline in the hepatic inflammation score) after 6 months of interferon therapy were eligible for enrollment. This improvement in liver inflammation was associated with a marked decline in serum HCV RNA level.9, 12 Continuing interferon in these patients maintained both histologic improvement and suppression of serum HCV RNA. Stopping interferon was associated with a rapid rise in serum HCV RNA back to the pretreatment baseline and a worsening in hepatic inflammation scores. Unlike the HALT-C, CO-PILOT, or EPIC3 trials, the majority of patients in this preliminary study did not have advanced fibrosis or cirrhosis, the trial lasted only 2 years, and the impact of treatment on morbidity and mortality was not assessed.
The study designs of the 3 large maintenance therapy trials did not require either prior histologic or virologic responses as criteria for inclusion. In addition, the dose of peginterferon in these trials (half-dose peginterferon alfa-2a and one third the standard dose of peginterferon alfa-2b) was selected based on tolerability over an extended treatment duration, not efficacy in achieving HCV RNA suppression. Only 23% of patients enrolled in the HALT-C trial had profound viral suppression (a ≥4-log10 decline in serum HCV RNA level) with full-dose peginterferon and ribavirin during the lead-in phase, and only 30 (8%) patients maintained profound viral suppression during maintenance therapy. Serum levels of HCV RNA were not assessed in the CO-PILOT trial, and data on viral suppression during the EPIC3 trial are not currently available. Thus, although the primary analysis of the HALT-C, CO-PILOT, and EPIC3 trials demonstrated that peginterferon maintenance therapy provided no overall benefit to patients with chronic hepatitis C, none of these studies was designed to address whether profound viral suppression with maintenance peginterferon therapy to keep HCV RNA undetectable or near undetectable had the potential to prevent complications of advanced hepatic fibrosis.
The present analysis was performed to investigate the relationship between viral suppression and outcomes during the HALT-C trial. Our results demonstrate that viral suppression with standard doses of peginterferon and ribavirin during the 24-week lead-in phase was associated with a significant reduction in clinical outcomes during the ensuing 3.5 years regardless of whether patients received maintenance peginterferon therapy or not. Several previous studies have suggested that patients who are treated with even a single, brief course of interferon-based therapy have a reduction in HCC and improved mortality.10, 11 The present study also suggests that profound viral suppression, even for a relatively brief period of time, is associated with clinical benefit.
Data from the present analysis also demonstrated that over half the patients with profound viral suppression during standard dose peginterferon/ribavirin could not maintain this virologic response when ribavirin was stopped and the peginterferon dose was reduced by half. The rate of liver-related outcomes observed in these patients was similar to that observed for patients who also achieved profound virologic suppression during the lead-in phase and were randomized to stop treatment (4.3% vs 5.6%, respectively). Only 30 patients had persistent suppression of HCV RNA by ≥4 log10 with half-dose peginterferon maintenance therapy. Although a complication of cirrhosis developed in only 1 of these patients (3.3%), the number of patients was not sufficient to demonstrate with any confidence that persistent suppression of HCV RNA, even to undetectable levels, was associated with a reduction in clinical outcomes.
The few patients in this study who appeared to benefit the most from peginterferon maintenance therapy were the ones who responded to full-dose peginterferon and ribavirin during the lead-in phase but experienced either breakthrough or relapse. As has been well established, the relapse rate after antiviral therapy for chronic hepatitis C is inversely proportional to the rapidity with which HCV RNA becomes undetectable during treatment.21, 22 The vast majority of patients who relapse do not lose detectable HCV RNA until they have received 12-24 weeks of treatment. Several recent studies have demonstrated that continuing peginterferon and ribavirin for a longer duration, up to 72 weeks, in patients with genotype 1 and delayed clearance of HCV RNA can reduce relapse and increase SVR significantly.23, 24 Unfortunately, many patients with advanced fibrosis or cirrhosis are unable to tolerate prolonged treatment with full doses of peginterferon and ribavirin. Data from the HALT-C trial suggest that, if such patients could be kept HCV RNA undetectable on half-dose peginterferon maintenance therapy for 3.5 years, an SVR of approximately 52% could be achieved.
The results of this analysis lay the foundation for future studies of maintenance therapy, not with peginterferon, but with potent oral protease and polymerase inhibitors of HCV. Several such agents are currently in various phases of development and, when combined with peginterferon and ribavirin, yield SVR rates that are significantly higher than those observed with peginterferon and ribavirin alone.25, 26, 27 Despite promising results with these agents, all patients with chronic hepatitis C are unlikely to be cured with a combination of 1 or more oral HCV inhibitors plus peginterferon and ribavirin in the future. Thus, a group of patients with advanced fibrosis or cirrhosis will eventually require multidrug antiviral regimens to achieve long-term suppression of HCV RNA. Whether such patients could achieve an SVR with multidrug oral agents without peginterferon remains to be determined.
In summary, this analysis has demonstrated that profound viral suppression by more than 4 logs10 with full-dose peginterferon and ribavirin was associated with a significant decline in clinical outcomes over the next 3.5 years. Continuing half-dose peginterferon-alfa 2a as maintenance therapy did not affect the development of clinical outcomes regardless of the degree of viral suppression achieved during the lead-in phase. This analysis confirms that no rationale exists for maintenance peginterferon therapy among patients in whom HCV RNA cannot be suppressed to undetectable levels. Our data did show, however, that an SVR of approximately 50% was achieved in the few patients who became HCV RNA undetectable during the lead-in phase, experienced breakthrough or relapse, and then remained persistently HCV RNA negative during maintenance peginterferon for 3.5 years.
Results
Patient Groups
Table 1 summarizes the clinical, biochemical, virologic, and histologic characteristics of the HALT-C trial patients included in this analysis grouped by randomization status to the maintenance therapy arm or control arm. All patients received 24 weeks of peginterferon and ribavirin during the lead-in phase, prior to randomization; 618 had detectable HCV RNA in serum at week 20 and were classified as nonresponders, and 146 had undetectable HCV RNA in serum at week 20 and entered the HALT-C trial only after breakthrough developed (n = 30) or they relapsed (n = 116). The mean duration of peginterferon and ribavirin in the breakthrough/relapse group was 48 weeks. The features of these 764 patients were not significantly different from those of the entire HALT-C trial cohort.14
Figure 1 illustrates mean serum HCV RNA levels during the lead-in phase and after randomization throughout the HALT-C trial for patients with nonresponse or breakthrough/relapse. Of the 618 nonresponders who entered the trial, 261 were still being followed in the maintenance group and 253 in the control group by month 42. Nonresponders had a mean decline in serum HCV RNA of 1.5-log10 IU/mL by the end of the 20-week lead-in phase (Figure 1A). In patients randomized to stop therapy, the mean serum HCV RNA level returned to the pretreatment baseline. Patients randomized to remain on peginterferon maintenance therapy had a significant reduction in serum HCV RNA levels compared with the control group (P < .0001); however, this reduction was only 0.56-log10 IU/mL (95% confidence interval [CI]: 0.50-0.63) below the pretreatment baseline. Patients with breakthrough/relapse (n = 146) had undetectable HCV RNA in serum by week 20 in the lead-in phase and remained on peginterferon and ribavirin until either breakthrough viremia developed before week 48 or HCV RNA reappeared in serum after completing treatment. These patients were randomized at variable times after the initiation of treatment depending on the time of HCV RNA recurrence. Forty-two months after randomization, 73 patients remained in the control group and 59 patients in the maintenance therapy group. With breakthrough or relapse, the level of serum HCV RNA increased to a mean of log10 6.0 IU/mL at the time of randomization. Breakthrough/relapse patients randomized to stop treatment had a further increase in serum HCV RNA back toward pretreatment baseline levels (Figure 1B). In contrast, patients with breakthrough or relapse who initiated peginterferon maintenance therapy had a decline in mean serum HCV RNA level that averaged 2.5 logs10 (95% CI: 2.21-2.78) below the pretreatment baseline throughout the maintenance phase. This decline was significantly different than the change in serum HCV RNA level in the breakthrough/relapse patients randomized to stop treatment (P < .0001). During the 3.5 years of maintenance therapy, the mean serum HCV RNA level drifted up gradually relative to the pretreatment baseline from a nadir of log10 -2.9 to -2.2 (P = .0001).
Change in HCV RNA During the Lead-In Phase and Impact on Outcomes
Figure 2 illustrates the distribution of virologic responses observed during the lead-in phase. Compared with their pretreatment baseline levels, 56% of patients had a <2-log10 decline in serum HCV RNA with full-dose peginterferon and ribavirin; 21% had a 2 to <4-log10 decline, and 23% had a ≥4-log10 reduction. Among patients with a ≥4-log10 decline in serum HCV RNA, 82% were in the breakthrough/relapse group and had undetectable HCV RNA at week 20.
Figure 3 illustrates clinical outcomes after randomization according to the decline in serum HCV RNA during the lead-in phase. A significant (P = .003) reduction in clinical outcomes was observed with increasing degrees of viral suppression (Figure 3A). Clinical outcomes developed in 21% of patients with <2-log10 decline in serum HCV RNA during the lead-in phase (95% CI: 17%-24%); 18% (95% CI: 12%-24%) of patients with a 2 to <4-log10 decline, and 8% (95% CI: 4%-12%) of patients with ≥4-log10 decline. Clinical outcomes also developed in 8% of the 146 patients with undetectable HCV RNA at the end of the lead-in phase (a subset of the 178 patients with ≥4-log decline in HCV RNA). This decline in the 3.5-year incidence of clinical outcomes was not significantly different between the control and maintenance therapy groups (P = .56). No effect of viral suppression during the lead-in phase was observed on histologic outcome (Figure 3B). Overall, a ≥2-point increase in fibrosis score on follow-up liver biopsy was observed in 24% and 33% of control and maintenance patients, respectively, regardless of the degree of viral suppression (P = .38). In patients with undetectable HCV RNA at the end of the lead-in phase, fibrosis progression was also observed in 23% and 28% of control and maintenance patients, respectively (P = .88).
Change in HCV RNA With Maintenance Peginterferon and Impact on Outcomes
Patients randomized to the control group had a rapid return in serum HCV RNA back to their pretreatment baseline regardless of their viral response during the lead-in phase (Figure 1). Figure 4 illustrates the impact of continuing peginterferon maintenance therapy, at a reduced dose of 90 µg/week, on viral suppression. Over 97% (204/210) of patients with <2-log10 decline in serum HCV RNA during the lead-in phase had <2-log10 decline during the maintenance phase. In patients with a 2 to <4-log10 decline in HCV RNA during the lead-in phase, 86% had <2-log10 decline in HCV RNA during the maintenance phase. In patients with ≥4-log10 decline in serum HCV RNA during the lead-in phase, over half (46/88) could not maintain viral suppression with half-dose peginterferon and failed to maintain HCV RNA at levels <2 logs10 below their pretreatment baseline. Only 30 of 88 (34%) patients continued to have marked viral suppression by ≥4 logs10 below their pretreatment baseline levels during the maintenance phase, and all but 1 of these maintained HCV RNA levels <10,000 IU/mL. These 30 patients accounted for 43% of the 69 patients who had undetectable HCV RNA at the end of the lead-in phase.
Figure 5 illustrates clinical and histologic outcomes as a function of the decline in serum HCV RNA during peginterferon maintenance therapy. Overall, no significant impact was observed in clinical outcomes regardless of the degree of viral suppression. Although the lowest frequency of clinical outcomes (13%) was observed in patients who maintained a ≥4-log10 decline in serum HCV RNA, this was not significantly different (P = .74) than that observed in patients with <4-log10 decline in serum HCV RNA during maintenance therapy (18%-23%). Similar results were obtained when clinical outcomes were evaluated with respect to the mean absolute level of HCV RNA during maintenance therapy. Clinical outcomes developed in 17% of patients with a mean serum HCV RNA of >100,000 IU/mL, 29% with a mean serum HCV RNA of 100,000-1000 IU/mL, and 18% with a mean serum HCV RNA of <1000 IU/mL. No significant impact of viral suppression was observed on fibrosis progression (P = .80). A histologic outcome was observed in 29% (95% CI: 22%-37%) of patients with <2-log10 decline in serum HCV RNA and in 25% (95% CI: 6%-44%) of patients with >4-log10 decline in HCV RNA during maintenance therapy. Fibrosis progression was observed in 30% of patients when HCV RNA was suppressed to <1000 IU/mL during maintenance therapy.
Table 2 summarizes clinical outcomes that developed in patients who achieved a ≥4-log10 decline in serum HCV RNA during the lead-in phase and various degrees of viral suppression during maintenance therapy. Because achieving a ≥4-log10 reduction in serum HCV RNA level during the lead-in phase was associated with significantly reduced outcomes during the maintenance phase, the clinical outcomes in patients who achieved this profound virologic suppression but were randomized to the control group were also examined. Patients with clinical complications of liver disease and liver-related mortality were separated from those in whom the trial end point reached was only an increase in CTP score without a discrete clinical complication and from patients with non-liver-related death. Patients with a clinical complication of liver disease were included in the liver-complication category even if they also had a CTP score increase or a non-liver-related death. Overall, complications of liver disease developed in 5.5% of patients with a ≥4-log decline in serum HCV RNA during the lead-in phase who were then randomized to stop treatment and in 4.3% of patients without viral suppression (serum HCV RNA remained <2 logs10 below the pretreatment baseline) despite receiving peginterferon maintenance therapy. A clinical complication of liver disease developed in only 1 of 30 patients (3.3%) who experienced viral suppression by ≥4 logs10 during both the lead-in phase and maintenance therapy. This single patient had undetectable HCV RNA at the end of the lead-in phase and during maintenance therapy. Patients who lost detectable HCV RNA during the lead-in phase with subsequent breakthrough/relapse were treated for 48 weeks (Figure 1). Clinical outcomes developed in 7.5% (11/146) of these patients vs 3 of 32 (9.3%) patients who had a >4-log decline in HCV RNA but failed to clear HCV RNA and were treated for only 24 weeks (P = .81).
Of the 69 patients with undetectable HCV RNA at the end of the lead-in phase, 25 were repeatedly (more than 3/7 values between months 12 and 48) HCV RNA undetectable during maintenance therapy. Thirteen (52%) of these patients achieved an SVR, and 5 (20%) relapsed when peginterferon alfa was discontinued after 3.5 years. The remaining patients experienced breakthrough viremia or dropped out of the trial while on maintenance therapy.
Patients and Methods
Patients and Study Design
The design of the HALT-C trial has been described previously.13 Briefly, 1050 subjects with bridging fibrosis or cirrhosis (Ishak fibrosis score, 3-6) who were nonresponders to prior treatment with interferon (with or without ribavirin) were re-treated with standard dose peginterferon alfa-2a and ribavirin. Subjects with detectable HCV RNA at week 20 were defined as nonresponders and randomized to receive either 90 µg/week of peginterferon alfa-2a as maintenance therapy or to stop treatment and be followed as the control group. Subjects with undetectable HCV RNA at treatment week 20 received up to 48 weeks of peginterferon and ribavirin. The SVR rate achieved in this population (18%) was previously reported.15 Patients in whom virologic breakthrough occurred after week 20 or in whom relapse occurred after 48 weeks of treatment were offered entry into the HALT-C trial and randomly assigned to receive maintenance therapy or no treatment. Both nonresponders and breakthrough/relapsers were followed for 3.5 years after randomization. The current analysis was restricted to 764 of the 813 patients treated during the lead-in phase and who entered the randomized HALT-C trial. The 49 excluded patients either had no follow-up after randomization, refused to remain on peginterferon if randomized to maintenance therapy, or were treated with peginterferon outside the trial despite being randomized to the control group. The 237 patients who entered the randomized HALT-C trial after receiving peginterferon and ribavirin treatment outside the formal HALT-C trial lead-in phase (express patients) were also excluded because their quantitative HCV RNA response to treatment had not been assessed in the HALT-C virology core laboratory. Clinical and other laboratory data were collected from all subjects according to standard protocol-defined procedures.13 Institutional review boards at all participating institutions approved the study protocol and all amendments. Written informed consent was obtained from all subjects prior to treatment.
Virologic Testing
Serum samples were obtained from all subjects at regular intervals, frozen at -70°C at each clinical site, and shipped at periodic intervals on dry ice to the virology core laboratory. HCV RNA was measured with both the quantitative Roche COBAS Amplicor HCV Monitor Test, v. 2.0 assay (lower limit of detection, 600 IU/mL; Roche Molecular Systems, Branchburg, NJ) and, if negative, by the Roche COBAS Amplicor HCV Test, v. 2.0 assay (lower limit of detection, 100 IU/mL) as described previously.16 HCV genotypes were determined with the INNO-LiPA HCV II kit (Siemens Medical Solutions Diagnostics, Tarrytown, NY).
For this retrospective analysis, patients were classified into 3 groups according to the decline from pretreatment baseline in HCV RNA levels during the lead-in phase and after randomization: <2-log10 decline, 2 to <4-log10, and ≥4-log10 decline in HCV RNA. The baseline log10 HCV RNA level was the mean of the screening and pretreatment log10 HCV RNA values. The log10 HCV RNA level during maintenance therapy was the mean of values obtained at months 6, 12, 18, 24, 30, and 36 after randomization. Patients were also grouped according to their mean serum HCV RNA level after randomization as follows: ≥100,000 IU/mL, <100,000-1000 IU/mL, and <1000 IU/mL. Patients who were HCV RNA negative by Roche Amplicor Monitor but positive by the Roche COBAS Amplicor HCV assay were assigned a value of log10 2.78 (600 IU/mL), and patients who were negative by both assays were assigned a value of log10 2.00.
Liver Histology
All patients underwent liver biopsy within 12 months prior to initiating peginterferon and ribavirin treatment in the lead-in phase and at 18 and 42 months after randomization. All biopsy specimens were reviewed by a team of 11 pathologists representing each of the clinical centers and a central lead pathologist. Each biopsy specimen was assigned a consensus Ishak inflammatory and fibrosis score at group review sessions.17
Definition of Outcomes
Protocol-defined clinical outcomes included an increase in the Child-Turcotte-Pugh (CTP) score to ≥7 points on 2 consecutive study visits 3 months apart; development of ascites, hepatic encephalopathy, variceal bleeding, or spontaneous bacterial peritonitis; the occurrence of HCC; or death from any cause. For patients with bridging fibrosis (Ishak fibrosis scores of 3 or 4) at study entry, a histologic end point, an increase by ≥2 points in the Ishak fibrosis score at either of the 2 follow-up biopsies (18 or 42 months after randomization) was also a primary outcome.
Statistical Analyses
Analyses were performed with SAS (Statistical Analysis Software, Cary, NC) version 9.1. Baseline variables in the 2 treatment groups were compared with χ2 tests or t tests. Mixed models were used to evaluate the changes in HCV RNA over time. Kaplan-Meier estimators were used to estimate clinical outcomes at 1400 days (3.83 years) after randomization and the rate of a ≥2-point increase in Ishak fibrosis score. Cox proportional hazards regression analyses were performed to test the effects of lead-in treatment and maintenance treatment on clinical outcomes. Complementary log-log regression analyses were performed to assess the effect of these treatments on the time to first 2-point increase in Ishak fibrosis score. Analyses of clinical outcomes and changes in serum HCV RNA level after randomization were restricted to patients who either had an outcome or were followed for at least 36 months after randomization.
Back grey arrow rt.gif
Effect of HCV RNA Suppression During Peginterferon Alfa-2a Maintenance Therapy on Clinical Outcomes in the HALT-C Trial -- full text pdf of published study attached
Download the PDF here
Gastroenterology Dec 2009
from Jules: I know of some patients who achieved undetectable HCV RNA, had an end of treatment response but relapsed or had breakthrough. These patients could have cirrhosis, advanced disease or coinfection making them more suscetible to progression to decompensation or increased risk for developing cancer one day, so should they consider maintenance full-dose peg/rbv therapy now or are they better off waiting until the first oral HCV protease comes out in 2011 to use in triple therapy. The data is I recall once a patient has compensated cirrhosis there is a 1-3 or 4% risk of progressing to decompensation per year, so a consideration I guess is how long the patient has had cirrhosis and is it worth just waiting until 2011 mid-2011 I think, or is the risk of progression over the next 1.5 years too great to wait. Or one could use full dose peg/rbv therapy now and then restart therapy again in 2011 with triple therapy, but as some would say is it worth going through the difficulties of peg/rbv therapy for another year until triple is available, and a number of clinicians would say NO, wait for triple. The authors raise the idea that for patients that are unable to achieve cure with future therapy of only oral drugs perhaps maintenance therapy may have application.
"Our results demonstrate that viral suppression with standard doses of peginterferon and ribavirin during the 24-week lead-in phase was associated with a significant reduction in clinical outcomes during the ensuing 3.5 years regardless of whether patients received maintenance peginterferon therapy or not. Several previous studies have suggested that patients who are treated with even a single, brief course of interferon-based therapy have a reduction in HCC and improved mortality.10, 11 The present study also suggests that profound viral suppression, even for a relatively brief period of time, is associated with clinical benefit."....."Data from the HALT-C trial suggest that, if such patients could be kept HCV RNA undetectable on half-dose peginterferon maintenance therapy for 3.5 years, an SVR of approximately 52% could be achieved."......."The results of this analysis lay the foundation for future studies of maintenance therapy, not with peginterferon, but with potent oral protease and polymerase inhibitors of HCV"
"this analysis has demonstrated that profound viral suppression by more than 4 logs10 with full-dose peginterferon and ribavirin was associated with a significant decline in clinical outcomes over the next 3.5 years. Continuing half-dose peginterferon-alfa 2a as maintenance therapy did not affect the development of clinical outcomes regardless of the degree of viral suppression achieved during the lead-in phase. This analysis confirms that no rationale exists for maintenance peginterferon therapy among patients in whom HCV RNA cannot be suppressed to undetectable levels. Our data did show, however, that an SVR of approximately 50% was achieved in the few patients who became HCV RNA undetectable during the lead-in phase, experienced breakthrough or relapse, and then remained persistently HCV RNA negative during maintenance peginterferon for 3.5 years."
from Jules: As I have previously reported, these results were presented at AASLD Nov 2009, wherein I discussed that 2 yrs ago HALT-C investigators reported at AASLD maintenance therapy did not improve outcomes, I asked but they would not share the sklides, they published. Then at EASL they reported a 4 log viral load reduction may have benefit but data was early, I took pics of slides and reported it. Now at this recent AASLD they reported this data in the link, and subsequently publish this report in Gastroenterology. I reported from the beginning that the initial HALT-C data finding no benefit to maintenance therapy did not appear believable and there were problems with the study design, but they had told the world after AASLD 2 yrs ago that maintenance therapy did not work, so many patients and clinicians stopped using it, although not all. They misled the community, the study was not well designed so as to be able to properly explore the potential benefits of maintenance therapy, as I reported 2 yrs ago, and now they report this, I still maintain the study design may not have been able to identify other benefits from maintenance therapy, you can't find what you don't study!
AASLD: SVR Improves Survival, Risk for Liver Cancer, Decompensated Liver Disease and Liver Transplant/Death - Also, Transient Viral Suppression (breakthroughs/relapsers) Improves Clinical Outcomes Too - (11/09/09)
HALT-C Trial GroupMitchell L. ShiffmanCorresponding Author Informationemail address, Chihiro Morishima, Jules L. Dienstag¤, Karen L. Lindsay, John C. Hoefs, William M. Lee, Elizabeth C. Wright, Deepa Naishadham, Gregory T. Everson, Anna S. Lok, Adrian M. Di Bisceglie, Herbert L. Bonkovsky##, Marc G. Ghany
Received 15 April 2009; accepted 31 August 2009. published online 11 September 2009.
ABSTRACT
Background & Aims
The Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial demonstrated that low-dose peginterferon maintenance therapy was ineffective in preventing clinical outcomes in patients with chronic hepatitis C, advanced fibrosis, and failure to achieve a sustained virologic response during lead-in phase treatment with standard dose peginterferon/ribavirin. This analysis was performed to determine whether suppressing HCV RNA during the trial was associated with a reduction in clinical outcomes.
Methods
Seven hundred sixty-four patients treated during the lead-in phase of HALT-C trial were randomized to either peginterferon alfa-2a (90 µg/week) maintenance therapy or no treatment (control) for 3.5 years. Clinical outcomes included an increase in Child-Turcotte-Pugh score, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, hepatocellular carcinoma, and mortality.
Results
During the lead-in, ≥4-log10 decline in serum HCV RNA occurred in 178 patients; 82% of whom lost detectable HCV RNA and later broke through or relapsed. These patients had significantly (P = .003) fewer clinical outcomes whether randomized to maintenance therapy or control. Following randomization, serum HCV RNA increased significantly in all 90 control patients and in 58 of 88 receiving maintenance therapy. Only 30 patients had persistent suppression of HCV RNA by ≥4 log10 during maintenance therapy. No significant reduction in clinical outcomes was observed in these patients.
Conclusions
Viral suppression by ≥4 log10 with full-dose peginterferon/ribavirin is associated with a significant reduction in clinical outcomes. Continuing low-dose peginterferon maintenance therapy, even in patients with persistent viral suppression, does not lead to a further decline in clinical outcomes.
Discussion
The HALT-C trial was a prospective, randomized controlled study designed to determine whether continuing peginterferon alfa-2a at a dose of 90 µg/week over 3.5 years could reduce complications of cirrhosis, HCC, and mortality in patients with chronic hepatitis C and advanced bridging fibrosis or cirrhosis who had failed to achieve an SVR following treatment with peginterferon and ribavirin. Unfortunately, no overall reduction in any of these clinical end points was achieved.14 The results of 2 similar studies, Colchicine Versus Pegintron Long-term Therapy (CO-PILOT) and Evaluation of Pegintron in Control of Hepatitis C Cirrhosis (EPIC),3 were also reported recently.18, 19 In the CO-PILOT trial, no lead-in treatment phase preceded randomization; patients with advanced fibrosis or cirrhosis who were nonresponders to either standard or peginterferon with or without ribavirin were randomized to receive either peginterferon alfa-2b at a dose of 0.5 µg/kg/week or colchicine for 4 years. The study design of the EPIC3 trial was similar to that of the HALT-C trial; subjects entered a lead-in treatment phase of peginterferon alfa-2b and weight-based ribavirin after which nonresponders were randomized to receive either peginterferon alfa-2b at a dose of 0.5 µg/kg/week or no treatment for up to 3 years. Despite differences in study design, the results of the CO-PILOT and EPIC3 trials were very similar to those observed in the HALT-C trial; no overall benefit of peginterferon maintenance therapy was observed. In EPIC,3 a significant reduction in variceal bleeding was observed in the subset of patients with esophageal varices suggesting that peginterferon may affect portal pressure. A recent substudy of the HALT-C trial has demonstrated that peginterferon alfa-2a 90 µg/week lowers portal pressure in patients with a baseline portal hypertension and esophageal varices.20 However, maintenance therapy in the HALT-C trial was not associated with a reduction in variceal hemorrhage.
Before these 3 large trials of maintenance therapy were initiated, a preliminary study of maintenance therapy with standard interferon alfa-2b (3 mU 3 times weekly) did suggest that a maintenance approach might be effective.12 In that study, however, only patients who achieved a histologic response (defined as a 50% decline in the hepatic inflammation score) after 6 months of interferon therapy were eligible for enrollment. This improvement in liver inflammation was associated with a marked decline in serum HCV RNA level.9, 12 Continuing interferon in these patients maintained both histologic improvement and suppression of serum HCV RNA. Stopping interferon was associated with a rapid rise in serum HCV RNA back to the pretreatment baseline and a worsening in hepatic inflammation scores. Unlike the HALT-C, CO-PILOT, or EPIC3 trials, the majority of patients in this preliminary study did not have advanced fibrosis or cirrhosis, the trial lasted only 2 years, and the impact of treatment on morbidity and mortality was not assessed.
The study designs of the 3 large maintenance therapy trials did not require either prior histologic or virologic responses as criteria for inclusion. In addition, the dose of peginterferon in these trials (half-dose peginterferon alfa-2a and one third the standard dose of peginterferon alfa-2b) was selected based on tolerability over an extended treatment duration, not efficacy in achieving HCV RNA suppression. Only 23% of patients enrolled in the HALT-C trial had profound viral suppression (a ≥4-log10 decline in serum HCV RNA level) with full-dose peginterferon and ribavirin during the lead-in phase, and only 30 (8%) patients maintained profound viral suppression during maintenance therapy. Serum levels of HCV RNA were not assessed in the CO-PILOT trial, and data on viral suppression during the EPIC3 trial are not currently available. Thus, although the primary analysis of the HALT-C, CO-PILOT, and EPIC3 trials demonstrated that peginterferon maintenance therapy provided no overall benefit to patients with chronic hepatitis C, none of these studies was designed to address whether profound viral suppression with maintenance peginterferon therapy to keep HCV RNA undetectable or near undetectable had the potential to prevent complications of advanced hepatic fibrosis.
The present analysis was performed to investigate the relationship between viral suppression and outcomes during the HALT-C trial. Our results demonstrate that viral suppression with standard doses of peginterferon and ribavirin during the 24-week lead-in phase was associated with a significant reduction in clinical outcomes during the ensuing 3.5 years regardless of whether patients received maintenance peginterferon therapy or not. Several previous studies have suggested that patients who are treated with even a single, brief course of interferon-based therapy have a reduction in HCC and improved mortality.10, 11 The present study also suggests that profound viral suppression, even for a relatively brief period of time, is associated with clinical benefit.
Data from the present analysis also demonstrated that over half the patients with profound viral suppression during standard dose peginterferon/ribavirin could not maintain this virologic response when ribavirin was stopped and the peginterferon dose was reduced by half. The rate of liver-related outcomes observed in these patients was similar to that observed for patients who also achieved profound virologic suppression during the lead-in phase and were randomized to stop treatment (4.3% vs 5.6%, respectively). Only 30 patients had persistent suppression of HCV RNA by ≥4 log10 with half-dose peginterferon maintenance therapy. Although a complication of cirrhosis developed in only 1 of these patients (3.3%), the number of patients was not sufficient to demonstrate with any confidence that persistent suppression of HCV RNA, even to undetectable levels, was associated with a reduction in clinical outcomes.
The few patients in this study who appeared to benefit the most from peginterferon maintenance therapy were the ones who responded to full-dose peginterferon and ribavirin during the lead-in phase but experienced either breakthrough or relapse. As has been well established, the relapse rate after antiviral therapy for chronic hepatitis C is inversely proportional to the rapidity with which HCV RNA becomes undetectable during treatment.21, 22 The vast majority of patients who relapse do not lose detectable HCV RNA until they have received 12-24 weeks of treatment. Several recent studies have demonstrated that continuing peginterferon and ribavirin for a longer duration, up to 72 weeks, in patients with genotype 1 and delayed clearance of HCV RNA can reduce relapse and increase SVR significantly.23, 24 Unfortunately, many patients with advanced fibrosis or cirrhosis are unable to tolerate prolonged treatment with full doses of peginterferon and ribavirin. Data from the HALT-C trial suggest that, if such patients could be kept HCV RNA undetectable on half-dose peginterferon maintenance therapy for 3.5 years, an SVR of approximately 52% could be achieved.
The results of this analysis lay the foundation for future studies of maintenance therapy, not with peginterferon, but with potent oral protease and polymerase inhibitors of HCV. Several such agents are currently in various phases of development and, when combined with peginterferon and ribavirin, yield SVR rates that are significantly higher than those observed with peginterferon and ribavirin alone.25, 26, 27 Despite promising results with these agents, all patients with chronic hepatitis C are unlikely to be cured with a combination of 1 or more oral HCV inhibitors plus peginterferon and ribavirin in the future. Thus, a group of patients with advanced fibrosis or cirrhosis will eventually require multidrug antiviral regimens to achieve long-term suppression of HCV RNA. Whether such patients could achieve an SVR with multidrug oral agents without peginterferon remains to be determined.
In summary, this analysis has demonstrated that profound viral suppression by more than 4 logs10 with full-dose peginterferon and ribavirin was associated with a significant decline in clinical outcomes over the next 3.5 years. Continuing half-dose peginterferon-alfa 2a as maintenance therapy did not affect the development of clinical outcomes regardless of the degree of viral suppression achieved during the lead-in phase. This analysis confirms that no rationale exists for maintenance peginterferon therapy among patients in whom HCV RNA cannot be suppressed to undetectable levels. Our data did show, however, that an SVR of approximately 50% was achieved in the few patients who became HCV RNA undetectable during the lead-in phase, experienced breakthrough or relapse, and then remained persistently HCV RNA negative during maintenance peginterferon for 3.5 years.
Results
Patient Groups
Table 1 summarizes the clinical, biochemical, virologic, and histologic characteristics of the HALT-C trial patients included in this analysis grouped by randomization status to the maintenance therapy arm or control arm. All patients received 24 weeks of peginterferon and ribavirin during the lead-in phase, prior to randomization; 618 had detectable HCV RNA in serum at week 20 and were classified as nonresponders, and 146 had undetectable HCV RNA in serum at week 20 and entered the HALT-C trial only after breakthrough developed (n = 30) or they relapsed (n = 116). The mean duration of peginterferon and ribavirin in the breakthrough/relapse group was 48 weeks. The features of these 764 patients were not significantly different from those of the entire HALT-C trial cohort.14
Figure 1 illustrates mean serum HCV RNA levels during the lead-in phase and after randomization throughout the HALT-C trial for patients with nonresponse or breakthrough/relapse. Of the 618 nonresponders who entered the trial, 261 were still being followed in the maintenance group and 253 in the control group by month 42. Nonresponders had a mean decline in serum HCV RNA of 1.5-log10 IU/mL by the end of the 20-week lead-in phase (Figure 1A). In patients randomized to stop therapy, the mean serum HCV RNA level returned to the pretreatment baseline. Patients randomized to remain on peginterferon maintenance therapy had a significant reduction in serum HCV RNA levels compared with the control group (P < .0001); however, this reduction was only 0.56-log10 IU/mL (95% confidence interval [CI]: 0.50-0.63) below the pretreatment baseline. Patients with breakthrough/relapse (n = 146) had undetectable HCV RNA in serum by week 20 in the lead-in phase and remained on peginterferon and ribavirin until either breakthrough viremia developed before week 48 or HCV RNA reappeared in serum after completing treatment. These patients were randomized at variable times after the initiation of treatment depending on the time of HCV RNA recurrence. Forty-two months after randomization, 73 patients remained in the control group and 59 patients in the maintenance therapy group. With breakthrough or relapse, the level of serum HCV RNA increased to a mean of log10 6.0 IU/mL at the time of randomization. Breakthrough/relapse patients randomized to stop treatment had a further increase in serum HCV RNA back toward pretreatment baseline levels (Figure 1B). In contrast, patients with breakthrough or relapse who initiated peginterferon maintenance therapy had a decline in mean serum HCV RNA level that averaged 2.5 logs10 (95% CI: 2.21-2.78) below the pretreatment baseline throughout the maintenance phase. This decline was significantly different than the change in serum HCV RNA level in the breakthrough/relapse patients randomized to stop treatment (P < .0001). During the 3.5 years of maintenance therapy, the mean serum HCV RNA level drifted up gradually relative to the pretreatment baseline from a nadir of log10 -2.9 to -2.2 (P = .0001).
Change in HCV RNA During the Lead-In Phase and Impact on Outcomes
Figure 2 illustrates the distribution of virologic responses observed during the lead-in phase. Compared with their pretreatment baseline levels, 56% of patients had a <2-log10 decline in serum HCV RNA with full-dose peginterferon and ribavirin; 21% had a 2 to <4-log10 decline, and 23% had a ≥4-log10 reduction. Among patients with a ≥4-log10 decline in serum HCV RNA, 82% were in the breakthrough/relapse group and had undetectable HCV RNA at week 20.
Figure 3 illustrates clinical outcomes after randomization according to the decline in serum HCV RNA during the lead-in phase. A significant (P = .003) reduction in clinical outcomes was observed with increasing degrees of viral suppression (Figure 3A). Clinical outcomes developed in 21% of patients with <2-log10 decline in serum HCV RNA during the lead-in phase (95% CI: 17%-24%); 18% (95% CI: 12%-24%) of patients with a 2 to <4-log10 decline, and 8% (95% CI: 4%-12%) of patients with ≥4-log10 decline. Clinical outcomes also developed in 8% of the 146 patients with undetectable HCV RNA at the end of the lead-in phase (a subset of the 178 patients with ≥4-log decline in HCV RNA). This decline in the 3.5-year incidence of clinical outcomes was not significantly different between the control and maintenance therapy groups (P = .56). No effect of viral suppression during the lead-in phase was observed on histologic outcome (Figure 3B). Overall, a ≥2-point increase in fibrosis score on follow-up liver biopsy was observed in 24% and 33% of control and maintenance patients, respectively, regardless of the degree of viral suppression (P = .38). In patients with undetectable HCV RNA at the end of the lead-in phase, fibrosis progression was also observed in 23% and 28% of control and maintenance patients, respectively (P = .88).
Change in HCV RNA With Maintenance Peginterferon and Impact on Outcomes
Patients randomized to the control group had a rapid return in serum HCV RNA back to their pretreatment baseline regardless of their viral response during the lead-in phase (Figure 1). Figure 4 illustrates the impact of continuing peginterferon maintenance therapy, at a reduced dose of 90 µg/week, on viral suppression. Over 97% (204/210) of patients with <2-log10 decline in serum HCV RNA during the lead-in phase had <2-log10 decline during the maintenance phase. In patients with a 2 to <4-log10 decline in HCV RNA during the lead-in phase, 86% had <2-log10 decline in HCV RNA during the maintenance phase. In patients with ≥4-log10 decline in serum HCV RNA during the lead-in phase, over half (46/88) could not maintain viral suppression with half-dose peginterferon and failed to maintain HCV RNA at levels <2 logs10 below their pretreatment baseline. Only 30 of 88 (34%) patients continued to have marked viral suppression by ≥4 logs10 below their pretreatment baseline levels during the maintenance phase, and all but 1 of these maintained HCV RNA levels <10,000 IU/mL. These 30 patients accounted for 43% of the 69 patients who had undetectable HCV RNA at the end of the lead-in phase.
Figure 5 illustrates clinical and histologic outcomes as a function of the decline in serum HCV RNA during peginterferon maintenance therapy. Overall, no significant impact was observed in clinical outcomes regardless of the degree of viral suppression. Although the lowest frequency of clinical outcomes (13%) was observed in patients who maintained a ≥4-log10 decline in serum HCV RNA, this was not significantly different (P = .74) than that observed in patients with <4-log10 decline in serum HCV RNA during maintenance therapy (18%-23%). Similar results were obtained when clinical outcomes were evaluated with respect to the mean absolute level of HCV RNA during maintenance therapy. Clinical outcomes developed in 17% of patients with a mean serum HCV RNA of >100,000 IU/mL, 29% with a mean serum HCV RNA of 100,000-1000 IU/mL, and 18% with a mean serum HCV RNA of <1000 IU/mL. No significant impact of viral suppression was observed on fibrosis progression (P = .80). A histologic outcome was observed in 29% (95% CI: 22%-37%) of patients with <2-log10 decline in serum HCV RNA and in 25% (95% CI: 6%-44%) of patients with >4-log10 decline in HCV RNA during maintenance therapy. Fibrosis progression was observed in 30% of patients when HCV RNA was suppressed to <1000 IU/mL during maintenance therapy.
Table 2 summarizes clinical outcomes that developed in patients who achieved a ≥4-log10 decline in serum HCV RNA during the lead-in phase and various degrees of viral suppression during maintenance therapy. Because achieving a ≥4-log10 reduction in serum HCV RNA level during the lead-in phase was associated with significantly reduced outcomes during the maintenance phase, the clinical outcomes in patients who achieved this profound virologic suppression but were randomized to the control group were also examined. Patients with clinical complications of liver disease and liver-related mortality were separated from those in whom the trial end point reached was only an increase in CTP score without a discrete clinical complication and from patients with non-liver-related death. Patients with a clinical complication of liver disease were included in the liver-complication category even if they also had a CTP score increase or a non-liver-related death. Overall, complications of liver disease developed in 5.5% of patients with a ≥4-log decline in serum HCV RNA during the lead-in phase who were then randomized to stop treatment and in 4.3% of patients without viral suppression (serum HCV RNA remained <2 logs10 below the pretreatment baseline) despite receiving peginterferon maintenance therapy. A clinical complication of liver disease developed in only 1 of 30 patients (3.3%) who experienced viral suppression by ≥4 logs10 during both the lead-in phase and maintenance therapy. This single patient had undetectable HCV RNA at the end of the lead-in phase and during maintenance therapy. Patients who lost detectable HCV RNA during the lead-in phase with subsequent breakthrough/relapse were treated for 48 weeks (Figure 1). Clinical outcomes developed in 7.5% (11/146) of these patients vs 3 of 32 (9.3%) patients who had a >4-log decline in HCV RNA but failed to clear HCV RNA and were treated for only 24 weeks (P = .81).
Of the 69 patients with undetectable HCV RNA at the end of the lead-in phase, 25 were repeatedly (more than 3/7 values between months 12 and 48) HCV RNA undetectable during maintenance therapy. Thirteen (52%) of these patients achieved an SVR, and 5 (20%) relapsed when peginterferon alfa was discontinued after 3.5 years. The remaining patients experienced breakthrough viremia or dropped out of the trial while on maintenance therapy.
Patients and Methods
Patients and Study Design
The design of the HALT-C trial has been described previously.13 Briefly, 1050 subjects with bridging fibrosis or cirrhosis (Ishak fibrosis score, 3-6) who were nonresponders to prior treatment with interferon (with or without ribavirin) were re-treated with standard dose peginterferon alfa-2a and ribavirin. Subjects with detectable HCV RNA at week 20 were defined as nonresponders and randomized to receive either 90 µg/week of peginterferon alfa-2a as maintenance therapy or to stop treatment and be followed as the control group. Subjects with undetectable HCV RNA at treatment week 20 received up to 48 weeks of peginterferon and ribavirin. The SVR rate achieved in this population (18%) was previously reported.15 Patients in whom virologic breakthrough occurred after week 20 or in whom relapse occurred after 48 weeks of treatment were offered entry into the HALT-C trial and randomly assigned to receive maintenance therapy or no treatment. Both nonresponders and breakthrough/relapsers were followed for 3.5 years after randomization. The current analysis was restricted to 764 of the 813 patients treated during the lead-in phase and who entered the randomized HALT-C trial. The 49 excluded patients either had no follow-up after randomization, refused to remain on peginterferon if randomized to maintenance therapy, or were treated with peginterferon outside the trial despite being randomized to the control group. The 237 patients who entered the randomized HALT-C trial after receiving peginterferon and ribavirin treatment outside the formal HALT-C trial lead-in phase (express patients) were also excluded because their quantitative HCV RNA response to treatment had not been assessed in the HALT-C virology core laboratory. Clinical and other laboratory data were collected from all subjects according to standard protocol-defined procedures.13 Institutional review boards at all participating institutions approved the study protocol and all amendments. Written informed consent was obtained from all subjects prior to treatment.
Virologic Testing
Serum samples were obtained from all subjects at regular intervals, frozen at -70°C at each clinical site, and shipped at periodic intervals on dry ice to the virology core laboratory. HCV RNA was measured with both the quantitative Roche COBAS Amplicor HCV Monitor Test, v. 2.0 assay (lower limit of detection, 600 IU/mL; Roche Molecular Systems, Branchburg, NJ) and, if negative, by the Roche COBAS Amplicor HCV Test, v. 2.0 assay (lower limit of detection, 100 IU/mL) as described previously.16 HCV genotypes were determined with the INNO-LiPA HCV II kit (Siemens Medical Solutions Diagnostics, Tarrytown, NY).
For this retrospective analysis, patients were classified into 3 groups according to the decline from pretreatment baseline in HCV RNA levels during the lead-in phase and after randomization: <2-log10 decline, 2 to <4-log10, and ≥4-log10 decline in HCV RNA. The baseline log10 HCV RNA level was the mean of the screening and pretreatment log10 HCV RNA values. The log10 HCV RNA level during maintenance therapy was the mean of values obtained at months 6, 12, 18, 24, 30, and 36 after randomization. Patients were also grouped according to their mean serum HCV RNA level after randomization as follows: ≥100,000 IU/mL, <100,000-1000 IU/mL, and <1000 IU/mL. Patients who were HCV RNA negative by Roche Amplicor Monitor but positive by the Roche COBAS Amplicor HCV assay were assigned a value of log10 2.78 (600 IU/mL), and patients who were negative by both assays were assigned a value of log10 2.00.
Liver Histology
All patients underwent liver biopsy within 12 months prior to initiating peginterferon and ribavirin treatment in the lead-in phase and at 18 and 42 months after randomization. All biopsy specimens were reviewed by a team of 11 pathologists representing each of the clinical centers and a central lead pathologist. Each biopsy specimen was assigned a consensus Ishak inflammatory and fibrosis score at group review sessions.17
Definition of Outcomes
Protocol-defined clinical outcomes included an increase in the Child-Turcotte-Pugh (CTP) score to ≥7 points on 2 consecutive study visits 3 months apart; development of ascites, hepatic encephalopathy, variceal bleeding, or spontaneous bacterial peritonitis; the occurrence of HCC; or death from any cause. For patients with bridging fibrosis (Ishak fibrosis scores of 3 or 4) at study entry, a histologic end point, an increase by ≥2 points in the Ishak fibrosis score at either of the 2 follow-up biopsies (18 or 42 months after randomization) was also a primary outcome.
Statistical Analyses
Analyses were performed with SAS (Statistical Analysis Software, Cary, NC) version 9.1. Baseline variables in the 2 treatment groups were compared with χ2 tests or t tests. Mixed models were used to evaluate the changes in HCV RNA over time. Kaplan-Meier estimators were used to estimate clinical outcomes at 1400 days (3.83 years) after randomization and the rate of a ≥2-point increase in Ishak fibrosis score. Cox proportional hazards regression analyses were performed to test the effects of lead-in treatment and maintenance treatment on clinical outcomes. Complementary log-log regression analyses were performed to assess the effect of these treatments on the time to first 2-point increase in Ishak fibrosis score. Analyses of clinical outcomes and changes in serum HCV RNA level after randomization were restricted to patients who either had an outcome or were followed for at least 36 months after randomization.
HUMAN GENOME SCIENCES ANNOUNCES SUBMISSION OF MARKETING AUTHORIZATION APPLICATION TO EMEA FOR JOULFERON® (ZALBIN™)
HUMAN GENOME SCIENCES ANNOUNCES SUBMISSION OF MARKETING AUTHORIZATION APPLICATION TO EMEA FOR JOULFERON® (ZALBIN™)
ROCKVILLE, Maryland – December 15, 2009 – Human Genome Sciences, Inc. (Nasdaq: HGSI) today announced that Novartis has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA) for approval to market JOULFERON® (albinterferon alfa-2b, known in the United States as ZALBIN™) for the treatment of chronic hepatitis C. In November 2009, HGS submitted a Biologics License Application (BLA) for ZALBIN to the FDA in the United States.
The MAA submission includes the results of two pivotal Phase 3 clinical trials showing that 900-mcg albinterferon alfa-2b dosed every two weeks met its primary endpoint of non-inferiority to peginterferon alfa-2a (Pegasys) dosed once each week. The Phase 3 studies, known as ACHIEVE 1 and ACHIEVE 2/3, evaluated albinterferon alfa-2b vs. peginterferon alfa-2a, in combination with ribavirin, for use in the treatment of interferon-naïve patients with chronic hepatitis C. In both studies, albinterferon alfa-2b, with half the injections, achieved sustained virologic response comparable to that achieved by peginterferon alfa-2a. The rates of serious and/or severe adverse events were also comparable in these studies. ACHIEVE 1 was conducted in patients infected with genotype 1 virus, and ACHIEVE 2/3 was conducted in patients with genotypes 2 or 3 virus. The two studies treated a total of 2255 patients.
“Assuming licensure by the EMEA and other regulatory agencies, HGS believes JOULFERON could become an important treatment for chronic hepatitis C,” said H. Thomas Watkins, President and Chief Executive Officer, HGS. “We look forward to continuing to work closely with Novartis to advance albinterferon alfa-2b to the market under the brand name ZALBIN in the United States.”
About the Collaboration with Novartis
Under an exclusive worldwide co-development and commercialization agreement entered into in 2006, HGS and Novartis will co-commercialize albinterferon alfa-2b in the United States as ZALBIN™, and will share clinical development costs, U.S. commercialization costs and U.S. profits equally. Novartis will be responsible for commercialization of albinterferon alfa-2b as JOULFERON® in the rest of the world, and will pay HGS a royalty on those sales. These brand names will be subject to confirmation by health authorities at the time of product approval.
HGS has primary responsibility for the bulk manufacture of albinterferon alfa-2b, and Novartis will have responsibility for commercial manufacturing of the finished drug product. Clinical development, commercial milestone and other payments to HGS could total as much as $507.5 million, including $207.5 million received to date. The remaining payments to HGS under the agreement relate to the achievement of certain regulatory approval and commercial milestones.
About ZALBIN (albinterferon alfa-2b)
ZALBIN (also known as JOULFERON) is a genetic fusion of human albumin and interferon alfa created using proprietary HGS albumin-fusion technology. Human albumin is the most prevalent naturally occurring blood protein in the human circulatory system, persisting in circulation in the body for approximately 19 days. Research has shown that genetic fusion of therapeutic proteins to human albumin decreases clearance and prolongs the half-life of the therapeutic proteins.
ZALBIN dosed once every two weeks has completed Phase 3 development. In April 2009, positive Phase 3 results of ZALBIN in patients with chronic hepatitis C were presented at the 44th annual meeting of the European Association for the Study of the Liver in Copenhagen. Data from two pivotal Phase 3 trials, ACHIEVE 1 and ACHIEVE 2/3, showed that ZALBIN met its primary endpoint of non-inferiority to Pegasys (peginterferon alfa-2a). With half the injections, ZALBIN achieved a rate of sustained virologic response comparable to Pegasys in these studies; rates of serious and/or severe adverse events were also comparable.
About Hepatitis C
Hepatitis C is an inflammation of the liver caused by the hepatitis C virus. It is estimated that as many as 170 million people worldwide are infected with hepatitis C virus. This includes nearly four million people in the United States. When detectable levels of HCV persist in the blood for at least six months, a person is diagnosed with chronic hepatitis C. Hepatitis C virus can cause serious liver disease, leading to cirrhosis, primary liver cancer and even death. Patients infected with the genotype 1 hepatitis C virus account for approximately 75% of the chronic hepatitis C patients in the U.S.
About Human Genome Sciences
The mission of HGS is to apply great science and great medicine to bring innovative drugs to patients with unmet medical needs. The HGS clinical development pipeline includes novel drugs to treat lupus, hepatitis C, inhalation anthrax and cancer.
The Company’s primary focus is rapid progress toward the commercialization of its two lead drugs, BENLYSTA™ (belimumab) for lupus and ZALBIN™ (albinterferon alfa-2b) for hepatitis C. Phase 3 development has been completed successfully for both BENLYSTA and Zalbin. The submission of marketing applications for BENLYSTA is planned in the U.S., Europe and other regions in the first half of 2010. A BLA has been submitted for ZALBIN to the FDA in the United States, and an MAA has been submitted under the brand name JOULFERON® to the EMEA in Europe.
In April 2009, HGS completed the delivery of 20,000 doses of raxibacumab to the U.S. Strategic National Stockpile for use in the event of an emergency to treat inhalational anthrax. In July 2009, HGS secured a new purchase order for 45,000 doses of raxibacumab to be delivered to the Stockpile over a three-year period beginning near the end of 2009. In May 2009, HGS submitted a Biologics License Application to the FDA for raxibacumab for the treatment of inhalation anthrax.
The Company also has several drugs in earlier stages of clinical development for the treatment of cancer, led by the TRAIL receptor antibody mapatumumab and a small-molecule antagonist of inhibitor-of-apoptosis proteins. In addition, HGS has substantial financial rights to certain products in the GSK clinical pipeline including darapladib, currently in Phase 3 development in patients with coronary heart disease, and Syncria® (albiglutide), currently in Phase 3 development in patients with type 2 diabetes.
For more information about HGS, please visit the Company’s web site at www.hgsi.com. Health professionals and patients interested in clinical trials of HGS products may inquire via e-mail to medinfo@hgsi.comThis e-mail address is being protected from spam bots, you need JavaScript enabled to view it or by calling HGS at (877) 822-8472.
Safe Harbor Statement
This announcement contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. The forward-looking statements are based on Human Genome Sciences’ current intent, belief and expectations. These statements are not guarantees of future performance and are subject to certain risks and uncertainties that are difficult to predict. Actual results may differ materially from these forward-looking statements because of Human Genome Sciences’ unproven business model, its dependence on new technologies, the uncertainty and timing of clinical trials, Human Genome Sciences’ ability to develop and commercialize products, its dependence on collaborators for services and revenue, its substantial indebtedness and lease obligations, its changing requirements and costs associated with facilities, intense competition, the uncertainty of patent and intellectual property protection, Human Genome Sciences’ dependence on key management and key suppliers, the uncertainty of regulation of products, the impact of future alliances or transactions and other risks described in the Company’s filings with the SEC. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of today’s date. Human Genome Sciences undertakes no obligation to update or revise the information contained in this announcement whether as a result of new information, future events or circumstances or otherwise.
###
Media Contact:
Jerry Parrott
Vice President, Corporate Communications
301-315-2777
Investor Contact:
Peter Vozzo
Senior Director, Investor Relations
301-251-6003
ROCKVILLE, Maryland – December 15, 2009 – Human Genome Sciences, Inc. (Nasdaq: HGSI) today announced that Novartis has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA) for approval to market JOULFERON® (albinterferon alfa-2b, known in the United States as ZALBIN™) for the treatment of chronic hepatitis C. In November 2009, HGS submitted a Biologics License Application (BLA) for ZALBIN to the FDA in the United States.
The MAA submission includes the results of two pivotal Phase 3 clinical trials showing that 900-mcg albinterferon alfa-2b dosed every two weeks met its primary endpoint of non-inferiority to peginterferon alfa-2a (Pegasys) dosed once each week. The Phase 3 studies, known as ACHIEVE 1 and ACHIEVE 2/3, evaluated albinterferon alfa-2b vs. peginterferon alfa-2a, in combination with ribavirin, for use in the treatment of interferon-naïve patients with chronic hepatitis C. In both studies, albinterferon alfa-2b, with half the injections, achieved sustained virologic response comparable to that achieved by peginterferon alfa-2a. The rates of serious and/or severe adverse events were also comparable in these studies. ACHIEVE 1 was conducted in patients infected with genotype 1 virus, and ACHIEVE 2/3 was conducted in patients with genotypes 2 or 3 virus. The two studies treated a total of 2255 patients.
“Assuming licensure by the EMEA and other regulatory agencies, HGS believes JOULFERON could become an important treatment for chronic hepatitis C,” said H. Thomas Watkins, President and Chief Executive Officer, HGS. “We look forward to continuing to work closely with Novartis to advance albinterferon alfa-2b to the market under the brand name ZALBIN in the United States.”
About the Collaboration with Novartis
Under an exclusive worldwide co-development and commercialization agreement entered into in 2006, HGS and Novartis will co-commercialize albinterferon alfa-2b in the United States as ZALBIN™, and will share clinical development costs, U.S. commercialization costs and U.S. profits equally. Novartis will be responsible for commercialization of albinterferon alfa-2b as JOULFERON® in the rest of the world, and will pay HGS a royalty on those sales. These brand names will be subject to confirmation by health authorities at the time of product approval.
HGS has primary responsibility for the bulk manufacture of albinterferon alfa-2b, and Novartis will have responsibility for commercial manufacturing of the finished drug product. Clinical development, commercial milestone and other payments to HGS could total as much as $507.5 million, including $207.5 million received to date. The remaining payments to HGS under the agreement relate to the achievement of certain regulatory approval and commercial milestones.
About ZALBIN (albinterferon alfa-2b)
ZALBIN (also known as JOULFERON) is a genetic fusion of human albumin and interferon alfa created using proprietary HGS albumin-fusion technology. Human albumin is the most prevalent naturally occurring blood protein in the human circulatory system, persisting in circulation in the body for approximately 19 days. Research has shown that genetic fusion of therapeutic proteins to human albumin decreases clearance and prolongs the half-life of the therapeutic proteins.
ZALBIN dosed once every two weeks has completed Phase 3 development. In April 2009, positive Phase 3 results of ZALBIN in patients with chronic hepatitis C were presented at the 44th annual meeting of the European Association for the Study of the Liver in Copenhagen. Data from two pivotal Phase 3 trials, ACHIEVE 1 and ACHIEVE 2/3, showed that ZALBIN met its primary endpoint of non-inferiority to Pegasys (peginterferon alfa-2a). With half the injections, ZALBIN achieved a rate of sustained virologic response comparable to Pegasys in these studies; rates of serious and/or severe adverse events were also comparable.
About Hepatitis C
Hepatitis C is an inflammation of the liver caused by the hepatitis C virus. It is estimated that as many as 170 million people worldwide are infected with hepatitis C virus. This includes nearly four million people in the United States. When detectable levels of HCV persist in the blood for at least six months, a person is diagnosed with chronic hepatitis C. Hepatitis C virus can cause serious liver disease, leading to cirrhosis, primary liver cancer and even death. Patients infected with the genotype 1 hepatitis C virus account for approximately 75% of the chronic hepatitis C patients in the U.S.
About Human Genome Sciences
The mission of HGS is to apply great science and great medicine to bring innovative drugs to patients with unmet medical needs. The HGS clinical development pipeline includes novel drugs to treat lupus, hepatitis C, inhalation anthrax and cancer.
The Company’s primary focus is rapid progress toward the commercialization of its two lead drugs, BENLYSTA™ (belimumab) for lupus and ZALBIN™ (albinterferon alfa-2b) for hepatitis C. Phase 3 development has been completed successfully for both BENLYSTA and Zalbin. The submission of marketing applications for BENLYSTA is planned in the U.S., Europe and other regions in the first half of 2010. A BLA has been submitted for ZALBIN to the FDA in the United States, and an MAA has been submitted under the brand name JOULFERON® to the EMEA in Europe.
In April 2009, HGS completed the delivery of 20,000 doses of raxibacumab to the U.S. Strategic National Stockpile for use in the event of an emergency to treat inhalational anthrax. In July 2009, HGS secured a new purchase order for 45,000 doses of raxibacumab to be delivered to the Stockpile over a three-year period beginning near the end of 2009. In May 2009, HGS submitted a Biologics License Application to the FDA for raxibacumab for the treatment of inhalation anthrax.
The Company also has several drugs in earlier stages of clinical development for the treatment of cancer, led by the TRAIL receptor antibody mapatumumab and a small-molecule antagonist of inhibitor-of-apoptosis proteins. In addition, HGS has substantial financial rights to certain products in the GSK clinical pipeline including darapladib, currently in Phase 3 development in patients with coronary heart disease, and Syncria® (albiglutide), currently in Phase 3 development in patients with type 2 diabetes.
For more information about HGS, please visit the Company’s web site at www.hgsi.com. Health professionals and patients interested in clinical trials of HGS products may inquire via e-mail to medinfo@hgsi.comThis e-mail address is being protected from spam bots, you need JavaScript enabled to view it or by calling HGS at (877) 822-8472.
Safe Harbor Statement
This announcement contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. The forward-looking statements are based on Human Genome Sciences’ current intent, belief and expectations. These statements are not guarantees of future performance and are subject to certain risks and uncertainties that are difficult to predict. Actual results may differ materially from these forward-looking statements because of Human Genome Sciences’ unproven business model, its dependence on new technologies, the uncertainty and timing of clinical trials, Human Genome Sciences’ ability to develop and commercialize products, its dependence on collaborators for services and revenue, its substantial indebtedness and lease obligations, its changing requirements and costs associated with facilities, intense competition, the uncertainty of patent and intellectual property protection, Human Genome Sciences’ dependence on key management and key suppliers, the uncertainty of regulation of products, the impact of future alliances or transactions and other risks described in the Company’s filings with the SEC. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of today’s date. Human Genome Sciences undertakes no obligation to update or revise the information contained in this announcement whether as a result of new information, future events or circumstances or otherwise.
###
Media Contact:
Jerry Parrott
Vice President, Corporate Communications
301-315-2777
Investor Contact:
Peter Vozzo
Senior Director, Investor Relations
301-251-6003
HCV Rapid Oral HCV Test-Orasure/Merck
From: nataphcvhiv@natap.org
Subject: NATAP: HCV Rapid Oral HCV Test-Orasure/Merck
Date: December 15, 2009 8:08:47 AM EST
To: hiv@natap.org, nataphcvhiv@natap.org, natapindustry@natap.org, natapdoctors@natap.org
NATAP http://natap.org/
_______________________________________________
OraSure has entered into agreements with Merck & Co. (through its predecessor Schering Plough Corporation) to collaborate on the development and promotion of the OraQuick(R) HCV test. Under the terms of these agreements, the Company has been and will be reimbursed by Merck for a portion of its costs to develop the test and obtain regulatory approvals. Additionally, Merck will provide promotional support, including detailing the test in the physicians' office market worldwide.
Dec 15, 2009 (M2 EQUITYBITES via COMTEX) -- -- Oral-fluid testing solutions provider OraSure Technologies Inc (Nasdaq:OSUR) declared on Tuesday the receipt of the CE mark for the company's OraQuick Rapid HCV Antibody Test to diagnose people with HCV infection.
A CE mark is required to sell this test in the 27 countries of the European Union.
The OraQuick Rapid HCV Antibody Test is the first and only rapid Hepatitis C test bearing a CE mark that can be used with oral fluid and the company plans to launch the test in Europe during the first quarter of 2010.
OraSure also said that it is actively seeking US Food and Drug Administration (FDA) approval of its OraQuick Rapid HCV Antibody Test.
OraSure Technologies Receives CE Mark for OraQuick(R) Rapid HCV Antibody Test
First and Only Oral Fluid Rapid HCV Test Bearing a CE Mark
OraQuick(R) Rapid HCV Antibody Test
The OraQuick(R) Rapid HCV Antibody Test by OraSure Technologies -- the first and only oral fluid rapid HCV test bearing a CE Mark.
BETHLEHEM, Pa., Dec. 15, 2009 (GLOBE NEWSWIRE) -- OraSure Technologies, Inc. (Nasdaq:OSUR) announced today that it has received approval to affix the CE mark to its OraQuick(R) Rapid HCV Antibody Test. A CE mark is required to sell this test in the 27 countries that currently make up the European Union. The OraQuick(R) Rapid HCV Antibody Test is the first and only rapid Hepatitis C test bearing a CE mark that can be used with oral fluid.
The European Union requires companies to comply with the Medical Devices Directive ("MDD") and In Vitro Diagnostics Directive ("IVDD") in order to sell medical devices in Europe. The CE mark is evidence that OraSure and its OraQuick(R) Rapid HCV Antibody Test meet the quality and other requirements of these directives. The Company is currently pursuing the required individual country registrations and expects to begin selling the test in Europe during the first quarter of 2010.
"We believe that the OraQuick(R) Rapid HCV Antibody Test, with its ability to test using a simple oral fluid or finger-stick blood sample, will be a valuable tool in identifying more individuals infected with Hepatitis C," said Douglas A. Michels, President and Chief Executive Officer of OraSure Technologies. "CE mark approval of our OraQuick(R) Rapid HCV Antibody Test represents a significant achievement and major milestone for our Company."
On a world-wide basis, there are an estimated 180 million people who are chronically infected with HCV, with an estimated three to four million individuals newly infected each year. According to the World Health Organization, most HCV infection is currently undiagnosed and up to 80 percent who have HCV show no signs or symptoms.
According to a new report issued by the UK Health Protection Agency on December 11, 2009, entitled "Hepatitis C in the UK -- The Health Protection Agency Annual Report 2009," it is currently estimated that approximately 185,000 individuals in the UK are chronically infected with Hepatitis C, including more than 8,000 people who were diagnosed in 2008 in England.
"This new hepatitis C test will help to diagnose people before their livers are damaged beyond repair," said Charles Gore, Chief Executive of The Hepatitis C Trust, the national charity for HCV in the United Kingdom. "Hepatitis C is preventable and treatable so it's a scandal that the death toll continues to rise simply because people haven't yet been diagnosed. The UK desperately needs to diagnose the 100,000 patients who are unaware they are living with the virus and to stop further transmissions. This simple, quick test will allow us to reach more people who would otherwise not have access to testing."
As previously announced, OraSure has entered into agreements with Merck & Co. (through its predecessor Schering Plough Corporation) to collaborate on the development and promotion of the OraQuick(R) HCV test. Under the terms of these agreements, the Company has been and will be reimbursed by Merck for a portion of its costs to develop the test and obtain regulatory approvals. Additionally, Merck will provide promotional support, including detailing the test in the physicians' office market worldwide.
With the CE mark, the OraQuick(R) Rapid HCV Antibody Test is the second rapid test manufactured by OraSure to receive such approval. In June 2007, OraSure received approval to affix the CE mark to its OraQuick ADVANCE(R) Rapid HIV-1/2 Antibody Test which is currently being sold widely in the European Union. OraSure is also actively seeking approval of its OraQuick(R) Rapid HCV Antibody Test by the U.S. Food and Drug Administration (FDA).
About OraSure Technologies
OraSure Technologies develops, manufactures and markets oral fluid specimen collection devices using proprietary oral fluid technologies, diagnostic products including immunoassays and other in vitro diagnostic tests, and other medical devices. These products are sold in the United States as well as internationally to various clinical laboratories, hospitals, clinics, community-based organizations and other public health organizations, distributors, government agencies, physicians' offices, and commercial and industrial entities.
OraSure Technologies is the leading supplier of oral-fluid testing solutions for drugs of abuse and for the detection of antibodies to HIV.
For more information on the Company, please go to www.orasure.com.
_______________________________________________
NATAP nataphcvhiv mailing list -- nataphcvhiv@natap.org
This is an annoucement-only mailing list. Do not reply.
To unsubscribe: send a blank email to nataphcvhiv-request@natap.org with a subject of unsubscribe.
For more information, see http://seven.pairlist.net/mailman/listinfo/nataphcvhiv
Subject: NATAP: HCV Rapid Oral HCV Test-Orasure/Merck
Date: December 15, 2009 8:08:47 AM EST
To: hiv@natap.org, nataphcvhiv@natap.org, natapindustry@natap.org, natapdoctors@natap.org
NATAP http://natap.org/
_______________________________________________
OraSure has entered into agreements with Merck & Co. (through its predecessor Schering Plough Corporation) to collaborate on the development and promotion of the OraQuick(R) HCV test. Under the terms of these agreements, the Company has been and will be reimbursed by Merck for a portion of its costs to develop the test and obtain regulatory approvals. Additionally, Merck will provide promotional support, including detailing the test in the physicians' office market worldwide.
Dec 15, 2009 (M2 EQUITYBITES via COMTEX) -- -- Oral-fluid testing solutions provider OraSure Technologies Inc (Nasdaq:OSUR) declared on Tuesday the receipt of the CE mark for the company's OraQuick Rapid HCV Antibody Test to diagnose people with HCV infection.
A CE mark is required to sell this test in the 27 countries of the European Union.
The OraQuick Rapid HCV Antibody Test is the first and only rapid Hepatitis C test bearing a CE mark that can be used with oral fluid and the company plans to launch the test in Europe during the first quarter of 2010.
OraSure also said that it is actively seeking US Food and Drug Administration (FDA) approval of its OraQuick Rapid HCV Antibody Test.
OraSure Technologies Receives CE Mark for OraQuick(R) Rapid HCV Antibody Test
First and Only Oral Fluid Rapid HCV Test Bearing a CE Mark
OraQuick(R) Rapid HCV Antibody Test
The OraQuick(R) Rapid HCV Antibody Test by OraSure Technologies -- the first and only oral fluid rapid HCV test bearing a CE Mark.
BETHLEHEM, Pa., Dec. 15, 2009 (GLOBE NEWSWIRE) -- OraSure Technologies, Inc. (Nasdaq:OSUR) announced today that it has received approval to affix the CE mark to its OraQuick(R) Rapid HCV Antibody Test. A CE mark is required to sell this test in the 27 countries that currently make up the European Union. The OraQuick(R) Rapid HCV Antibody Test is the first and only rapid Hepatitis C test bearing a CE mark that can be used with oral fluid.
The European Union requires companies to comply with the Medical Devices Directive ("MDD") and In Vitro Diagnostics Directive ("IVDD") in order to sell medical devices in Europe. The CE mark is evidence that OraSure and its OraQuick(R) Rapid HCV Antibody Test meet the quality and other requirements of these directives. The Company is currently pursuing the required individual country registrations and expects to begin selling the test in Europe during the first quarter of 2010.
"We believe that the OraQuick(R) Rapid HCV Antibody Test, with its ability to test using a simple oral fluid or finger-stick blood sample, will be a valuable tool in identifying more individuals infected with Hepatitis C," said Douglas A. Michels, President and Chief Executive Officer of OraSure Technologies. "CE mark approval of our OraQuick(R) Rapid HCV Antibody Test represents a significant achievement and major milestone for our Company."
On a world-wide basis, there are an estimated 180 million people who are chronically infected with HCV, with an estimated three to four million individuals newly infected each year. According to the World Health Organization, most HCV infection is currently undiagnosed and up to 80 percent who have HCV show no signs or symptoms.
According to a new report issued by the UK Health Protection Agency on December 11, 2009, entitled "Hepatitis C in the UK -- The Health Protection Agency Annual Report 2009," it is currently estimated that approximately 185,000 individuals in the UK are chronically infected with Hepatitis C, including more than 8,000 people who were diagnosed in 2008 in England.
"This new hepatitis C test will help to diagnose people before their livers are damaged beyond repair," said Charles Gore, Chief Executive of The Hepatitis C Trust, the national charity for HCV in the United Kingdom. "Hepatitis C is preventable and treatable so it's a scandal that the death toll continues to rise simply because people haven't yet been diagnosed. The UK desperately needs to diagnose the 100,000 patients who are unaware they are living with the virus and to stop further transmissions. This simple, quick test will allow us to reach more people who would otherwise not have access to testing."
As previously announced, OraSure has entered into agreements with Merck & Co. (through its predecessor Schering Plough Corporation) to collaborate on the development and promotion of the OraQuick(R) HCV test. Under the terms of these agreements, the Company has been and will be reimbursed by Merck for a portion of its costs to develop the test and obtain regulatory approvals. Additionally, Merck will provide promotional support, including detailing the test in the physicians' office market worldwide.
With the CE mark, the OraQuick(R) Rapid HCV Antibody Test is the second rapid test manufactured by OraSure to receive such approval. In June 2007, OraSure received approval to affix the CE mark to its OraQuick ADVANCE(R) Rapid HIV-1/2 Antibody Test which is currently being sold widely in the European Union. OraSure is also actively seeking approval of its OraQuick(R) Rapid HCV Antibody Test by the U.S. Food and Drug Administration (FDA).
About OraSure Technologies
OraSure Technologies develops, manufactures and markets oral fluid specimen collection devices using proprietary oral fluid technologies, diagnostic products including immunoassays and other in vitro diagnostic tests, and other medical devices. These products are sold in the United States as well as internationally to various clinical laboratories, hospitals, clinics, community-based organizations and other public health organizations, distributors, government agencies, physicians' offices, and commercial and industrial entities.
OraSure Technologies is the leading supplier of oral-fluid testing solutions for drugs of abuse and for the detection of antibodies to HIV.
For more information on the Company, please go to www.orasure.com.
_______________________________________________
NATAP nataphcvhiv mailing list -- nataphcvhiv@natap.org
This is an annoucement-only mailing list. Do not reply.
To unsubscribe: send a blank email to nataphcvhiv-request@natap.org with a subject of unsubscribe.
For more information, see http://seven.pairlist.net/mailman/listinfo/nataphcvhiv
Milk Thistle Cuts Liver Toxicity from ALL Chemotherapy
Milk Thistle Cuts Liver Toxicity from ALL Chemotherapy
By John Gever, Senior Editor, MedPage Today
Published: December 14, 2009
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit
for reading medical news
An extract from the milk thistle plant significantly reduced some signs of liver inflammation in children receiving chemotherapy for acute lymphoblastic leukemia and showed favorable trends in other measures, researchers said.
After 56 days of oral treatment with milk thistle in capsule form, children in a placebo-controlled trial showed significantly lower levels of aspartate aminotransferase (AST) and trends toward lower alanine aminotransferase (ALT) and bilirubin, according to Kara M. Kelly, MD, of Columbia University, and colleagues.
The study "provides preliminary evidence that milk thistle may be a safe, effective, supportive-care agent," the researchers concluded in an online report in Cancer.
"Milk thistle needs to be studied further, to see how effective it is for a longer course of treatment, and whether it works well in reducing liver inflammation in other types of cancers and with other types of chemotherapy," Kelly said in a press release issued by the American Cancer Society, publisher of Cancer. "However, our results are promising as there are no substitute medications for treating liver toxicity."
Action Points
* Explain to interested patients that liver toxicity often limits the chemotherapy doses that may be given, reducing the effectiveness of cancer treatment.
* Explain that milk thistle appeared to be safe in the study, but its effectiveness in reducing liver toxicity was relatively modest.
Milk thistle (Silybum marianum) is an herbal plant, native to Mediterranean Europe, North Africa and the Middle East, that has been shown to protect the liver and kidneys against damage from known toxins. Extracts are widely available in drugstores and herbal medicine shops, as well as from Internet vendors.
The version used in the current study was a 1:2 mixture of silibinin, believed to be the most active component of the herb, and soy phosphatidylcholine to improve the former's bioavailability.
Among the herb's purported benefits is limiting liver toxicity from cancer chemotherapy, but this had not previously been tested in a placebo-controlled trial.
So Kelly and colleagues assigned 50 children receiving treatment for ALL with a regimen of vincristine, methotrexate, 6-mercaptopurine or thioguanine, and prednisone or dexamethasone to receive daily doses of the milk thistle product or placebo.
Participants ranged in age from under two to 19 (mean age 8.7 in the milk thistle group, 7 in the placebo group). About 60% in each group were classed as standard risk and the rest were high risk.
Milk thistle was given in quantities designed to equate to a silibinin dose of 5.1 mg/kg/day, for 28 days.
Levels of AST, ALT, and bilirubin were measured at baseline and at days 28 and 56.
The only significant difference between the milk thistle and placebo groups in these outcomes was for AST at day 56, with mean levels of about 47 U/L with milk thistle versus 67 U/L with placebo (P=0.04). Mean AST levels were also lower at day 28, but the difference was smaller and not significant.
ALT levels were slightly higher on day 28 in the milk thistle group versus placebo. On day 56, mean ALT levels were 122 U/L with milk thistle versus 140 U/L with placebo, but the P value remained above 0.05.
Bilirubin levels were virtually identical in the two groups at day 28. They were somewhat lower at day 56 with milk thistle (0.70 versus 0.87 in the placebo group) but this also failed to reach significance.
Chemotherapy dose reductions because of toxicity were also somewhat less common in the milk thistle group, with 61% taking reductions compared with 73% of the placebo group (not significant).
Milk thistle appeared to have no impact on delays in planned chemotherapy, and grade 3-4 toxicities were, if anything, more frequent in the actively-treated group.
During the first four weeks of treatment, five patients in the milk thistle group and three taking placebo experienced grade 3-4 hepatic toxicity. From day 28 to 56, eight children on milk thistle and five in the placebo group had grade 3-4 hepatic toxicity.
Kelly and colleagues said there were no toxicities or other untoward results attributable to the milk thistle. They suggested that the equivocal efficacy findings could have resulted from inadequate dosing of milk thistle, especially since testing of plasma samples from 18 children in the study failed to find detectable levels of silibinin in any patient.
"An evaluation of clinical literature shows a wide range of therapeutic doses and duration," they noted in their report, adding that they had chosen a "conservative" dose level and duration to be on the safe side.
It's also possible that children metabolize silibinin at different rates from adults, which would account for the lack of detectable silibinin in plasma samples.
Finally, Kelly and colleagues noted that compliance was poorer in the milk thistle group: 68% of planned doses were given, compared with 96% of placebo capsules. The milk thistle product was identical in smell and taste to the placebo.
The only difference the researchers identified that might have accounted for the compliance disparity was age. The milk thistle group had a significantly higher mean age, and noncompliant patients were significantly older than compliant children (mean 13.1 versus 6.9 years old, P=0.01).
"Future clinical trials should explore milk thistle in the setting of patients in which hepatic toxicity prevents provision of the recommended chemotherapy in individuals with cancer," Kelly and colleagues concluded.
The study was funded by the American Institute for Cancer Research, the Tamarind Foundation, and the National Cancer Institute. Study drugs were donated by Thorn Research, which produces the milk thistle extract used in the study.
Study authors reported no potential conflicts of interest.
By John Gever, Senior Editor, MedPage Today
Published: December 14, 2009
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit
for reading medical news
An extract from the milk thistle plant significantly reduced some signs of liver inflammation in children receiving chemotherapy for acute lymphoblastic leukemia and showed favorable trends in other measures, researchers said.
After 56 days of oral treatment with milk thistle in capsule form, children in a placebo-controlled trial showed significantly lower levels of aspartate aminotransferase (AST) and trends toward lower alanine aminotransferase (ALT) and bilirubin, according to Kara M. Kelly, MD, of Columbia University, and colleagues.
The study "provides preliminary evidence that milk thistle may be a safe, effective, supportive-care agent," the researchers concluded in an online report in Cancer.
"Milk thistle needs to be studied further, to see how effective it is for a longer course of treatment, and whether it works well in reducing liver inflammation in other types of cancers and with other types of chemotherapy," Kelly said in a press release issued by the American Cancer Society, publisher of Cancer. "However, our results are promising as there are no substitute medications for treating liver toxicity."
Action Points
* Explain to interested patients that liver toxicity often limits the chemotherapy doses that may be given, reducing the effectiveness of cancer treatment.
* Explain that milk thistle appeared to be safe in the study, but its effectiveness in reducing liver toxicity was relatively modest.
Milk thistle (Silybum marianum) is an herbal plant, native to Mediterranean Europe, North Africa and the Middle East, that has been shown to protect the liver and kidneys against damage from known toxins. Extracts are widely available in drugstores and herbal medicine shops, as well as from Internet vendors.
The version used in the current study was a 1:2 mixture of silibinin, believed to be the most active component of the herb, and soy phosphatidylcholine to improve the former's bioavailability.
Among the herb's purported benefits is limiting liver toxicity from cancer chemotherapy, but this had not previously been tested in a placebo-controlled trial.
So Kelly and colleagues assigned 50 children receiving treatment for ALL with a regimen of vincristine, methotrexate, 6-mercaptopurine or thioguanine, and prednisone or dexamethasone to receive daily doses of the milk thistle product or placebo.
Participants ranged in age from under two to 19 (mean age 8.7 in the milk thistle group, 7 in the placebo group). About 60% in each group were classed as standard risk and the rest were high risk.
Milk thistle was given in quantities designed to equate to a silibinin dose of 5.1 mg/kg/day, for 28 days.
Levels of AST, ALT, and bilirubin were measured at baseline and at days 28 and 56.
The only significant difference between the milk thistle and placebo groups in these outcomes was for AST at day 56, with mean levels of about 47 U/L with milk thistle versus 67 U/L with placebo (P=0.04). Mean AST levels were also lower at day 28, but the difference was smaller and not significant.
ALT levels were slightly higher on day 28 in the milk thistle group versus placebo. On day 56, mean ALT levels were 122 U/L with milk thistle versus 140 U/L with placebo, but the P value remained above 0.05.
Bilirubin levels were virtually identical in the two groups at day 28. They were somewhat lower at day 56 with milk thistle (0.70 versus 0.87 in the placebo group) but this also failed to reach significance.
Chemotherapy dose reductions because of toxicity were also somewhat less common in the milk thistle group, with 61% taking reductions compared with 73% of the placebo group (not significant).
Milk thistle appeared to have no impact on delays in planned chemotherapy, and grade 3-4 toxicities were, if anything, more frequent in the actively-treated group.
During the first four weeks of treatment, five patients in the milk thistle group and three taking placebo experienced grade 3-4 hepatic toxicity. From day 28 to 56, eight children on milk thistle and five in the placebo group had grade 3-4 hepatic toxicity.
Kelly and colleagues said there were no toxicities or other untoward results attributable to the milk thistle. They suggested that the equivocal efficacy findings could have resulted from inadequate dosing of milk thistle, especially since testing of plasma samples from 18 children in the study failed to find detectable levels of silibinin in any patient.
"An evaluation of clinical literature shows a wide range of therapeutic doses and duration," they noted in their report, adding that they had chosen a "conservative" dose level and duration to be on the safe side.
It's also possible that children metabolize silibinin at different rates from adults, which would account for the lack of detectable silibinin in plasma samples.
Finally, Kelly and colleagues noted that compliance was poorer in the milk thistle group: 68% of planned doses were given, compared with 96% of placebo capsules. The milk thistle product was identical in smell and taste to the placebo.
The only difference the researchers identified that might have accounted for the compliance disparity was age. The milk thistle group had a significantly higher mean age, and noncompliant patients were significantly older than compliant children (mean 13.1 versus 6.9 years old, P=0.01).
"Future clinical trials should explore milk thistle in the setting of patients in which hepatic toxicity prevents provision of the recommended chemotherapy in individuals with cancer," Kelly and colleagues concluded.
The study was funded by the American Institute for Cancer Research, the Tamarind Foundation, and the National Cancer Institute. Study drugs were donated by Thorn Research, which produces the milk thistle extract used in the study.
Study authors reported no potential conflicts of interest.
Genotype C Is Associated With More Severe Liver Fibrosis Than Genotype B
Hepatitis B Virus Genotype C Is Associated With More Severe Liver Fibrosis Than Genotype B
Clinical Gastroenterology and Hepatology Dec 2009
Henry Lik–Yuen ChanCorresponding Author Informationemail address, Grace Lai–Hung Wong, Chi–Hang Tse, Angel Mei–Ling Chim, Karen Kar–Lum Yiu, Hoi–Yun Chan, Joseph Jao–Yiu Sung, Vincent Wai–Sun Wong
ABSTRACT
Background & Aims
Histologic analyses of liver fibrosis have been limited by small sample sizes and the predominance of samples from patients with active hepatitis.
Methods
We performed a prospective study of transient elastography in treatment-naive patients with chronic hepatitis B, to investigate the relationship between hepatitis B virus (HBV) genotype and liver fibrosis. A validated liver stiffness measurement algorithm was used to define insignificant fibrosis and advanced fibrosis.
Results
Of 1106 patients, 711 (64%) were older than age 40, 370 (34%) had positive test results for hepatitis B e antigen (HBeAg), and 386 (35%) had increased serum levels of alanine aminotransferase. Of the patients, 524 (49%) had genotype B and 582 (51%) had genotype C HBV infection. Patients with genotype C infection had insignificant fibrosis less often (42% vs 55%; P < .0001) and advanced fibrosis more often (25% vs 19%; P = .015) than those infected with genotype B HBV. The difference in the severity of liver fibrosis between the 2 HBV genotypes was most marked among patients older than age 40 and those who tested negative for HBeAg. The mean age of patients infected by genotype C was greater than that of patients infected by genotype B HBV (41 vs 36 y). Among patients who were older than age 40 and tested negative for HBeAg, those with genotype C infection had higher levels of HBV DNA and alanine aminotransferase than those with genotype B HBV.
Conclusions
Genotype C HBV was associated with more severe liver fibrosis than genotype B HBV, probably because of delayed HBeAg seroconversion and prolonged active disease.
Clinical Gastroenterology and Hepatology Dec 2009
Henry Lik–Yuen ChanCorresponding Author Informationemail address, Grace Lai–Hung Wong, Chi–Hang Tse, Angel Mei–Ling Chim, Karen Kar–Lum Yiu, Hoi–Yun Chan, Joseph Jao–Yiu Sung, Vincent Wai–Sun Wong
ABSTRACT
Background & Aims
Histologic analyses of liver fibrosis have been limited by small sample sizes and the predominance of samples from patients with active hepatitis.
Methods
We performed a prospective study of transient elastography in treatment-naive patients with chronic hepatitis B, to investigate the relationship between hepatitis B virus (HBV) genotype and liver fibrosis. A validated liver stiffness measurement algorithm was used to define insignificant fibrosis and advanced fibrosis.
Results
Of 1106 patients, 711 (64%) were older than age 40, 370 (34%) had positive test results for hepatitis B e antigen (HBeAg), and 386 (35%) had increased serum levels of alanine aminotransferase. Of the patients, 524 (49%) had genotype B and 582 (51%) had genotype C HBV infection. Patients with genotype C infection had insignificant fibrosis less often (42% vs 55%; P < .0001) and advanced fibrosis more often (25% vs 19%; P = .015) than those infected with genotype B HBV. The difference in the severity of liver fibrosis between the 2 HBV genotypes was most marked among patients older than age 40 and those who tested negative for HBeAg. The mean age of patients infected by genotype C was greater than that of patients infected by genotype B HBV (41 vs 36 y). Among patients who were older than age 40 and tested negative for HBeAg, those with genotype C infection had higher levels of HBV DNA and alanine aminotransferase than those with genotype B HBV.
Conclusions
Genotype C HBV was associated with more severe liver fibrosis than genotype B HBV, probably because of delayed HBeAg seroconversion and prolonged active disease.
Factors That Predict Response of Patients With Hepatitis B
Factors That Predict Response of Patients With Hepatitis B e Antigen–Positive Chronic Hepatitis B to Peginterferon-Alfa
Gastroenterology Dec 2009
Erik H.C.J. Buster, Bettina E. Hansen‡, George K.K. Lau§, Teerha Piratvisuth∥, Stefan Zeuzem¶, Ewout W. Steyerberg#, Harry L.A. Janssen
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
‡ Department of Epidemiology and Biostatistics, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
# Department of Public Health, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
§ Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong SAR, China
∥ Department of Medicine, Songklanakarin Hospital, Songkla, Thailand
¶ Medizinische Klinik I, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany
Received 25 March 2009; accepted 26 August 2009. published online 07 September 2009.
ABSTRACT
Background & Aims
Therapy with pegylated interferon (PEG-IFN)–alfa results in sustained response in a minority of patients with chronic hepatitis B virus (HBV) infection and has considerable side effects. We analyzed data from the 2 largest global trials of hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B to determine which are most likely to respond to PEG-IFN–alfa therapy.
Methods
The study included 542 patients treated with PEG-IFN–alfa-2a (180 μg/wk, 48 wk) and 266 patients treated with PEG-IFN–alfa-2b (100 μg/wk, 52 wk). Eighty-seven patients were excluded, leaving 721 patients for analysis. A sustained response was defined as HBeAg loss and HBV-DNA level less than 2.0 × 103 IU/mL 6 months after treatment. Logistic regression analysis was used to identify predictors of sustained response and a multivariable model was constructed.
Results
HBV genotype, high levels of alanine aminotransferase (ALT; ≥2 × upper limit of normal), low levels of HBV DNA (<2.0 × 108 IU/mL), female sex, older age, and absence of previous IFN therapy predicted a sustained response. Genotype A patients with high ALT and/or low HBV-DNA levels had a high predicted probability (>30%) of a sustained response. The strongest predictors of response were a high level of ALT in genotype B patients and a low level of HBV DNA in genotype C patients. Genotype D patients had a low chance of sustained response, irrespective of ALT or HBV-DNA levels.
Conclusions
The best candidates for a sustained response to PEG-IFN–alfa are genotype A patients with high levels of ALT or low levels of HBV DNA, and genotypes B and C patients who have both high levels of ALT and low HBV DNA. Genotype D patients have a low chance of sustained response.
Funding The Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study was supported by a research grant from Roche (Basel, Switzerland). The HBV99-01 study was organized and sponsored by the Foundation for Liver Research (SLO), Rotterdam, The Netherlands. Financial support and study medication for the HBV99-01 study was provided by Schering-Plough International (Kenilworth, NJ) and GlaxoSmithKline (Greenford, UK).
Hepatitis B is a major global health problem. The World Health Organization reported that there are more than 400 million carriers in the world, approximately 75% of whom reside in Asia and the Western Pacific.1 In this part of the world, hepatitis B virus (HBV) infection usually is acquired perinatally or in early childhood. Most patients from these areas typically have hepatitis B e antigen (HBeAg)-positive chronic hepatitis B with high HBV-DNA levels, and they develop moderate to severe hepatic inflammation with increased alanine aminotransferase (ALT) levels after 10–30 years of infection.2 In contrast, patients infected in late childhood, adolescence, or adulthood present with increased aminotransferase levels after a shorter duration of infection. Although spontaneous HBeAg seroconversion occurs in the majority of HBeAg-positive patients, the duration of hepatic inflammation can be prolonged and severe, and may result in cirrhosis. Therefore, antiviral treatment is indicated in patients who remain HBeAg positive with high HBV-DNA levels after a 3- to 6-month period of increased ALT levels.3
Successful treatment of chronic HBV infection with loss of HBeAg, decline in serum HBV-DNA level, and normalization of ALT level is associated with favorable long-term outcome, independent of the antiviral drug used.4, 5 In HBeAg-positive patients, sustained clearance of HBeAg from serum is associated with a higher likelihood of losing hepatitis B surface antigen (HBsAg), reduced incidence of cirrhosis and hepatocellular carcinoma (HCC), and improved survival.5, 6, 7, 8 Of currently available drugs for the treatment of chronic hepatitis B, pegylated interferon (PEG-IFN) still results in the highest rate of off-treatment sustained response after a 1-year course of therapy.9, 10, 11, 12 Furthermore, responders to IFN-based therapy have a considerable chance of losing HBsAg, which has been observed in 12%–65% of patients within 5 years after HBeAg loss.7, 8, 13, 14, 15, 16, 17, 18 Treatment with PEG-IFN, however, often is complicated by the occurrence of side effects such as flu-like symptoms, cytopenia, and depression.19 Nucleos(t)ide analogues such as lamivudine, adefovir, entecavir, and tenofovir on the other hand are well tolerated, but because of the modest seroconversion rate and the high risk of posttreatment relapse, prolonged therapy usually is required.20 Nowadays, maintenance of virologic response over prolonged periods is feasible,21 but still may pose a considerable risk for resistance in the long term.22, 23, 24
Because treatment with both PEG-IFN and nucleos(t)ide analogues has proven effective, but also have their advantages and limitations, the question arises of what treatment regimen should be used as first-line therapy in which patients. Both the chance of achieving response and specific patient characteristics play a role in the decision on what type of antiviral therapy should be started. Recently performed studies with 1 year of PEG-IFN in HBeAg-positive patients identified high baseline ALT levels, low baseline HBV-DNA levels, absence of previous IFN therapy, low baseline HBeAg levels, and HBV genotype A or B as predictors of response.10, 25, 26 Current guidelines do not provide specific recommendations as to which patients should be treated with peginterferon27; the earlier-mentioned studies were considered to provide insufficient evidence for such recommendations. The aim of this study therefore was to develop a solid model for the prediction of sustained response to PEG-IFN in individual HBeAg-positive patients, which would allow physicians throughout the world to choose the optimal candidates for treatment with this drug.
Discussion
We combined the data of the 2 largest studies investigating PEG-IFN in HBeAg-positive chronic hepatitis B to develop a model for the prediction of response to PEG-IFN in all HBV genotypes. Although the model is based on the data of patients enrolled in randomized clinical trials with predefined inclusion and exclusion criteria, generalizability of our results probably is good because of the large sample size and wide geographic distribution of the patients. We provided nomograms that can be used to calculate the predicted probability of response in individual patients. A rapid estimate can be obtained from the provided flowcharts.
We recommend starting PEG-IFN therapy in patients with the highest chance of achieving sustained response (Table 2). We arbitrarily chose those with a predicted probability of sustained response of at least 30% to be good candidates for PEG-IFN therapy. About 25% of patients included in this study had a predicted probability of sustained response above this level. This includes all HBV genotype A–infected patients, except for those with low ALT and high HBV-DNA levels. In addition, genotypes B- and C–infected patients with high ALT and low HBV-DNA levels have a high likelihood of response to PEG-IFN. All remaining patients are moderate candidates for PEG-IFN except for those with genotype D, who have a rather low chance of achieving sustained response and are in our view generally not candidates for treatment with PEG-IFN. It should be noted that Table 2 provides recommendations for patient groups, not individual patients. In selected patients, the given response rate in Table 2 thus may differ slightly from the more accurate predicted probability of response obtained from the nomograms.
With the licensing of PEG-IFN and an additional 5 nucleos(t)ide analogues for the treatment of chronic hepatitis B in past years, choice of antiviral therapy has become more important and more complex at the same time. Because both treatment with IFN-based therapy and nucleos(t)ide analogue therapy have proven effective and can improve long-term outcome, the pros and cons of these drugs as well as patient-specific characteristics should be taken into consideration. All of the major practice guidelines have advocated IFN-based therapy as potential first-line therapy for both HBeAg-positive and HBeAg-negative patients,3, 27, 33, 34 particularly because sustained response and HBsAg loss seem to occur more often with IFN and PEG-IFN than with the direct antiviral agents.20 To reduce the risk of relapse, nucleos(t)ide analogue therapy can be extended for several months after HBeAg seroconversion because this reduces relapse rates.35, 36 HBeAg seroconversion was sustained in 86% of patients treated with telbivudine or lamivudine who discontinued therapy after at least 6 months of maintenance therapy.37, 38 Whether these responses also can be sustained in the long term, however, still is unknown.
However, the use of PEG-IFN currently accounts for no more than 10% of all prescriptions for the treatment of chronic hepatitis B.39 The relatively low use of PEG-IFN may be explained by its significant side effects and need for administration by injection. Furthermore, recommendations on the use of PEG-IFN in specific subsets of patients who are most likely to have a sustained response and HBsAg seroconversion were lacking. When we are able to identify patients with a high likelihood of response to PEG-IFN, the proportion of patients achieving sustained response after treatment with this drug probably can be increased.
Most studies investigating IFN-based therapy in HBeAg-positive chronic hepatitis B found that high baseline ALT level, low baseline HBV-DNA level, and HBV genotype A or B were associated with response.10, 25, 26, 40 In addition to these factors, we identified sex and age as predictors of response to PEG-IFN. It should be mentioned that in both studies more men than women were included. We found that the influence of sex, age, HBV DNA, and previous IFN therapy was significantly different across HBV genotypes. HBV genotype thus has great influence on the outcome of PEG-IFN therapy. Therefore, contrary to a statement on this topic in the newest guidelines from the European Association for the Study of the Liver,27 we believe that determination of HBV genotype is essential in all patients in whom sustained off-treatment response is pursued. Other potential approaches to tailor PEG-IFN therapy in chronic hepatitis B include quantification of serum HBeAg and HBsAg.41 These approaches still are being validated and are not routinely available to most physicians. Because of limited availability in clinical practice, we also chose not to include liver histology.
Previously we presented a model based on 266 HBeAg-positive patients participating in a single randomized trial.42 However, a vast majority of these patients were infected with HBV genotype A or D; only a small proportion of patients harbored HBV genotype B or C. To gain a good prediction model for all HBeAg-positive patients, we now combined the data of the 2 largest randomized trials investigating PEG-IFN in HBeAg-positive chronic hepatitis B. We showed that a model based on readily available baseline factors can provide an adequate prediction of sustained response. Ideally, a large confirmatory group would have been used for external validation. Unfortunately, such a group is not available. Clinical trials that currently still are ongoing may allow for further validation of the model in the near future.
Because substantial viral replication may persist despite HBeAg loss in some patients, a combined end point of HBeAg clearance from serum and low HBV-DNA level is crucial in HBeAg-positive chronic hepatitis B. Particularly, patients with HBV genotype non-A infection can develop mutations in the precore or core promoter region and still may be at risk for progressive liver disease despite HBeAg loss.6, 43 Both clearance of HBeAg and suppression of HBV replication are key events in the natural course and during antiviral therapy in HBeAg-positive chronic hepatitis B. HBeAg loss after IFN-based therapy was associated with reduced progression to cirrhosis and HCC, and improved survival.5, 44 In addition, large population studies have established a clear link between HBV viremia and the risk for HBV-related complications.45, 46 Serum HBV DNA was the strongest predictor of progression to cirrhosis and HCC, with a significantly higher risk for patients with an HBV-DNA level greater than 10,000 copies/mL (2000 IU/mL) as compared with those with a serum HBV-DNA level less than 300 copies/mL (relative risk, 2.5; 95% CI, 1.6–3.8; and relative risk, 2.3; 95% CI, 1.1–4.9 for developing cirrhosis and HCC, respectively). Although the proportion of patients with undetectable HBV DNA was relatively low shortly after PEG-IFN therapy,10 it further increased with prolonged duration of follow-up evaluation.6 Because the presence of anti-HBe at 6 months posttreatment was not associated with long-term sustainability of response to PEG-IFN,6 the combined end point of HBeAg loss and low HBV DNA seems optimal.
The parties involved in this study agreed not to perform a direct comparison between the 2 formulations of PEG-IFN. However, the previously reported results of 2 studies included in this retrospective analysis were very similar.10, 11 Unfortunately, we cannot provide recommendations for HBeAg-negative patients because we only had data of HBeAg-positive patients treated with PEG-IFN. Because of the low sustained response rate in HBeAg-negative patients,47 PEG-IFN is given relatively less often to HBeAg-negative as compared with HBeAg-positive patients. Prediction of response to PEG-IFN therefore seems of greater importance in HBeAg-positive than in HBeAg-negative chronic hepatitis B.
In conclusion, we provide a practical tool to calculate the probability of sustained response to PEG-IFN in individual HBeAg-positive patients, which easily can be used in clinical practice and thus can allow for the selection of the optimal candidates for PEG-IFN therapy. Unfortunately, we were not able to perform external validation because such a database is not available. Clearly, this should be performed when an appropriate patient group is available. We recommend consideration of PEG-IFN therapy in all genotype A patients with either high ALT or low HBV-DNA levels, and in genotypes B– and C–infected patients with both high ALT and low HBV-DNA levels. HBeAg-positive genotype D–infected patients are generally not good candidates for treatment with PEG-IFN.
Results
Of 808 patients eligible for participation in this study, 87 were excluded because of missing values (n = 76) or infection with HBV genotype other than A–D (n = 11), leaving 721 patients for analysis. HBeAg loss, HBeAg seroconversion, and HBV-DNA level less than 10,000 copies/mL (<2.0 × 103 IU/mL) were observed in 254 (35.2%), 232 (32.2%), and 174 (24.1%) of 721 patients, respectively. Sustained response, defined as HBeAg loss and HBV-DNA level less than 10,000 copies/mL (<2.0 × 103 IU/mL) at 6 months posttreatment, was observed in 158 of 721 patients (21.9%). Sustained response was observed in 22.4% of patients treated with PEG-IFN alone and in 21.4% of those treated with PEG-IFN and lamivudine combination therapy (P = .73). Sustained response was observed in 37% of patients with genotype A, 25% with genotype B, 20% with genotype C, and 8% with genotype D.
There were no differences in baseline characteristics between patients enrolled and those excluded from participation in this study, except for a lower rate of previous IFN therapy among the participants than the excluded patients (14% vs 24%; P = .01). Baseline characteristics of patients with and without sustained response are given in Table 1. Patients with sustained response were older, more often were female, had higher baseline ALT and lower HBV-DNA levels, and were more likely to have genotype A but less likely to have genotype D infection compared with those without sustained response. The proportion of patients who previously were treated with IFN or lamivudine therapy did not differ between patients with sustained response and those without.
Predictors of Sustained Response
Factors associated with an increased likelihood of sustained response included HBV genotype A infection, high baseline ALT level, low baseline HBV-DNA level, female sex, and older age (Table 1). There was no association between sustained response and previous treatment with IFN or lamivudine on univariate analysis. By using multivariate analysis, high baseline ALT was found to be an independent predictor of sustained response (OR, 1.57 per 1 log10 × ULN increase; 95% CI, 1.19–2.09; P = .002). In addition, HBV genotype was associated with sustained response, with higher rates of sustained response in patients with genotype A (OR, 1; reference) than B (ORB vs ORA, 0.46; 95% CI, 0.21–0.99; P = .05), C (ORC vs ORA, 0.30; 95% CI, 0.16–0.59; P < .001), or D (ORD vs ORA, 0.08; 95% CI, 0.02–0.31; P < .001). The influence of sex, age, HBV DNA, and previous IFN therapy was significantly different across HBV genotypes (P < .02 for the interaction between HBV genotype and each of these factors). These variables therefore also were included in the model. We here describe the most important predictive factors. Genotype C– and D–infected females had a significantly higher chance of sustained response compared with males (OR, 2.78; 95% CI, 0.51–5.11; and OR, 7.69; 95% CI, 1.48–39.90; P < .02). Older age was associated with a significantly higher chance of sustained response in genotype A–infected patients (OR, 1.04 per year increase in age; 95% CI, 1.01–1.08; P = .01). High baseline HBV-DNA level was associated with a lower likelihood of sustained response in patients with genotypes A (OR, 0.57; 95% CI, 0.40–0.82; P = .003) and C (OR, 0.77; 95% CI, 0.65–0.91; P = .002). Previous IFN therapy resulted in a significantly lower chance of sustained response in patients with genotype A or D (OR, 0.21; 95% CI, 0.07–0.58; P = .003). We found no differences in the predictors of response for the 2 treatment groups.
Performance of the Model
The distribution of the predicted probabilities of sustained response in genotypes A–D is shown in Figure 1. The agreement between the predicted probabilities and the observed frequency of sustained response was good (P = .27 by the Hosmer–Lemeshow goodness-of-fit test). A multivariable model including the variables of age, sex, ALT level, HBV-DNA level, HBV genotype, and previous IFN therapy had adequate discriminative ability as shown by an AUC of 0.72 (95% CI, 0.67–0.77). The AUC was 0.75 (95% CI, 0.65–0.85), 0.65 (95% CI, 0.55–0.75), 0.68 (95% CI, 0.61–0.75), and 0.78 (95% CI, 0.65–0.92) for genotypes A–D, respectively. After bootstrap validation, the AUC was 0.69 (95% CI, 0.60–0.77). Because the influence of the predictors was significantly different across genotypes, a validated formula for the prediction of sustained response was generated for each HBV genotype separately. The PEG-IFN HBV Treatment Index is based on these formulas (Figure 2). An automated calculator can be found at www.liver-gi.nl/peg-ifn.
Application of the Model in Clinical Practice
To allow for application of the model in clinical practice, a nomogram for IFN-naive patients was generated from the validated formula for each of the HBV genotypes separately (Figure 2). These nomograms can be used for calculating the probability of sustained response in individual HBeAg-positive patients based on their sex, age, and ALT and HBV-DNA levels. Average response rates based on the presence of low (<2 × ULN) or high ALT levels (≥2 × ULN), and low (<9 log10 copies/mL [<2.0 × 108 IU/mL]) or high HBV-DNA levels (≥9 log10 copies/mL [≥2.0 × 108 IU/mL]) are shown in Figure 3.
Materials and Methods
Patients and Study Design
Individual data of 542 patients treated with PEG-IFN–alfa-2a 180 μg/wk for 48 weeks (271 patients with added lamivudine 100 mg/day) and 266 patients treated with PEG-IFN–alfa-2b 100 μg/wk for 52 weeks (130 patients with added lamivudine 100 mg/day) were analyzed.10, 11 Posttreatment follow-up evaluation lasted 6 months. Addition of lamivudine did not influence response rates at the end of the follow-up period (6 months posttreatment) in any way. For the current study, sustained response was defined as clearance of HBeAg from serum and HBV DNA less than 10,000 copies/mL (2000 IU/mL) at 6 months after treatment.
The inclusion and exclusion criteria were reported in detail previously and were similar for the 2 studies.10, 11 In short, patients were eligible if they had been HBsAg positive for at least 6 months, were HBeAg positive, had increased serum ALT levels between 1 and 10 times the upper limit of normal (ULN), had serum HBV-DNA levels greater than 1.0 × 105 copies/mL (2.0 × 104 IU/mL), and had findings on a liver biopsy within the preceding 12 months that were consistent with the presence of chronic hepatitis B. Exclusion criteria included decompensated liver disease, antiviral therapy within 6 months before randomization, viral co-infections (hepatitis C virus, hepatitis delta virus, or human immunodeficiency virus), or pre-existent neutropenia or thrombocytopenia.
Laboratory Testing
During therapy and posttreatment follow-up evaluation, all patients were monitored monthly by routine physical examination, as well as biochemical and hematologic assessments. ALT level was assessed locally and therefore expressed as times ULN. HBV DNA was assessed monthly using an in-house–developed Taqman (Applied Biosystems Inc, Foster City, CA) polymerase chain reaction assay based on the Eurohep standard (lower limit of detection, 373 copies/mL) or the Cobas Amplicor HBV Monitor Test (Roche Diagnostics, Basel, Switzerland).28 We compared the 2 HBV-DNA quantification assays and found an excellent correlation between the 2 assays (r = 0.930, P < .001). Plotting the difference against the average of the assays showed no significant correlation (Bland–Altman test; r = 0.12, P = .49), strengthening the conclusion that both assays are comparable in the dynamic range.6 HBeAg, anti-HBe, HBsAg, and anti-HBs were measured with the use of the AxSYM test (Abbott, Abbott Park, IL). HBV genotype analysis was performed by INNO-LiPA Assay (Innogenetics, Gent, Belgium).
Statistical Analysis
Statistical analysis was performed using the SPSS 15.0 program (SPSS, Inc, Chicago, IL) and the R 2.3.1 Project for Statistical Computing (Harrell's Design, HMisc and Foreign libraries).29 A P value less than .05 was considered statistically significant (all 2-tailed). We performed univariate logistic regression analysis to identify predictors of sustained response among the variables of age, sex, HBV genotype (A–D), serum HBV DNA (log10 copies/mL), ALT (ln ALT × ULN), treatment allocation (PEG-IFN monotherapy or combination therapy of PEG-IFN and lamivudine), and previous treatment with IFN or lamivudine. We used multivariable logistic regression analysis with backward stepwise selection, using a P value greater than .05 for removal of variables, to construct a multivariable linear model that provides a natural logarithm transformed prediction of sustained response. We used restricted cubic spline functions to assess the linearity of the effect of continuous variables. Interactions between variables were explored. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CI). Because there were interactions between HBV genotype and other factors, ORs for HBV genotype were calculated for 33-year-old (mean age), IFN-naive men with ALT and HBV-DNA levels fixed at 2 × ULN and 1.0 × 109 copies/mL (2.0 × 108 IU/mL), respectively.
Discrimination, which is the ability to distinguish patients who will achieve sustained response from those who will not, was quantified by the area under the receiver-operating characteristic curve (AUC). An AUC of 0.5 indicates no discriminative ability at all, whereas an AUC of 1.0 indicates perfect discrimination. Internal validity was assessed with bootstrap sampling.30, 31 Two hundred bootstrap samples were drawn with replacement and with the same size as the original sample. The final prediction model was constructed by applying the penalized maximum likelihood estimation acquired from the bootstrap samples.32 Nomograms for IFN-naive patients were constructed based on the logistic regression formulas. A nomogram allows for the approximate graphic computation of sustained response with points allocated to each variable based on the logistic regression formula. To develop a simple rule for each of the genotypes independent of sex and age, the predicted probability of sustained response in different patient subgroups was calculated with the logistic regression formulas. Because sex and age also predicted sustained response, but were not included in the flowchart, age was fixed at the respective mean value of each subgroup and the mean predicted probability of sustained response for males and females was calculated. For serum ALT, a low level (<2 × ULN) was considered to be between 1 × ULN and 2 × ULN, and a high level (≥2 × ULN) was considered to be between 2 × ULN and 10 × ULN. For serum HBV DNA, a low level (<1.0 × 109 copies/mL [<2.0 × 108 IU/mL]) was considered to be between 1.0 × 107 copies/mL (2.0 × 106 IU/mL) and 1.0 × 109 copies/mL (2.0 × 108 IU/mL), and a high level (≥1.0 × 109 copies/mL [≥2.0 × 108 IU/mL]) was considered to be between 1.0 × 109 copies/mL (2.0 × 108 IU/mL) and 1.0 × 1011 copies/mL (2.0 × 1010 IU/mL). These cut-off levels were chosen because the majority of patients had ALT (95%) and HBV-DNA (80%) levels between these values. In addition, these cut-off levels generally are used in clinical practice and are recommended by international guidelines for the treatment of chronic hepatitis B.3, 27, 33, 34
Gastroenterology Dec 2009
Erik H.C.J. Buster, Bettina E. Hansen‡, George K.K. Lau§, Teerha Piratvisuth∥, Stefan Zeuzem¶, Ewout W. Steyerberg#, Harry L.A. Janssen
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
‡ Department of Epidemiology and Biostatistics, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
# Department of Public Health, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
§ Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong SAR, China
∥ Department of Medicine, Songklanakarin Hospital, Songkla, Thailand
¶ Medizinische Klinik I, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany
Received 25 March 2009; accepted 26 August 2009. published online 07 September 2009.
ABSTRACT
Background & Aims
Therapy with pegylated interferon (PEG-IFN)–alfa results in sustained response in a minority of patients with chronic hepatitis B virus (HBV) infection and has considerable side effects. We analyzed data from the 2 largest global trials of hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B to determine which are most likely to respond to PEG-IFN–alfa therapy.
Methods
The study included 542 patients treated with PEG-IFN–alfa-2a (180 μg/wk, 48 wk) and 266 patients treated with PEG-IFN–alfa-2b (100 μg/wk, 52 wk). Eighty-seven patients were excluded, leaving 721 patients for analysis. A sustained response was defined as HBeAg loss and HBV-DNA level less than 2.0 × 103 IU/mL 6 months after treatment. Logistic regression analysis was used to identify predictors of sustained response and a multivariable model was constructed.
Results
HBV genotype, high levels of alanine aminotransferase (ALT; ≥2 × upper limit of normal), low levels of HBV DNA (<2.0 × 108 IU/mL), female sex, older age, and absence of previous IFN therapy predicted a sustained response. Genotype A patients with high ALT and/or low HBV-DNA levels had a high predicted probability (>30%) of a sustained response. The strongest predictors of response were a high level of ALT in genotype B patients and a low level of HBV DNA in genotype C patients. Genotype D patients had a low chance of sustained response, irrespective of ALT or HBV-DNA levels.
Conclusions
The best candidates for a sustained response to PEG-IFN–alfa are genotype A patients with high levels of ALT or low levels of HBV DNA, and genotypes B and C patients who have both high levels of ALT and low HBV DNA. Genotype D patients have a low chance of sustained response.
Funding The Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study was supported by a research grant from Roche (Basel, Switzerland). The HBV99-01 study was organized and sponsored by the Foundation for Liver Research (SLO), Rotterdam, The Netherlands. Financial support and study medication for the HBV99-01 study was provided by Schering-Plough International (Kenilworth, NJ) and GlaxoSmithKline (Greenford, UK).
Hepatitis B is a major global health problem. The World Health Organization reported that there are more than 400 million carriers in the world, approximately 75% of whom reside in Asia and the Western Pacific.1 In this part of the world, hepatitis B virus (HBV) infection usually is acquired perinatally or in early childhood. Most patients from these areas typically have hepatitis B e antigen (HBeAg)-positive chronic hepatitis B with high HBV-DNA levels, and they develop moderate to severe hepatic inflammation with increased alanine aminotransferase (ALT) levels after 10–30 years of infection.2 In contrast, patients infected in late childhood, adolescence, or adulthood present with increased aminotransferase levels after a shorter duration of infection. Although spontaneous HBeAg seroconversion occurs in the majority of HBeAg-positive patients, the duration of hepatic inflammation can be prolonged and severe, and may result in cirrhosis. Therefore, antiviral treatment is indicated in patients who remain HBeAg positive with high HBV-DNA levels after a 3- to 6-month period of increased ALT levels.3
Successful treatment of chronic HBV infection with loss of HBeAg, decline in serum HBV-DNA level, and normalization of ALT level is associated with favorable long-term outcome, independent of the antiviral drug used.4, 5 In HBeAg-positive patients, sustained clearance of HBeAg from serum is associated with a higher likelihood of losing hepatitis B surface antigen (HBsAg), reduced incidence of cirrhosis and hepatocellular carcinoma (HCC), and improved survival.5, 6, 7, 8 Of currently available drugs for the treatment of chronic hepatitis B, pegylated interferon (PEG-IFN) still results in the highest rate of off-treatment sustained response after a 1-year course of therapy.9, 10, 11, 12 Furthermore, responders to IFN-based therapy have a considerable chance of losing HBsAg, which has been observed in 12%–65% of patients within 5 years after HBeAg loss.7, 8, 13, 14, 15, 16, 17, 18 Treatment with PEG-IFN, however, often is complicated by the occurrence of side effects such as flu-like symptoms, cytopenia, and depression.19 Nucleos(t)ide analogues such as lamivudine, adefovir, entecavir, and tenofovir on the other hand are well tolerated, but because of the modest seroconversion rate and the high risk of posttreatment relapse, prolonged therapy usually is required.20 Nowadays, maintenance of virologic response over prolonged periods is feasible,21 but still may pose a considerable risk for resistance in the long term.22, 23, 24
Because treatment with both PEG-IFN and nucleos(t)ide analogues has proven effective, but also have their advantages and limitations, the question arises of what treatment regimen should be used as first-line therapy in which patients. Both the chance of achieving response and specific patient characteristics play a role in the decision on what type of antiviral therapy should be started. Recently performed studies with 1 year of PEG-IFN in HBeAg-positive patients identified high baseline ALT levels, low baseline HBV-DNA levels, absence of previous IFN therapy, low baseline HBeAg levels, and HBV genotype A or B as predictors of response.10, 25, 26 Current guidelines do not provide specific recommendations as to which patients should be treated with peginterferon27; the earlier-mentioned studies were considered to provide insufficient evidence for such recommendations. The aim of this study therefore was to develop a solid model for the prediction of sustained response to PEG-IFN in individual HBeAg-positive patients, which would allow physicians throughout the world to choose the optimal candidates for treatment with this drug.
Discussion
We combined the data of the 2 largest studies investigating PEG-IFN in HBeAg-positive chronic hepatitis B to develop a model for the prediction of response to PEG-IFN in all HBV genotypes. Although the model is based on the data of patients enrolled in randomized clinical trials with predefined inclusion and exclusion criteria, generalizability of our results probably is good because of the large sample size and wide geographic distribution of the patients. We provided nomograms that can be used to calculate the predicted probability of response in individual patients. A rapid estimate can be obtained from the provided flowcharts.
We recommend starting PEG-IFN therapy in patients with the highest chance of achieving sustained response (Table 2). We arbitrarily chose those with a predicted probability of sustained response of at least 30% to be good candidates for PEG-IFN therapy. About 25% of patients included in this study had a predicted probability of sustained response above this level. This includes all HBV genotype A–infected patients, except for those with low ALT and high HBV-DNA levels. In addition, genotypes B- and C–infected patients with high ALT and low HBV-DNA levels have a high likelihood of response to PEG-IFN. All remaining patients are moderate candidates for PEG-IFN except for those with genotype D, who have a rather low chance of achieving sustained response and are in our view generally not candidates for treatment with PEG-IFN. It should be noted that Table 2 provides recommendations for patient groups, not individual patients. In selected patients, the given response rate in Table 2 thus may differ slightly from the more accurate predicted probability of response obtained from the nomograms.
With the licensing of PEG-IFN and an additional 5 nucleos(t)ide analogues for the treatment of chronic hepatitis B in past years, choice of antiviral therapy has become more important and more complex at the same time. Because both treatment with IFN-based therapy and nucleos(t)ide analogue therapy have proven effective and can improve long-term outcome, the pros and cons of these drugs as well as patient-specific characteristics should be taken into consideration. All of the major practice guidelines have advocated IFN-based therapy as potential first-line therapy for both HBeAg-positive and HBeAg-negative patients,3, 27, 33, 34 particularly because sustained response and HBsAg loss seem to occur more often with IFN and PEG-IFN than with the direct antiviral agents.20 To reduce the risk of relapse, nucleos(t)ide analogue therapy can be extended for several months after HBeAg seroconversion because this reduces relapse rates.35, 36 HBeAg seroconversion was sustained in 86% of patients treated with telbivudine or lamivudine who discontinued therapy after at least 6 months of maintenance therapy.37, 38 Whether these responses also can be sustained in the long term, however, still is unknown.
However, the use of PEG-IFN currently accounts for no more than 10% of all prescriptions for the treatment of chronic hepatitis B.39 The relatively low use of PEG-IFN may be explained by its significant side effects and need for administration by injection. Furthermore, recommendations on the use of PEG-IFN in specific subsets of patients who are most likely to have a sustained response and HBsAg seroconversion were lacking. When we are able to identify patients with a high likelihood of response to PEG-IFN, the proportion of patients achieving sustained response after treatment with this drug probably can be increased.
Most studies investigating IFN-based therapy in HBeAg-positive chronic hepatitis B found that high baseline ALT level, low baseline HBV-DNA level, and HBV genotype A or B were associated with response.10, 25, 26, 40 In addition to these factors, we identified sex and age as predictors of response to PEG-IFN. It should be mentioned that in both studies more men than women were included. We found that the influence of sex, age, HBV DNA, and previous IFN therapy was significantly different across HBV genotypes. HBV genotype thus has great influence on the outcome of PEG-IFN therapy. Therefore, contrary to a statement on this topic in the newest guidelines from the European Association for the Study of the Liver,27 we believe that determination of HBV genotype is essential in all patients in whom sustained off-treatment response is pursued. Other potential approaches to tailor PEG-IFN therapy in chronic hepatitis B include quantification of serum HBeAg and HBsAg.41 These approaches still are being validated and are not routinely available to most physicians. Because of limited availability in clinical practice, we also chose not to include liver histology.
Previously we presented a model based on 266 HBeAg-positive patients participating in a single randomized trial.42 However, a vast majority of these patients were infected with HBV genotype A or D; only a small proportion of patients harbored HBV genotype B or C. To gain a good prediction model for all HBeAg-positive patients, we now combined the data of the 2 largest randomized trials investigating PEG-IFN in HBeAg-positive chronic hepatitis B. We showed that a model based on readily available baseline factors can provide an adequate prediction of sustained response. Ideally, a large confirmatory group would have been used for external validation. Unfortunately, such a group is not available. Clinical trials that currently still are ongoing may allow for further validation of the model in the near future.
Because substantial viral replication may persist despite HBeAg loss in some patients, a combined end point of HBeAg clearance from serum and low HBV-DNA level is crucial in HBeAg-positive chronic hepatitis B. Particularly, patients with HBV genotype non-A infection can develop mutations in the precore or core promoter region and still may be at risk for progressive liver disease despite HBeAg loss.6, 43 Both clearance of HBeAg and suppression of HBV replication are key events in the natural course and during antiviral therapy in HBeAg-positive chronic hepatitis B. HBeAg loss after IFN-based therapy was associated with reduced progression to cirrhosis and HCC, and improved survival.5, 44 In addition, large population studies have established a clear link between HBV viremia and the risk for HBV-related complications.45, 46 Serum HBV DNA was the strongest predictor of progression to cirrhosis and HCC, with a significantly higher risk for patients with an HBV-DNA level greater than 10,000 copies/mL (2000 IU/mL) as compared with those with a serum HBV-DNA level less than 300 copies/mL (relative risk, 2.5; 95% CI, 1.6–3.8; and relative risk, 2.3; 95% CI, 1.1–4.9 for developing cirrhosis and HCC, respectively). Although the proportion of patients with undetectable HBV DNA was relatively low shortly after PEG-IFN therapy,10 it further increased with prolonged duration of follow-up evaluation.6 Because the presence of anti-HBe at 6 months posttreatment was not associated with long-term sustainability of response to PEG-IFN,6 the combined end point of HBeAg loss and low HBV DNA seems optimal.
The parties involved in this study agreed not to perform a direct comparison between the 2 formulations of PEG-IFN. However, the previously reported results of 2 studies included in this retrospective analysis were very similar.10, 11 Unfortunately, we cannot provide recommendations for HBeAg-negative patients because we only had data of HBeAg-positive patients treated with PEG-IFN. Because of the low sustained response rate in HBeAg-negative patients,47 PEG-IFN is given relatively less often to HBeAg-negative as compared with HBeAg-positive patients. Prediction of response to PEG-IFN therefore seems of greater importance in HBeAg-positive than in HBeAg-negative chronic hepatitis B.
In conclusion, we provide a practical tool to calculate the probability of sustained response to PEG-IFN in individual HBeAg-positive patients, which easily can be used in clinical practice and thus can allow for the selection of the optimal candidates for PEG-IFN therapy. Unfortunately, we were not able to perform external validation because such a database is not available. Clearly, this should be performed when an appropriate patient group is available. We recommend consideration of PEG-IFN therapy in all genotype A patients with either high ALT or low HBV-DNA levels, and in genotypes B– and C–infected patients with both high ALT and low HBV-DNA levels. HBeAg-positive genotype D–infected patients are generally not good candidates for treatment with PEG-IFN.
Results
Of 808 patients eligible for participation in this study, 87 were excluded because of missing values (n = 76) or infection with HBV genotype other than A–D (n = 11), leaving 721 patients for analysis. HBeAg loss, HBeAg seroconversion, and HBV-DNA level less than 10,000 copies/mL (<2.0 × 103 IU/mL) were observed in 254 (35.2%), 232 (32.2%), and 174 (24.1%) of 721 patients, respectively. Sustained response, defined as HBeAg loss and HBV-DNA level less than 10,000 copies/mL (<2.0 × 103 IU/mL) at 6 months posttreatment, was observed in 158 of 721 patients (21.9%). Sustained response was observed in 22.4% of patients treated with PEG-IFN alone and in 21.4% of those treated with PEG-IFN and lamivudine combination therapy (P = .73). Sustained response was observed in 37% of patients with genotype A, 25% with genotype B, 20% with genotype C, and 8% with genotype D.
There were no differences in baseline characteristics between patients enrolled and those excluded from participation in this study, except for a lower rate of previous IFN therapy among the participants than the excluded patients (14% vs 24%; P = .01). Baseline characteristics of patients with and without sustained response are given in Table 1. Patients with sustained response were older, more often were female, had higher baseline ALT and lower HBV-DNA levels, and were more likely to have genotype A but less likely to have genotype D infection compared with those without sustained response. The proportion of patients who previously were treated with IFN or lamivudine therapy did not differ between patients with sustained response and those without.
Predictors of Sustained Response
Factors associated with an increased likelihood of sustained response included HBV genotype A infection, high baseline ALT level, low baseline HBV-DNA level, female sex, and older age (Table 1). There was no association between sustained response and previous treatment with IFN or lamivudine on univariate analysis. By using multivariate analysis, high baseline ALT was found to be an independent predictor of sustained response (OR, 1.57 per 1 log10 × ULN increase; 95% CI, 1.19–2.09; P = .002). In addition, HBV genotype was associated with sustained response, with higher rates of sustained response in patients with genotype A (OR, 1; reference) than B (ORB vs ORA, 0.46; 95% CI, 0.21–0.99; P = .05), C (ORC vs ORA, 0.30; 95% CI, 0.16–0.59; P < .001), or D (ORD vs ORA, 0.08; 95% CI, 0.02–0.31; P < .001). The influence of sex, age, HBV DNA, and previous IFN therapy was significantly different across HBV genotypes (P < .02 for the interaction between HBV genotype and each of these factors). These variables therefore also were included in the model. We here describe the most important predictive factors. Genotype C– and D–infected females had a significantly higher chance of sustained response compared with males (OR, 2.78; 95% CI, 0.51–5.11; and OR, 7.69; 95% CI, 1.48–39.90; P < .02). Older age was associated with a significantly higher chance of sustained response in genotype A–infected patients (OR, 1.04 per year increase in age; 95% CI, 1.01–1.08; P = .01). High baseline HBV-DNA level was associated with a lower likelihood of sustained response in patients with genotypes A (OR, 0.57; 95% CI, 0.40–0.82; P = .003) and C (OR, 0.77; 95% CI, 0.65–0.91; P = .002). Previous IFN therapy resulted in a significantly lower chance of sustained response in patients with genotype A or D (OR, 0.21; 95% CI, 0.07–0.58; P = .003). We found no differences in the predictors of response for the 2 treatment groups.
Performance of the Model
The distribution of the predicted probabilities of sustained response in genotypes A–D is shown in Figure 1. The agreement between the predicted probabilities and the observed frequency of sustained response was good (P = .27 by the Hosmer–Lemeshow goodness-of-fit test). A multivariable model including the variables of age, sex, ALT level, HBV-DNA level, HBV genotype, and previous IFN therapy had adequate discriminative ability as shown by an AUC of 0.72 (95% CI, 0.67–0.77). The AUC was 0.75 (95% CI, 0.65–0.85), 0.65 (95% CI, 0.55–0.75), 0.68 (95% CI, 0.61–0.75), and 0.78 (95% CI, 0.65–0.92) for genotypes A–D, respectively. After bootstrap validation, the AUC was 0.69 (95% CI, 0.60–0.77). Because the influence of the predictors was significantly different across genotypes, a validated formula for the prediction of sustained response was generated for each HBV genotype separately. The PEG-IFN HBV Treatment Index is based on these formulas (Figure 2). An automated calculator can be found at www.liver-gi.nl/peg-ifn.
Application of the Model in Clinical Practice
To allow for application of the model in clinical practice, a nomogram for IFN-naive patients was generated from the validated formula for each of the HBV genotypes separately (Figure 2). These nomograms can be used for calculating the probability of sustained response in individual HBeAg-positive patients based on their sex, age, and ALT and HBV-DNA levels. Average response rates based on the presence of low (<2 × ULN) or high ALT levels (≥2 × ULN), and low (<9 log10 copies/mL [<2.0 × 108 IU/mL]) or high HBV-DNA levels (≥9 log10 copies/mL [≥2.0 × 108 IU/mL]) are shown in Figure 3.
Materials and Methods
Patients and Study Design
Individual data of 542 patients treated with PEG-IFN–alfa-2a 180 μg/wk for 48 weeks (271 patients with added lamivudine 100 mg/day) and 266 patients treated with PEG-IFN–alfa-2b 100 μg/wk for 52 weeks (130 patients with added lamivudine 100 mg/day) were analyzed.10, 11 Posttreatment follow-up evaluation lasted 6 months. Addition of lamivudine did not influence response rates at the end of the follow-up period (6 months posttreatment) in any way. For the current study, sustained response was defined as clearance of HBeAg from serum and HBV DNA less than 10,000 copies/mL (2000 IU/mL) at 6 months after treatment.
The inclusion and exclusion criteria were reported in detail previously and were similar for the 2 studies.10, 11 In short, patients were eligible if they had been HBsAg positive for at least 6 months, were HBeAg positive, had increased serum ALT levels between 1 and 10 times the upper limit of normal (ULN), had serum HBV-DNA levels greater than 1.0 × 105 copies/mL (2.0 × 104 IU/mL), and had findings on a liver biopsy within the preceding 12 months that were consistent with the presence of chronic hepatitis B. Exclusion criteria included decompensated liver disease, antiviral therapy within 6 months before randomization, viral co-infections (hepatitis C virus, hepatitis delta virus, or human immunodeficiency virus), or pre-existent neutropenia or thrombocytopenia.
Laboratory Testing
During therapy and posttreatment follow-up evaluation, all patients were monitored monthly by routine physical examination, as well as biochemical and hematologic assessments. ALT level was assessed locally and therefore expressed as times ULN. HBV DNA was assessed monthly using an in-house–developed Taqman (Applied Biosystems Inc, Foster City, CA) polymerase chain reaction assay based on the Eurohep standard (lower limit of detection, 373 copies/mL) or the Cobas Amplicor HBV Monitor Test (Roche Diagnostics, Basel, Switzerland).28 We compared the 2 HBV-DNA quantification assays and found an excellent correlation between the 2 assays (r = 0.930, P < .001). Plotting the difference against the average of the assays showed no significant correlation (Bland–Altman test; r = 0.12, P = .49), strengthening the conclusion that both assays are comparable in the dynamic range.6 HBeAg, anti-HBe, HBsAg, and anti-HBs were measured with the use of the AxSYM test (Abbott, Abbott Park, IL). HBV genotype analysis was performed by INNO-LiPA Assay (Innogenetics, Gent, Belgium).
Statistical Analysis
Statistical analysis was performed using the SPSS 15.0 program (SPSS, Inc, Chicago, IL) and the R 2.3.1 Project for Statistical Computing (Harrell's Design, HMisc and Foreign libraries).29 A P value less than .05 was considered statistically significant (all 2-tailed). We performed univariate logistic regression analysis to identify predictors of sustained response among the variables of age, sex, HBV genotype (A–D), serum HBV DNA (log10 copies/mL), ALT (ln ALT × ULN), treatment allocation (PEG-IFN monotherapy or combination therapy of PEG-IFN and lamivudine), and previous treatment with IFN or lamivudine. We used multivariable logistic regression analysis with backward stepwise selection, using a P value greater than .05 for removal of variables, to construct a multivariable linear model that provides a natural logarithm transformed prediction of sustained response. We used restricted cubic spline functions to assess the linearity of the effect of continuous variables. Interactions between variables were explored. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CI). Because there were interactions between HBV genotype and other factors, ORs for HBV genotype were calculated for 33-year-old (mean age), IFN-naive men with ALT and HBV-DNA levels fixed at 2 × ULN and 1.0 × 109 copies/mL (2.0 × 108 IU/mL), respectively.
Discrimination, which is the ability to distinguish patients who will achieve sustained response from those who will not, was quantified by the area under the receiver-operating characteristic curve (AUC). An AUC of 0.5 indicates no discriminative ability at all, whereas an AUC of 1.0 indicates perfect discrimination. Internal validity was assessed with bootstrap sampling.30, 31 Two hundred bootstrap samples were drawn with replacement and with the same size as the original sample. The final prediction model was constructed by applying the penalized maximum likelihood estimation acquired from the bootstrap samples.32 Nomograms for IFN-naive patients were constructed based on the logistic regression formulas. A nomogram allows for the approximate graphic computation of sustained response with points allocated to each variable based on the logistic regression formula. To develop a simple rule for each of the genotypes independent of sex and age, the predicted probability of sustained response in different patient subgroups was calculated with the logistic regression formulas. Because sex and age also predicted sustained response, but were not included in the flowchart, age was fixed at the respective mean value of each subgroup and the mean predicted probability of sustained response for males and females was calculated. For serum ALT, a low level (<2 × ULN) was considered to be between 1 × ULN and 2 × ULN, and a high level (≥2 × ULN) was considered to be between 2 × ULN and 10 × ULN. For serum HBV DNA, a low level (<1.0 × 109 copies/mL [<2.0 × 108 IU/mL]) was considered to be between 1.0 × 107 copies/mL (2.0 × 106 IU/mL) and 1.0 × 109 copies/mL (2.0 × 108 IU/mL), and a high level (≥1.0 × 109 copies/mL [≥2.0 × 108 IU/mL]) was considered to be between 1.0 × 109 copies/mL (2.0 × 108 IU/mL) and 1.0 × 1011 copies/mL (2.0 × 1010 IU/mL). These cut-off levels were chosen because the majority of patients had ALT (95%) and HBV-DNA (80%) levels between these values. In addition, these cut-off levels generally are used in clinical practice and are recommended by international guidelines for the treatment of chronic hepatitis B.3, 27, 33, 34
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