-Outlines Phase 2 Clinical Development Plan-
CAMBRIDGE, Mass.--(BUSINESS WIRE)--Idera Pharmaceuticals, Inc. (Nasdaq: IDRA) announced today preliminary data from a 4-week dose-ranging Phase 1 clinical trial of IMO-2125 in combination with ribavirin in 60 treatment-naïve patients with genotype 1 chronic hepatitis C virus (HCV) infection. In the trial, treatment with IMO-2125 in combination with ribavirin was well tolerated and achieved substantial decline in virus levels at two days after the first dose of IMO-2125 and after four weeks of treatment. IMO-2125 is a Toll-like Receptor 9 (TLR9) agonist which stimulates production of natural interferons and other antiviral cytokines
"In this study, IMO-2125 plus ribavirin was well tolerated with no treatment-related discontinuations, and demonstrated substantial antiviral activity," said Robert Arbeit, M.D., Vice President of Clinical Development at Idera. "We believe that IMO-2125 may provide an alternative immune modulatory component to pegylated interferons in the anticipated HCV therapy combinations using direct-acting antivirals. In this treatment scenario, effective stimulation of the host immune system through TLR activation could minimize the risk of viral breakthrough.”
"Based on the overall data from this trial and our Phase 1 clinical trial of IMO-2125 in null-responder HCV patients, our next step in clinical development will be a 12-week Phase 2 trial of IMO-2125 in combination with ribavirin in treatment-naïve HCV patients,” said Sudhir Agrawal, D.Phil., Chairman and Chief Executive Officer at Idera. “We expect that the objectives of the Phase 2 study will be to determine optimal dosing, provide longer-term safety data and generate additional antiviral activity data in support of the future clinical development of IMO-2125.”
IMO-2125 Phase 1 Clinical Trial in Treatment-naïve Genotype 1 HCV Patients
Study Design:
In this Phase 1 clinical trial, treatment-naïve genotype 1 HCV patients received IMO-2125 by subcutaneous injection over four weeks in combination with daily oral administration of standard weight-based doses of ribavirin in one of four regimens of 12 patients each. The four regimens of IMO-2125 were 0.08, 0.16, and 0.32 mg/kg once weekly and 0.16 mg/kg twice weekly. In addition, 12 patients received current standard of care treatment (Pegasys® plus ribavirin).
Study Results:
Safety
• Treatment with IMO-2125 in combination with ribavirin was well tolerated at all dose levels for four weeks of treatment, with no treatment-related serious adverse events and no treatment discontinuations.
• The most common adverse events observed in the IMO-2125 regimens were flu-like symptoms and injection site reactions.
• Of the 12 patients receiving the standard of care therapy in this trial, neutropenia requiring intervention occurred in two patients and platelet counts dropped below the normal range during the treatment period in seven patients. None of the 48 patients receiving IMO-2125 had neutropenia requiring intervention, and four of the 48 IMO-2125 patients had platelet counts drop below the normal range during the treatment period.
Antiviral Activity
• IMO-2125 induced substantial declines in viral levels at two days after the first dose at all dose levels.
• At the mid-week evaluation in the fourth week of treatment, mean viral load reductions with the three higher-dose IMO-2125 regimens ranged from -2.0 to -3.4 log10. Patients who received Pegasys® plus ribavirin achieved a mean viral load reduction of -3.8 log10 at the same timepoint.
• At the end of the fourth week of treatment, mean viral load reductions with the three higher-dose IMO-2125 regimens ranged from -0.6 to -2.4 log10. The mean viral load reduction for patients treated with Pegasys® plus ribavirin at the end of the fourth week of treatment was -3.4 log10.
• The initial dose level in this Phase 1 safety trial, 0.08 mg/kg/week, produced minimal changes in viral load although liver enzyme decreases were observed.
• Liver enzymes (AST/ALT) decreased during the treatment period and were within the normal range by the end of the fourth week of treatment in the majority of IMO-2125-treated patients.
• There was unequal distribution among the treatment groups of patients with poor prognostic factors at baseline, including CT or TT IL28B genotype, IP-10 values >600 pg/mL, and older age.
The Company plans to present detailed results of this study at a scientific meeting in 2011.
Planned Phase 2 Clinical Trial
In the planned 12-week Phase 2 randomized clinical trial, patients will be stratified for IL28B genotype (CC vs. CT/TT) and will receive either IMO-2125 plus ribavirin or Pegasys® plus ribavirin. The Company plans for recruitment of this clinical trial to start in the first quarter of 2011, pending regulatory concurrence. The Company expects that the objective of this clinical trial will be to provide the basis for subsequent clinical development of IMO-2125 as an alternative to pegylated-interferon in triple combination therapy with ribavirin and a direct-acting antiviral.
IMO-2125 Monotherapy Phase 1 Clinical Trial in Null-Responder HCV Patients
IMO-2125 has also been evaluated in a Phase 1 clinical trial in 51 null-responder HCV patients; 41 patients received IMO-2125 monotherapy at one of five dose levels and 10 patients received placebo once per week for four weeks. Interim safety, antiviral activity and mechanism of action data were presented for the once-weekly dosing regimens in April 2010 at the Annual Meeting of the European Association for the Study of the Liver and complete data were presented in October 2010 at the Annual Meeting of the American Association for the Study of Liver Diseases.
Seven patients were enrolled in an additional cohort to evaluate twice-weekly dosing of IMO-2125 at 0.16 mg/kg/dose. Consistent with the patients’ null-responder status, 6 of 7 patients had CT or TT IL28B genotype. There were no treatment-related serious adverse events or discontinuations. As previously observed, the most common adverse events were injection site reactions and flu-like symptoms. Three patients in this cohort achieved greater than 1 log10 reduction, ranging from -1.9 to -3.5 log10, in viral load at least once during the treatment period. One of the patients with CT genotype achieved HCV viral levels at the lower limit of quantification (100 copies/mL) at Day 29, four days after the last IMO-2125 dose.
“We are pleased that the results of our Phase 1 clinical trials have shown that IMO-2125 stimulates the immune system in a manner consistent with the intended TLR9 agonist mechanism of action, and that this biological activity has led to reductions in HCV viral load,” said Tim Sullivan, Vice President of Development Programs and Alliance Management at Idera. “IMO-2125 was designed using our chemistry-based approach to optimize the activity of TLR-targeted drug candidates.”
About IMO-2125
IMO-2125, a Toll-like Receptor (TLR) 9 agonist, is a novel immune modulator being developed as a component of treatment for chronic hepatitis C virus (HCV) infection. IMO-2125 is designed to stimulate the immune system, causing the body to generate natural interferons and other antiviral cytokines. IMO-2125 has been evaluated in a Phase 1 clinical trial in null-responder HCV patients, defined as those who did not achieve a 2 log10 reduction with prior standard of care treatment, as monotherapy for 4 weeks and in a Phase 1 clinical trial in treatment-naïve HCV patients in combination with ribavirin for 4 weeks.
About Idera Pharmaceuticals, Inc.
Idera Pharmaceuticals is developing drug candidates that act by modulating immune responses through specific Toll-like Receptors (TLRs). TLRs, a family of immune system receptors and the immune system’s first line of defense, recognize pathogens and initiate an immune response. Idera’s DNA and RNA chemistry expertise has generated a pipeline of compounds designed to interact with specific TLRs for a broad range of diseases. Through its internal pipeline and collaborative alliances, Idera has established a portfolio of TLR-targeted therapeutic candidates for infectious diseases, autoimmune and inflammatory diseases, cancer, and respiratory diseases, and for use as vaccine adjuvants. For more information, visit http://www.iderapharma.com/.
Idera Forward Looking Statements
This press release contains forward-looking statements concerning Idera Pharmaceuticals, Inc. that involve a number of risks and uncertainties. For this purpose, any statements contained herein that are not statements of historical fact may be deemed to be forward-looking statements. Without limiting the foregoing, the words "believes," "anticipates," "plans," "expects," "estimates," "intends," "should," "could," "will," "may," and similar expressions are intended to identify forward-looking statements. There are a number of important factors that could cause Idera's actual results to differ materially from those indicated by such forward-looking statements; whether results obtained in preclinical and clinical studies such as the studies referred to in this release will be indicative of results obtained in future clinical trials; whether products based on Idera's technology will advance into or through the clinical trial process on a timely basis or at all and receive approval from the United States Food and Drug Administration or equivalent foreign regulatory agencies; whether, if the Company's products receive approval, they will be successfully distributed and marketed; whether the Company's collaborations will be successful; whether the patents and patent applications owned or licensed by the Company will protect the Company’s technology and prevent others from infringing it; whether Idera's cash resources will be sufficient to fund the Company's operations; and such other important factors as are set forth under the caption "Risk Factors" in Idera's Quarterly Report on Form 10-Q for the three months ended September 30, 2010, which important factors are incorporated herein by reference. Idera disclaims any intention or obligation to update any forward-looking statements.
Pegasys® is a registered trademark of F. Hoffmann-La Roche Company.
Contacts
Idera Pharmaceuticals, Inc.
Teri Dahlman, 617-679-5519
tdahlman@iderapharma.com
or
MacDougall Biomedical Communications
Chris Erdman, 781-235-3060
cerdman@macbiocom.com
Source
December 21, 2010
Rapid Virological Response Is the Most Important Predictor of Sustained Virological Response Across Genotypes in Patients with Chronic Hepatitis C Virus Infection
J Hepatol. 2010 Nov 23. [Epub ahead of print]
Fried MW, Hadziyannis SJ, Shiffman ML, Messinger D, Zeuzem S.
University of North Carolina, Chapel Hill, USA.
Abstract
The probability of response to peginterferon and ribavirin is associated with numerous host and virological factors. Attainment of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 during treatment with peginterferon and ribavirin, is highly predictive of sustained virological response (SVR). The aim of the present study was to determine the relative importance of the kinetics of antiviral response compared to baseline host and virological factors for predicting SVR.
METHODS: A retrospective analysis of 1,383 patients, encompassing genotypes 1-4, treated with peginterferon alfa-2a and ribavirin was performed. Baseline characteristics were compared across HCV genotypes and pretreatment factors associated with RVR were identified. The relative significance of RVR compared to other baseline factors for predicting SVR was analyzed by multiple logistic regression analysis.
RESULTS: RVR was achieved by 16% of patients with genotype 1 and 71% and 60% of those with genotype 2 and 3, respectively. Among patients who achieved RVR, the rate of SVR was high across all genotypes and ranged from 88% to 100% (genotypes 1-4). Baseline factors predictive of RVR included genotype, younger age, lower initial viral load, higher ALT ratio, absence of advanced fibrosis, and younger age. Notably, the presence of RVR generated the highest odds ratio (5.47, 95% confidence interval 3.97-7.52) for predicting SVR in multiple logistic regression analysis of these factors.
CONCLUSIONS: Attainment of RVR varies by genotype and is associated with several baseline factors. Patients who achieve RVR have the highest rates of SVR, regardless of genotype. These findings have important implications for predicting and managing response-guided combination antiviral therapies.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145856 [PubMed - as supplied by publisher]
Source
Fried MW, Hadziyannis SJ, Shiffman ML, Messinger D, Zeuzem S.
University of North Carolina, Chapel Hill, USA.
Abstract
The probability of response to peginterferon and ribavirin is associated with numerous host and virological factors. Attainment of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 during treatment with peginterferon and ribavirin, is highly predictive of sustained virological response (SVR). The aim of the present study was to determine the relative importance of the kinetics of antiviral response compared to baseline host and virological factors for predicting SVR.
METHODS: A retrospective analysis of 1,383 patients, encompassing genotypes 1-4, treated with peginterferon alfa-2a and ribavirin was performed. Baseline characteristics were compared across HCV genotypes and pretreatment factors associated with RVR were identified. The relative significance of RVR compared to other baseline factors for predicting SVR was analyzed by multiple logistic regression analysis.
RESULTS: RVR was achieved by 16% of patients with genotype 1 and 71% and 60% of those with genotype 2 and 3, respectively. Among patients who achieved RVR, the rate of SVR was high across all genotypes and ranged from 88% to 100% (genotypes 1-4). Baseline factors predictive of RVR included genotype, younger age, lower initial viral load, higher ALT ratio, absence of advanced fibrosis, and younger age. Notably, the presence of RVR generated the highest odds ratio (5.47, 95% confidence interval 3.97-7.52) for predicting SVR in multiple logistic regression analysis of these factors.
CONCLUSIONS: Attainment of RVR varies by genotype and is associated with several baseline factors. Patients who achieve RVR have the highest rates of SVR, regardless of genotype. These findings have important implications for predicting and managing response-guided combination antiviral therapies.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145856 [PubMed - as supplied by publisher]
Source
Vertex Provides Update to Ongoing Phase 2 Study Evaluating Combinations of Telaprevir and VX-222 for the Treatment of Hepatitis C
- Two-drug treatment arm of telaprevir and VX-222 alone discontinued
- Study continues with three arms, including all-oral combination of Vertex's lead protease and polymerase inhibitors with ribavirin
- Both of the four-drug treatment arms are fully enrolled; the majority of patients in these arms have reached 8 weeks or more of treatment
CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced a modification of its Phase 2 clinical trial evaluating 12-week, response-guided regimens of its lead investigational hepatitis C virus (HCV) protease inhibitor, telaprevir, in combination with its lead investigational HCV polymerase inhibitor, VX-222. The company has discontinued the second two-drug treatment arm of telaprevir and VX-222 alone as a result of meeting a pre-defined stopping rule related to viral breakthrough. This two-drug arm was designed to evaluate a 12-week combination regimen of VX-222 (400 mg) and telaprevir (1,125 mg) dosed twice daily without pegylated-interferon and ribavirin. The first two-drug arm was discontinued in October 2010 and was designed to evaluate a 12-week combination regimen of VX-222 (100 mg) and telaprevir (1,125 mg).
The study will continue as planned with three treatment arms. Two of the treatment arms are fully enrolled and are evaluating four-drug combinations of telaprevir (1,125 mg), VX-222 (400 mg or 100 mg), Pegasys® (pegylated-interferon alfa-2a) and Copegus® (ribavirin). The last patient was randomized and began treatment with a four-drug regimen in November 2010. There are patients in the four-drug treatment arms who have recently started treatment and have not yet reached week 8 of therapy. More than half of patients in the treatment arms have received eight weeks or more of treatment and approximately one third of patients are in weeks 10 through 12 of treatment. Some patients in this study have completed therapy. Interim data from both of the four-drug treatment arms are expected in the first quarter of 2011. In November 2010, Vertex announced the planned addition of a new three-drug treatment arm designed to evaluate the potential of an all-oral, interferon-free regimen of telaprevir (1,125 mg), VX-222 (400 mg) and ribavirin dosed twice daily. Enrollment in this new treatment arm is expected to begin in the first quarter of 2011.
"This trial has provided important information regarding telaprevir and VX-222-based combination regimens, and three of the five treatment arms are proceeding as planned," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "We are pleased with the progress of both four-drug treatment arms and look forward to the first quarter of 2011 when on-treatment data from these arms will become available and enrollment in the three-drug treatment arm is expected to begin."
About the Ongoing Phase 2 Trial of Telaprevir and VX-222
In August 2010, patients enrolled in this randomized, parallel-group, dose-ranging Phase 2 trial started receiving treatment. The primary endpoint of this trial is to assess safety and tolerability of 12-week, telaprevir/VX-222-based combination therapy in people with genotype 1 chronic hepatitis C. A secondary endpoint of this study is to assess on-treatment antiviral activity and the proportion of patients in each study arm who achieve a sustained viral response (SVR; defined as undetectable HCV RNA 24 weeks after the end of treatment). Patients who meet the response-guided criteria during treatment (undetectable HCV RNA at week 2 and week 8 of treatment) stop all therapy at week 12.
The planned addition of the three-drug treatment arm to the study took into account an initial review of adverse events among people treated with telaprevir/VX-222 combination regimens in this study. Enrollment in this new study arm is expected to begin in the first quarter of 2011 pending completion of institutional review board (IRB) approvals and consultations with regulatory agencies. A sixth and final arm may be added to the trial per protocol based on data from the study expected in the first quarter of 2011.
European and United States Regulatory Submissions for Telaprevir
On December 17, 2010, Janssen-Cilag International NV announced the submission of a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for telaprevir in combination with pegylated-interferon and ribavirin for the treatment of people with genotype 1 hepatitis C. Additionally, Janssen announced that the EMA has accepted telaprevir for accelerated assessment, which is granted to new medicines of major public health interest. In November 2010, Vertex announced it has completed the submission of a New Drug Application to the U.S. Food and Drug Administration for telaprevir in combination with pegylated-interferon and ribavirin for the treatment of people with genotype 1 hepatitis C. The submission included a request for six-month Priority Review, which can be granted for several reasons, including if the medicine is considered a major advance in treatment.
Telaprevir is being developed by Vertex Pharmaceuticals in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.
About Telaprevir and VX-222
Telaprevir is an investigational, oral inhibitor of HCV protease, an enzyme essential for viral replication. VX-222 is an investigational, oral, non-nucleoside inhibitor of HCV NS5B polymerase. Vertex added VX-222 to its development pipeline as part of the acquisition of ViroChem Pharma Inc. in March 2009. Vertex retains worldwide commercial rights to VX-222.
About Hepatitis C
Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.2 Up to 3.9 million people in the United States have chronic hepatitis C and 75% of those infected are unaware of their infection.3 The majority of people with hepatitis C were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.11 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.2 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.2
Approximately 60 percent of genotype 1 patients who undergo an initial 48-week regimen with pegylated-interferon and ribavirin, the currently approved medicines, do not achieve SVR, 4,5,6 or viral cure.1 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8,9,10,11 In the United States, hepatitis C is the leading cause of liver transplantations and is reported to contribute to 4,600 to 12,000 deaths annually.8 By 2029, total annual medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.11
Additional resources for media are available at: http://investors.vrtx.com/press.cfm.
About Vertex
Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with other pharmaceutical companies. Vertex's product pipeline is focused on viral diseases, cystic fibrosis, inflammation, autoimmune diseases, epilepsy, cancer and pain.
Vertex co-discovered the HIV protease inhibitor, Lexiva, with GlaxoSmithKline.
Lexiva is a registered trademark of the GlaxoSmithKline group of companies.
PEGASYS® and COPEGUS® are registered trademarks of Hoffman-La Roche.
References:
1 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009; 49 (4): 1-40.
2 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed May 25, 2010.
3 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed May 25, 2010.
4 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001; 358: 958-965.
5 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002; 347: 975-982.
6 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.
7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
8 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.
9 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
10 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
11 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. This report was commissioned by Vertex Pharmaceuticals, Inc.
12 Picchio G, et al. Discrepancies between definitions of null response to treatment with peginterferon alfa-2a and ribavirin: Implications for new HCV drug development. [poster 289]. In: Program and Abstracts of the 2010 International Liver Conference by the European Association for the Study of Liver Disease. . Athens, Greece: April 2010.
13 United States Food and Drug Administration. Chronic hepatitis C virus infection: developing direct-acting antiviral agents for treatment. http://www.federalregister.gov/articles/2010/09/14/2010-22806/draft-guidance-for-industry-on-chronic-hepatitis-c-virus-infection-developing-directacting-antiviral. Updated September 14, 2010. Accessed September 14, 2010.
Special Note Regarding Forward-looking Statements
This press release contains forward-looking statements including statements regarding (i) that the study will continue with three treatment arms, including an all-oral, interferon-free regimen of telaprevir, VX-222 (400 mg) and ribavirin; (ii) the expectation that interim data from both of the four-drug treatment arms are expected in the first quarter of 2011; (iii) Vertex looking forward to on-treatment data that is expected to become available from these arms in the first quarter of 2011; (iv) the plan to evaluate a 12-week combination of the three oral therapies — VX-222, telaprevir and ribavirin — dosed twice daily within a response-guided regimen; (v) the expectation that the additional three-drug treatment arm announced in November 2010 will begin patient enrollment in the first quarter of 2011, pending completion of IRB approvals and consultation with regulatory agencies; and (vi) the possibility that a sixth and final arm may be added to the trial. While Vertex believes the forward-looking statements contained in this press release are accurate, these statements are subject to risks and uncertainties that could cause actual outcomes to vary materially from the outcomes referenced in the forward-looking statements. These risks and uncertainties include, among other things, the risks that efforts to develop telaprevir and VX-222 separately or in combination may not proceed due to technical, scientific, commercial, financial or other reasons, that clinical trials may not proceed as planned, that additional clinical trials of telaprevir and VX-222 will not reflect the results obtained to date, that an adverse event profile for telaprevir or VX-222 could be revealed in further nonclinical or clinical studies that could put further development of telaprevir or VX-222 in jeopardy or adversely impact their therapeutic value, and other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the Company's website at http://www.vrtx.com/. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
(VRTX-GEN)
Vertex Pharmaceuticals Incorporated
Media: 617-444-6992
Amy Pasqua
Dawn Kalmar
Zachry Barber
or
Investors:
Michael Partridge, 617-444-6108
Lora Pike, 617-444-6755
Matthew Osborne, 617-444-6057
Source: Vertex Pharmaceuticals Incorporated
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- Study continues with three arms, including all-oral combination of Vertex's lead protease and polymerase inhibitors with ribavirin
- Both of the four-drug treatment arms are fully enrolled; the majority of patients in these arms have reached 8 weeks or more of treatment
CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced a modification of its Phase 2 clinical trial evaluating 12-week, response-guided regimens of its lead investigational hepatitis C virus (HCV) protease inhibitor, telaprevir, in combination with its lead investigational HCV polymerase inhibitor, VX-222. The company has discontinued the second two-drug treatment arm of telaprevir and VX-222 alone as a result of meeting a pre-defined stopping rule related to viral breakthrough. This two-drug arm was designed to evaluate a 12-week combination regimen of VX-222 (400 mg) and telaprevir (1,125 mg) dosed twice daily without pegylated-interferon and ribavirin. The first two-drug arm was discontinued in October 2010 and was designed to evaluate a 12-week combination regimen of VX-222 (100 mg) and telaprevir (1,125 mg).
The study will continue as planned with three treatment arms. Two of the treatment arms are fully enrolled and are evaluating four-drug combinations of telaprevir (1,125 mg), VX-222 (400 mg or 100 mg), Pegasys® (pegylated-interferon alfa-2a) and Copegus® (ribavirin). The last patient was randomized and began treatment with a four-drug regimen in November 2010. There are patients in the four-drug treatment arms who have recently started treatment and have not yet reached week 8 of therapy. More than half of patients in the treatment arms have received eight weeks or more of treatment and approximately one third of patients are in weeks 10 through 12 of treatment. Some patients in this study have completed therapy. Interim data from both of the four-drug treatment arms are expected in the first quarter of 2011. In November 2010, Vertex announced the planned addition of a new three-drug treatment arm designed to evaluate the potential of an all-oral, interferon-free regimen of telaprevir (1,125 mg), VX-222 (400 mg) and ribavirin dosed twice daily. Enrollment in this new treatment arm is expected to begin in the first quarter of 2011.
"This trial has provided important information regarding telaprevir and VX-222-based combination regimens, and three of the five treatment arms are proceeding as planned," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "We are pleased with the progress of both four-drug treatment arms and look forward to the first quarter of 2011 when on-treatment data from these arms will become available and enrollment in the three-drug treatment arm is expected to begin."
About the Ongoing Phase 2 Trial of Telaprevir and VX-222
In August 2010, patients enrolled in this randomized, parallel-group, dose-ranging Phase 2 trial started receiving treatment. The primary endpoint of this trial is to assess safety and tolerability of 12-week, telaprevir/VX-222-based combination therapy in people with genotype 1 chronic hepatitis C. A secondary endpoint of this study is to assess on-treatment antiviral activity and the proportion of patients in each study arm who achieve a sustained viral response (SVR; defined as undetectable HCV RNA 24 weeks after the end of treatment). Patients who meet the response-guided criteria during treatment (undetectable HCV RNA at week 2 and week 8 of treatment) stop all therapy at week 12.
The planned addition of the three-drug treatment arm to the study took into account an initial review of adverse events among people treated with telaprevir/VX-222 combination regimens in this study. Enrollment in this new study arm is expected to begin in the first quarter of 2011 pending completion of institutional review board (IRB) approvals and consultations with regulatory agencies. A sixth and final arm may be added to the trial per protocol based on data from the study expected in the first quarter of 2011.
European and United States Regulatory Submissions for Telaprevir
On December 17, 2010, Janssen-Cilag International NV announced the submission of a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for telaprevir in combination with pegylated-interferon and ribavirin for the treatment of people with genotype 1 hepatitis C. Additionally, Janssen announced that the EMA has accepted telaprevir for accelerated assessment, which is granted to new medicines of major public health interest. In November 2010, Vertex announced it has completed the submission of a New Drug Application to the U.S. Food and Drug Administration for telaprevir in combination with pegylated-interferon and ribavirin for the treatment of people with genotype 1 hepatitis C. The submission included a request for six-month Priority Review, which can be granted for several reasons, including if the medicine is considered a major advance in treatment.
Telaprevir is being developed by Vertex Pharmaceuticals in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.
About Telaprevir and VX-222
Telaprevir is an investigational, oral inhibitor of HCV protease, an enzyme essential for viral replication. VX-222 is an investigational, oral, non-nucleoside inhibitor of HCV NS5B polymerase. Vertex added VX-222 to its development pipeline as part of the acquisition of ViroChem Pharma Inc. in March 2009. Vertex retains worldwide commercial rights to VX-222.
About Hepatitis C
Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.2 Up to 3.9 million people in the United States have chronic hepatitis C and 75% of those infected are unaware of their infection.3 The majority of people with hepatitis C were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.11 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.2 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.2
Approximately 60 percent of genotype 1 patients who undergo an initial 48-week regimen with pegylated-interferon and ribavirin, the currently approved medicines, do not achieve SVR, 4,5,6 or viral cure.1 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8,9,10,11 In the United States, hepatitis C is the leading cause of liver transplantations and is reported to contribute to 4,600 to 12,000 deaths annually.8 By 2029, total annual medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.11
Additional resources for media are available at: http://investors.vrtx.com/press.cfm.
About Vertex
Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with other pharmaceutical companies. Vertex's product pipeline is focused on viral diseases, cystic fibrosis, inflammation, autoimmune diseases, epilepsy, cancer and pain.
Vertex co-discovered the HIV protease inhibitor, Lexiva, with GlaxoSmithKline.
Lexiva is a registered trademark of the GlaxoSmithKline group of companies.
PEGASYS® and COPEGUS® are registered trademarks of Hoffman-La Roche.
References:
1 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009; 49 (4): 1-40.
2 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed May 25, 2010.
3 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed May 25, 2010.
4 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001; 358: 958-965.
5 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002; 347: 975-982.
6 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.
7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
8 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.
9 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
10 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
11 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. This report was commissioned by Vertex Pharmaceuticals, Inc.
12 Picchio G, et al. Discrepancies between definitions of null response to treatment with peginterferon alfa-2a and ribavirin: Implications for new HCV drug development. [poster 289]. In: Program and Abstracts of the 2010 International Liver Conference by the European Association for the Study of Liver Disease. . Athens, Greece: April 2010.
13 United States Food and Drug Administration. Chronic hepatitis C virus infection: developing direct-acting antiviral agents for treatment. http://www.federalregister.gov/articles/2010/09/14/2010-22806/draft-guidance-for-industry-on-chronic-hepatitis-c-virus-infection-developing-directacting-antiviral. Updated September 14, 2010. Accessed September 14, 2010.
Special Note Regarding Forward-looking Statements
This press release contains forward-looking statements including statements regarding (i) that the study will continue with three treatment arms, including an all-oral, interferon-free regimen of telaprevir, VX-222 (400 mg) and ribavirin; (ii) the expectation that interim data from both of the four-drug treatment arms are expected in the first quarter of 2011; (iii) Vertex looking forward to on-treatment data that is expected to become available from these arms in the first quarter of 2011; (iv) the plan to evaluate a 12-week combination of the three oral therapies — VX-222, telaprevir and ribavirin — dosed twice daily within a response-guided regimen; (v) the expectation that the additional three-drug treatment arm announced in November 2010 will begin patient enrollment in the first quarter of 2011, pending completion of IRB approvals and consultation with regulatory agencies; and (vi) the possibility that a sixth and final arm may be added to the trial. While Vertex believes the forward-looking statements contained in this press release are accurate, these statements are subject to risks and uncertainties that could cause actual outcomes to vary materially from the outcomes referenced in the forward-looking statements. These risks and uncertainties include, among other things, the risks that efforts to develop telaprevir and VX-222 separately or in combination may not proceed due to technical, scientific, commercial, financial or other reasons, that clinical trials may not proceed as planned, that additional clinical trials of telaprevir and VX-222 will not reflect the results obtained to date, that an adverse event profile for telaprevir or VX-222 could be revealed in further nonclinical or clinical studies that could put further development of telaprevir or VX-222 in jeopardy or adversely impact their therapeutic value, and other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the Company's website at http://www.vrtx.com/. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
(VRTX-GEN)
Vertex Pharmaceuticals Incorporated
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December 19, 2010
Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy
J Hepatol. 2010 Dec 8. [Epub ahead of print]
Lange CM, Bojunga J, Ramos-Lopez E, Wagner MV, Hassler A, Vermehren J, Herrmann E, Badenhoop K, Zeuzem S, Sarrazin C.
Klinikum der J. W. Goethe-Universität Frankfurt am Main, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Abstract
AIMS: Vitamin D is an important immune modulator and preliminary data indicated an association between vitamin D deficiency and sustained virologic response (SVR) rates in hepatitis C virus (HCV) genotype 1 patients. We therefore performed a comprehensive analysis on the impact of vitamin D serum levels and of genetic polymorphisms with functional relevance within the vitamin D cascade on chronic hepatitis C and its treatment
METHODS: Vitamin D serum levels, genetic polymorphisms within the vitamin D receptor and 1α-hydroxylase were determined in a cohort of 468 HCV genotype 1, 2 and 3 infected patients who were treated with interferon-alfa based regimens
RESULTS: Chronic hepatitis C was associated with a high incidence of severe vitamin D deficiency compared to controls (25(OH)D(3)<10 ng/ml in 25% versus 12%, p<0.00001). 25(OH)D(3) deficiency correlated with SVR in HCV genotype 2 and 3 patients (50% and 81% SVR for patients with and without severe vitamin D deficiency, respectively, p<0.0001). In addition, the CYPB27-1260 promoter polymorphism rs10877012 had substantial impact on 1-25-dihydroxyvitamin D serum levels (72, 61, and 60 pmol/ml for rs10877012 AA, AC, and CC, respectively, p=0.04) and on SVR rates in HCV genotype 1, 2 and 3 infected patients (77% and 65% versus 42% for rs10877012 AA, AC, and CC, respectively, p=0.02)
CONCLUSIONS: Chronic hepatitis C virus infection is associated with vitamin D deficiency. Reduced 25-hydroxyvitamin D levels and CYPB27-1260 promotor polymorphism leading to reduced 1,25-dihydroxyvitamin D levels are associated with failure to achieve SVR in HCV genotype 1, 2, 3 infected patients.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145801 [PubMed - as supplied by publisher]
Source
Lange CM, Bojunga J, Ramos-Lopez E, Wagner MV, Hassler A, Vermehren J, Herrmann E, Badenhoop K, Zeuzem S, Sarrazin C.
Klinikum der J. W. Goethe-Universität Frankfurt am Main, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Abstract
AIMS: Vitamin D is an important immune modulator and preliminary data indicated an association between vitamin D deficiency and sustained virologic response (SVR) rates in hepatitis C virus (HCV) genotype 1 patients. We therefore performed a comprehensive analysis on the impact of vitamin D serum levels and of genetic polymorphisms with functional relevance within the vitamin D cascade on chronic hepatitis C and its treatment
METHODS: Vitamin D serum levels, genetic polymorphisms within the vitamin D receptor and 1α-hydroxylase were determined in a cohort of 468 HCV genotype 1, 2 and 3 infected patients who were treated with interferon-alfa based regimens
RESULTS: Chronic hepatitis C was associated with a high incidence of severe vitamin D deficiency compared to controls (25(OH)D(3)<10 ng/ml in 25% versus 12%, p<0.00001). 25(OH)D(3) deficiency correlated with SVR in HCV genotype 2 and 3 patients (50% and 81% SVR for patients with and without severe vitamin D deficiency, respectively, p<0.0001). In addition, the CYPB27-1260 promoter polymorphism rs10877012 had substantial impact on 1-25-dihydroxyvitamin D serum levels (72, 61, and 60 pmol/ml for rs10877012 AA, AC, and CC, respectively, p=0.04) and on SVR rates in HCV genotype 1, 2 and 3 infected patients (77% and 65% versus 42% for rs10877012 AA, AC, and CC, respectively, p=0.02)
CONCLUSIONS: Chronic hepatitis C virus infection is associated with vitamin D deficiency. Reduced 25-hydroxyvitamin D levels and CYPB27-1260 promotor polymorphism leading to reduced 1,25-dihydroxyvitamin D levels are associated with failure to achieve SVR in HCV genotype 1, 2, 3 infected patients.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145801 [PubMed - as supplied by publisher]
Source
Association Of Caffeine Intake and Histological Features of Chronic Hepatitis C
J Hepatol. 2010 Dec 8. [Epub ahead of print]
Costentin CE, Roudot-Thoraval F, Zafrani ES, Medkour F, Pawlotsky JM, Mallat A, Hézode C.
AP-HP, Service d'Hépatologie et de Gastroentérologie, Groupe Hospitalier Henri Mondor-Albert Chenevier, Créteil, 94000 France.
Abstract
Rational The severity of chronic hepatitis C (CHC) is modulated by host and environmental factors. Several reports suggest that caffeine intake exerts hepatoprotective effects in patients with chronic liver disease. The aim of this study was to evaluate the impact of caffeine consumption on activity grade and fibrosis stage in patients with CHC. Methods 238 treatment-naı¨ve patients with histologically-proven CHC were included. Demographic, epidemiological, environmental, virological and metabolic features were collected, including daily consumptions of alcohol, cannabis, tobacco and caffeine during the six month preceding liver biopsy. Daily caffeine consumption was estimated as the sum of mean intakes of caffeinated coffee, tea and caffeine-containing sodas. Histological activity grade and fibrosis stage were scored according to Metavir. Patients (154 men, 84 women, mean age: 45±11 years) were categorized according to caffeine consumption quartiles: group 1 (<225 mg/day, n=59), group 2 (225-407 mg/day, n=57), group 3 (408-678 mg/day, n=62) and group 4 (>678 mg/day, n=60). Results There was a significant inverse relationship between activity grade and daily caffeine consumption: Activity grade >A2 was present in 78%, 61%, 52% and 48% of patients in group 1, 2, 3 and 4, respectively (p<0.001). By multivariate analysis, daily caffeine consumption greater than 408 mg/day was associated with a lesser risk of activity grade >A2 (OR=0.32 (0.12-0.85)). Caffeine intake showed no relation with the fibrosis stage. Conclusions Caffeine consumption greater than 408 mg/day (3 cups or more) is associated with reduced histological activity in patients with CHC. These findings support potential hepatoprotective properties of caffeine in chronic liver diseases.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145804 [PubMed - as supplied by publisher]
Source
Costentin CE, Roudot-Thoraval F, Zafrani ES, Medkour F, Pawlotsky JM, Mallat A, Hézode C.
AP-HP, Service d'Hépatologie et de Gastroentérologie, Groupe Hospitalier Henri Mondor-Albert Chenevier, Créteil, 94000 France.
Abstract
Rational The severity of chronic hepatitis C (CHC) is modulated by host and environmental factors. Several reports suggest that caffeine intake exerts hepatoprotective effects in patients with chronic liver disease. The aim of this study was to evaluate the impact of caffeine consumption on activity grade and fibrosis stage in patients with CHC. Methods 238 treatment-naı¨ve patients with histologically-proven CHC were included. Demographic, epidemiological, environmental, virological and metabolic features were collected, including daily consumptions of alcohol, cannabis, tobacco and caffeine during the six month preceding liver biopsy. Daily caffeine consumption was estimated as the sum of mean intakes of caffeinated coffee, tea and caffeine-containing sodas. Histological activity grade and fibrosis stage were scored according to Metavir. Patients (154 men, 84 women, mean age: 45±11 years) were categorized according to caffeine consumption quartiles: group 1 (<225 mg/day, n=59), group 2 (225-407 mg/day, n=57), group 3 (408-678 mg/day, n=62) and group 4 (>678 mg/day, n=60). Results There was a significant inverse relationship between activity grade and daily caffeine consumption: Activity grade >A2 was present in 78%, 61%, 52% and 48% of patients in group 1, 2, 3 and 4, respectively (p<0.001). By multivariate analysis, daily caffeine consumption greater than 408 mg/day was associated with a lesser risk of activity grade >A2 (OR=0.32 (0.12-0.85)). Caffeine intake showed no relation with the fibrosis stage. Conclusions Caffeine consumption greater than 408 mg/day (3 cups or more) is associated with reduced histological activity in patients with CHC. These findings support potential hepatoprotective properties of caffeine in chronic liver diseases.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145804 [PubMed - as supplied by publisher]
Source
Early virologic response and IL28B polymorphisms in patients with chronic hepatitis C genotype 3 treated with peginterferon alfa-2a and ribavirin
J Hepatol. 2010 Dec 8. [Epub ahead of print]
Scherzer TM, Hofer H, Staettermayer AF, Rutter K, Beinhardt S, Steindl-Munda P, Kerschner H, Kessler HH, Ferenci P.
Medical University of Vienna, Internal Medicine III, Department of Gastroenterology and Hepatology, Austria.
Abstract
BACKGROUND: and Aim: Polymorphisms of the IL28B-gene (rs12979860 and rs8099917) are associated with high sustained virological response (SVR) rates in HCV genotype 1 patients. This study analyses the impact of these IL28B polymorphisms on early treatment response (week 2 and 4) and on SVR in HCV genotype 3 patients.
METHODS: : rs12979860 and rs8099917 were analyzed by the StepOnePlus Real time PCR system in 71 of 72 Caucasian HCV genotype 3 patients participating at our center in a randomized study comparing 400 mg with 800 mg ribavirin/day. HCV RNA was determined at weeks 2 and 4 of 180 μg/week peginterferon alfa-2a/ribavirin treatment. Sixty nine patients completed treatment and follow-up.
RESULTS: : rs12979860 genotyping revealed that 27 (37.5%) pts had C/C, 39 (54.2%) T/C and 5 (6.9%) T/T. Thirteen pts (18.1%) became HCV RNA negative at week 2 and additional 30 (41.7%) at week 4 (rapid virologic response; RVR); thus a total of 43 had a RVR (C/C: 77.8%; C/T or T/T: 50.0%). Irrespective of the ribavirin dose the viral load decline was larger than in those with T allele (C/T or T/T) (week 2: 4.46;[0.36-6.02] median; [range] vs. 3.50;[0.14-5.62]; log IU HCV-RNA/mL; p<0.001; week 4: 4.97;[1.21-6.20] vs. 4.49;[1.16-6.23]; p=0.003). Despite the faster initial viral response in C/C carriers, SVR rates were not different compared to T-allele carriers. Results of the SNP in the rs8099917 region showed similar results.
CONCLUSION: : IL28B polymorphisms modulate early virologic response to peginterferon/ribavirin treatment. In contrast to HCV genotype 1 patients no effect on SVR rates was observed in genotype 3 patients. The clinical relevance of an earlier viral decline of C/C patients needs to be determined.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145807 [PubMed - as supplied by publisher]
Source
Scherzer TM, Hofer H, Staettermayer AF, Rutter K, Beinhardt S, Steindl-Munda P, Kerschner H, Kessler HH, Ferenci P.
Medical University of Vienna, Internal Medicine III, Department of Gastroenterology and Hepatology, Austria.
Abstract
BACKGROUND: and Aim: Polymorphisms of the IL28B-gene (rs12979860 and rs8099917) are associated with high sustained virological response (SVR) rates in HCV genotype 1 patients. This study analyses the impact of these IL28B polymorphisms on early treatment response (week 2 and 4) and on SVR in HCV genotype 3 patients.
METHODS: : rs12979860 and rs8099917 were analyzed by the StepOnePlus Real time PCR system in 71 of 72 Caucasian HCV genotype 3 patients participating at our center in a randomized study comparing 400 mg with 800 mg ribavirin/day. HCV RNA was determined at weeks 2 and 4 of 180 μg/week peginterferon alfa-2a/ribavirin treatment. Sixty nine patients completed treatment and follow-up.
RESULTS: : rs12979860 genotyping revealed that 27 (37.5%) pts had C/C, 39 (54.2%) T/C and 5 (6.9%) T/T. Thirteen pts (18.1%) became HCV RNA negative at week 2 and additional 30 (41.7%) at week 4 (rapid virologic response; RVR); thus a total of 43 had a RVR (C/C: 77.8%; C/T or T/T: 50.0%). Irrespective of the ribavirin dose the viral load decline was larger than in those with T allele (C/T or T/T) (week 2: 4.46;[0.36-6.02] median; [range] vs. 3.50;[0.14-5.62]; log IU HCV-RNA/mL; p<0.001; week 4: 4.97;[1.21-6.20] vs. 4.49;[1.16-6.23]; p=0.003). Despite the faster initial viral response in C/C carriers, SVR rates were not different compared to T-allele carriers. Results of the SNP in the rs8099917 region showed similar results.
CONCLUSION: : IL28B polymorphisms modulate early virologic response to peginterferon/ribavirin treatment. In contrast to HCV genotype 1 patients no effect on SVR rates was observed in genotype 3 patients. The clinical relevance of an earlier viral decline of C/C patients needs to be determined.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145807 [PubMed - as supplied by publisher]
Source
Can antiviral therapy for Hepatitis C reduce the prevalence of HCV among injecting drug user populations? A modeling analysis of its prevention utility
J Hepatol. 2010 Dec 8. [Epub ahead of print]
Martin NK, Vickerman P, Foster GR, Hutchinson SJ, Goldberg DJ, Hickman M.
Department of Social Medicine, University of Bristol, Bristol, UK; Health Policy Unit, London School of Hygiene and Tropical Medicine, London, UK.
Abstract
BACKGROUND&
AIMS: Hepatitis C virus antiviral treatment is effective for individual patients, but few active injecting drug users are treated. We considered the utility of antiviral treatment for primary prevention of hepatitis C.
METHODS: A hepatitis C transmission model amongst injecting drug users was developed, incorporating treatment (62.5% average sustained viral response) with no retreatment after initial treatment failure, potential re-infection for those cured, equal genotype setting (genotype 1: genotype 2/3) and no immunity. In addition, we examined scenarios with varied treatment response rates, immunity, or retreatment of treatment failures.
RESULTS: In the baseline scenario, annually treating 10 infections per 1000 injecting drug users results in a relative decrease in hepatitis C prevalence over 10 years of 31%, 13% or 7% for baseline (untreated endemic chronic infection) prevalences of 20%, 40% or 60%, respectively. Sensitivity analyses show that: including the potential for immunity has minimal effect on the predictions; prevalence reductions remain even if SVR is assumed to be 25% lower among active IDU then current evidence suggests; retreatment of treatment failures does not alter the short-term (<5 year) projections, but does increase treatment gains within 20 years; hepatitis C free life years gained from treating active injecting drug users are projected to be higher than from treating non-injecting drug users for prevalences below 60%.
CONCLUSIONS: Despite the possibility of re-infection, modest rates of hepatitis C treatment amongst active injecting drug users could effectively reduce transmission. Evaluating and extending strategies to treat hepatitis C among active injectors is warranted.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145810 [PubMed - as supplied by publisher]
Source
Martin NK, Vickerman P, Foster GR, Hutchinson SJ, Goldberg DJ, Hickman M.
Department of Social Medicine, University of Bristol, Bristol, UK; Health Policy Unit, London School of Hygiene and Tropical Medicine, London, UK.
Abstract
BACKGROUND&
AIMS: Hepatitis C virus antiviral treatment is effective for individual patients, but few active injecting drug users are treated. We considered the utility of antiviral treatment for primary prevention of hepatitis C.
METHODS: A hepatitis C transmission model amongst injecting drug users was developed, incorporating treatment (62.5% average sustained viral response) with no retreatment after initial treatment failure, potential re-infection for those cured, equal genotype setting (genotype 1: genotype 2/3) and no immunity. In addition, we examined scenarios with varied treatment response rates, immunity, or retreatment of treatment failures.
RESULTS: In the baseline scenario, annually treating 10 infections per 1000 injecting drug users results in a relative decrease in hepatitis C prevalence over 10 years of 31%, 13% or 7% for baseline (untreated endemic chronic infection) prevalences of 20%, 40% or 60%, respectively. Sensitivity analyses show that: including the potential for immunity has minimal effect on the predictions; prevalence reductions remain even if SVR is assumed to be 25% lower among active IDU then current evidence suggests; retreatment of treatment failures does not alter the short-term (<5 year) projections, but does increase treatment gains within 20 years; hepatitis C free life years gained from treating active injecting drug users are projected to be higher than from treating non-injecting drug users for prevalences below 60%.
CONCLUSIONS: Despite the possibility of re-infection, modest rates of hepatitis C treatment amongst active injecting drug users could effectively reduce transmission. Evaluating and extending strategies to treat hepatitis C among active injectors is warranted.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145810 [PubMed - as supplied by publisher]
Source
Potency, safety and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection
J Hepatol. 2010 Nov 11. [Epub ahead of print]
Manns MP, Bourlière M, Benhamou Y, Pol S, Bonacini M, Trepo C, Wright D, Berg T, Calleja JL, White PW, Stern JO, Steinmann G, Yong CL, Kukolj G, Scherer J, Boecher WO.
Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Center for Internal Medicine, Hannover, Germany.
Abstract
BACKGROUND AND AIMS: BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients.
METHODS: 34 treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan.
RESULTS: In treatment naïve patients, median maximal viral load (VL) reductions during 14 day monotherapy were -3.0, -3.6, -3.7 and -4.2 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (⩾1 log(10) from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15 to 28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL <25 IU/ml at Day 28 in 3/6, 4/7 and 5/6 patients in the 48, 120 and 240 mg dose groups. VL breakthroughs were observed during triple combination in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in 4 patients. Mild unconjugated hyperbilirubinemia was the only dose-dependent laboratory abnormality of BI201335. BI201335 elimination half-life supports once-daily dosing.
CONCLUSIONS: BI201335 combined with PegIFN/RBV was well tolerated and induced strong antiviral responses. These results support further development of BI201335 in HCV genotype-1 patients.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145839 [PubMed - as supplied by publisher]
Source
Manns MP, Bourlière M, Benhamou Y, Pol S, Bonacini M, Trepo C, Wright D, Berg T, Calleja JL, White PW, Stern JO, Steinmann G, Yong CL, Kukolj G, Scherer J, Boecher WO.
Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Center for Internal Medicine, Hannover, Germany.
Abstract
BACKGROUND AND AIMS: BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients.
METHODS: 34 treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan.
RESULTS: In treatment naïve patients, median maximal viral load (VL) reductions during 14 day monotherapy were -3.0, -3.6, -3.7 and -4.2 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (⩾1 log(10) from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15 to 28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL <25 IU/ml at Day 28 in 3/6, 4/7 and 5/6 patients in the 48, 120 and 240 mg dose groups. VL breakthroughs were observed during triple combination in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in 4 patients. Mild unconjugated hyperbilirubinemia was the only dose-dependent laboratory abnormality of BI201335. BI201335 elimination half-life supports once-daily dosing.
CONCLUSIONS: BI201335 combined with PegIFN/RBV was well tolerated and induced strong antiviral responses. These results support further development of BI201335 in HCV genotype-1 patients.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145839 [PubMed - as supplied by publisher]
Source
Treatment of Chronic Hepatitis C Patients with the NS3/4A Protease Inhibitor Danoprevir (ITMN-191/RG7227) Leads to Robust Reductions in Viral RNA: A Phase 1b Multiple Ascending Dose Study
J Hepatol. 2010 Dec 8. [Epub ahead of print]
Forestier N, Larrey D, Guyader D, Marcellin P, Rouzier R, Patat A, Smith P, Bradford W, Porter S, Blatt L, Seiwert SD, Zeuzem S.
J.W. Goethe Universität, Frankfurt, Germany.
Abstract
Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection. Four cohorts of treatment-naïve (TN) patients (100 mg q12h, 100 mg q8h, 200 mg q12h, 200 mg q8h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12h) were investigated. RESULTS: Danoprevir was safe and well tolerated; adverse events were generally mild, transient and without association to treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were -3.9 log(10) IU/mL and -3.2 log(10) IU/mL in TN receiving 200 mg q8h and 200 mg q12h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log(10) IU/mL of viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with R155K substitution in NS3 regardless of HCV subtype. CONCLUSION: Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log(10) IU/mL reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145848 [PubMed - as supplied by publisher]
Source
Forestier N, Larrey D, Guyader D, Marcellin P, Rouzier R, Patat A, Smith P, Bradford W, Porter S, Blatt L, Seiwert SD, Zeuzem S.
J.W. Goethe Universität, Frankfurt, Germany.
Abstract
Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection. Four cohorts of treatment-naïve (TN) patients (100 mg q12h, 100 mg q8h, 200 mg q12h, 200 mg q8h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12h) were investigated. RESULTS: Danoprevir was safe and well tolerated; adverse events were generally mild, transient and without association to treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were -3.9 log(10) IU/mL and -3.2 log(10) IU/mL in TN receiving 200 mg q8h and 200 mg q12h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log(10) IU/mL of viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with R155K substitution in NS3 regardless of HCV subtype. CONCLUSION: Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log(10) IU/mL reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145848 [PubMed - as supplied by publisher]
Source
Adherence to treatment for recently acquired hepatitis C virus (HCV) infection among injecting drug users
J Hepatol. 2010 Nov 23. [Epub ahead of print]
Grebely J, Matthews GV, Hellard M, Shaw D, van Beek I, Petoumenos K, Alavi M, Yeung B, Haber PS, Lloyd AR, Kaldor JM, Dore GJ; for the ATAHC Study Group.
National Centre in HIV Epidemiology and Clinical Research, University of New South Wales (UNSW), Sydney.
Abstract
BACKGROUND AND AIMS: Adherence to HCV therapy impacts sustained virological response (SVR), but there are limited data on adherence, particularly among injecting drug users (IDUs). We assessed 80/80 adherence (>80% of PEG-IFN doses, >80% treatment), on-treatment adherence and treatment completion in a study of treatment of recent HCV infection (ATAHC)
METHODS: Participants with HCV received pegylated interferon (PEG-IFN) alfa-2a (180 μg/week, n=74); those with HCV/HIV received PEG-IFN alfa-2a with ribavirin (n=35). Everyone received 24 weeks of therapy. Logistic regression analyses were used to identify predictors of PEG-IFN 80/80 adherence.
RESULTS: Of 163, 109 received treatment (HCV, n=74; HCV/HIV, n=35), with 75% ever reporting IDU. The proportion with 80/80 PEG-IFN adherence was 82% (n=89). During treatment, 14% missed >1 dose (on-treatment adherence=99%). Completion of 0-4, 5-19, 20-23 and all 24 weeks of PEG-IFN therapy occurred in 10% (n=11), 14% (n=15), 6% (n=7) and 70% (n=76), respectively. Participants with no tertiary education were less likely to have 80/80 PEG-IFN adherence (AOR 0.29,P=0.045). IDU prior to or during treatment did not impact 80/80 PEG-IFN adherence. SVR was higher among those with >80/80 PEG-IFN adherence (67% vs. 35%,P=0.007), but similar among those with and without missed doses during therapy (73% vs. 60%,P=0.309). SVR in those discontinuing therapy between 0-4, 5-19, 20-23 and 24 weeks was 9%, 33%, 43% and 76%, respectively (P<0.001).
CONCLUSION: High adherence to treatment for recent HCV was observed, irrespective of IDU prior to, or during, therapy. Sub-optimal PEG-IFN exposure was mainly driven by early treatment discontinuation rather than missed doses during therapy.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145855 [PubMed - as supplied by publisher]
Source
Grebely J, Matthews GV, Hellard M, Shaw D, van Beek I, Petoumenos K, Alavi M, Yeung B, Haber PS, Lloyd AR, Kaldor JM, Dore GJ; for the ATAHC Study Group.
National Centre in HIV Epidemiology and Clinical Research, University of New South Wales (UNSW), Sydney.
Abstract
BACKGROUND AND AIMS: Adherence to HCV therapy impacts sustained virological response (SVR), but there are limited data on adherence, particularly among injecting drug users (IDUs). We assessed 80/80 adherence (>80% of PEG-IFN doses, >80% treatment), on-treatment adherence and treatment completion in a study of treatment of recent HCV infection (ATAHC)
METHODS: Participants with HCV received pegylated interferon (PEG-IFN) alfa-2a (180 μg/week, n=74); those with HCV/HIV received PEG-IFN alfa-2a with ribavirin (n=35). Everyone received 24 weeks of therapy. Logistic regression analyses were used to identify predictors of PEG-IFN 80/80 adherence.
RESULTS: Of 163, 109 received treatment (HCV, n=74; HCV/HIV, n=35), with 75% ever reporting IDU. The proportion with 80/80 PEG-IFN adherence was 82% (n=89). During treatment, 14% missed >1 dose (on-treatment adherence=99%). Completion of 0-4, 5-19, 20-23 and all 24 weeks of PEG-IFN therapy occurred in 10% (n=11), 14% (n=15), 6% (n=7) and 70% (n=76), respectively. Participants with no tertiary education were less likely to have 80/80 PEG-IFN adherence (AOR 0.29,P=0.045). IDU prior to or during treatment did not impact 80/80 PEG-IFN adherence. SVR was higher among those with >80/80 PEG-IFN adherence (67% vs. 35%,P=0.007), but similar among those with and without missed doses during therapy (73% vs. 60%,P=0.309). SVR in those discontinuing therapy between 0-4, 5-19, 20-23 and 24 weeks was 9%, 33%, 43% and 76%, respectively (P<0.001).
CONCLUSION: High adherence to treatment for recent HCV was observed, irrespective of IDU prior to, or during, therapy. Sub-optimal PEG-IFN exposure was mainly driven by early treatment discontinuation rather than missed doses during therapy.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145855 [PubMed - as supplied by publisher]
Source
Rapid Virological Response Is the Most Important Predictor of Sustained Virological Response Across Genotypes in Patients with Chronic Hepatitis C Virus Infection
J Hepatol. 2010 Nov 23. [Epub ahead of print]
Fried MW, Hadziyannis SJ, Shiffman ML, Messinger D, Zeuzem S.
University of North Carolina, Chapel Hill, USA.
Abstract
The probability of response to peginterferon and ribavirin is associated with numerous host and virological factors. Attainment of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 during treatment with peginterferon and ribavirin, is highly predictive of sustained virological response (SVR). The aim of the present study was to determine the relative importance of the kinetics of antiviral response compared to baseline host and virological factors for predicting SVR.
METHODS: A retrospective analysis of 1,383 patients, encompassing genotypes 1-4, treated with peginterferon alfa-2a and ribavirin was performed. Baseline characteristics were compared across HCV genotypes and pretreatment factors associated with RVR were identified. The relative significance of RVR compared to other baseline factors for predicting SVR was analyzed by multiple logistic regression analysis.
RESULTS: RVR was achieved by 16% of patients with genotype 1 and 71% and 60% of those with genotype 2 and 3, respectively. Among patients who achieved RVR, the rate of SVR was high across all genotypes and ranged from 88% to 100% (genotypes 1-4). Baseline factors predictive of RVR included genotype, younger age, lower initial viral load, higher ALT ratio, absence of advanced fibrosis, and younger age. Notably, the presence of RVR generated the highest odds ratio (5.47, 95% confidence interval 3.97-7.52) for predicting SVR in multiple logistic regression analysis of these factors.
CONCLUSIONS: Attainment of RVR varies by genotype and is associated with several baseline factors. Patients who achieve RVR have the highest rates of SVR, regardless of genotype. These findings have important implications for predicting and managing response-guided combination antiviral therapies.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145856 [PubMed - as supplied by publisher]
Source
Fried MW, Hadziyannis SJ, Shiffman ML, Messinger D, Zeuzem S.
University of North Carolina, Chapel Hill, USA.
Abstract
The probability of response to peginterferon and ribavirin is associated with numerous host and virological factors. Attainment of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 during treatment with peginterferon and ribavirin, is highly predictive of sustained virological response (SVR). The aim of the present study was to determine the relative importance of the kinetics of antiviral response compared to baseline host and virological factors for predicting SVR.
METHODS: A retrospective analysis of 1,383 patients, encompassing genotypes 1-4, treated with peginterferon alfa-2a and ribavirin was performed. Baseline characteristics were compared across HCV genotypes and pretreatment factors associated with RVR were identified. The relative significance of RVR compared to other baseline factors for predicting SVR was analyzed by multiple logistic regression analysis.
RESULTS: RVR was achieved by 16% of patients with genotype 1 and 71% and 60% of those with genotype 2 and 3, respectively. Among patients who achieved RVR, the rate of SVR was high across all genotypes and ranged from 88% to 100% (genotypes 1-4). Baseline factors predictive of RVR included genotype, younger age, lower initial viral load, higher ALT ratio, absence of advanced fibrosis, and younger age. Notably, the presence of RVR generated the highest odds ratio (5.47, 95% confidence interval 3.97-7.52) for predicting SVR in multiple logistic regression analysis of these factors.
CONCLUSIONS: Attainment of RVR varies by genotype and is associated with several baseline factors. Patients who achieve RVR have the highest rates of SVR, regardless of genotype. These findings have important implications for predicting and managing response-guided combination antiviral therapies.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145856 [PubMed - as supplied by publisher]
Source
Low Dose Ribavirin for Treatment of HCV Infected Thalassemia Major Patients; New Indications for Combination Therapy
J Hepatol. 2010 Nov 23. [Epub ahead of print]
Tabatabaei SV, Alavian SM, Keshvari M, Behnava B, Miri SM, Elizee PK, Zamani F, Kafi-Abad SA, Gharehbaghian A, Hajibeigy B, Lankarani KB.
Baqiyatallah University of Medical Sciences, Baqiyatallah Research Center for Gastroenterology and Liver Disease, Tehran, Iran.
Abstract
BACKGROUND AND AIMS: Treatment guidelines contraindicate ribavirin for treatment of hepatitis C virus (HCV) infection in thalassemia major patients. Nevertheless, the current evidence suggests that ribavirin might be tolerated by these patients. Despite this evidence, low dose ribavirin combination therapy has not been compared with peginterferon monotherapy in these patients so far.
MATERIAL AND METHODS: Two hundred eighty thalassemia patients with detectable HCV-RNA PCR (⩾50 IU/mL) and liver histology consistent with chronic HCV infection were self-assigned to receive peginterferon alfa-2a (n=81) monotherapy or its combination therapy with ribavirin, 600-800 mg QD, according to hemoglobin levels (n=199). Treatment experienced patients were eligible for this study.
RESULTS: Sustained virological response (SVR) was significantly higher in patients who received ribavirin (51% vs. 38% P=0.02). In multivariate regression, OR of ribavirin for prediction of SVR was 2.2 (95% CI 1.24-3.91). The SVR was significantly higher in the ribavirin group in subgroups of patients with more than 24 years of age, elevated ALT, ferritin<2006 ng/mL, previous treatment failure, genotype 1, positive history of splenectomy, fibrosis score of 0-4 HAI and viral load<600,000 IU/mL. Treatment discontinuations due to the safety concerns were comparable between the treatment groups (6.5 and 8%). Furthermore, transfusion intervals were almost halved in patients who received low dose ribavirin.
CONCLUSION: According to the present study, adult thalassemia patients with HCV infection can be treated successfully with low dose ribavirin. Hence, we strongly advise combination therapy in thalassemia patients with aforementioned clinical characteristics. Moreover, ribavirin does not seem to be beneficial in thalassemia patients below 18 years of age.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145858 [PubMed - as supplied by publisher]
Source
Tabatabaei SV, Alavian SM, Keshvari M, Behnava B, Miri SM, Elizee PK, Zamani F, Kafi-Abad SA, Gharehbaghian A, Hajibeigy B, Lankarani KB.
Baqiyatallah University of Medical Sciences, Baqiyatallah Research Center for Gastroenterology and Liver Disease, Tehran, Iran.
Abstract
BACKGROUND AND AIMS: Treatment guidelines contraindicate ribavirin for treatment of hepatitis C virus (HCV) infection in thalassemia major patients. Nevertheless, the current evidence suggests that ribavirin might be tolerated by these patients. Despite this evidence, low dose ribavirin combination therapy has not been compared with peginterferon monotherapy in these patients so far.
MATERIAL AND METHODS: Two hundred eighty thalassemia patients with detectable HCV-RNA PCR (⩾50 IU/mL) and liver histology consistent with chronic HCV infection were self-assigned to receive peginterferon alfa-2a (n=81) monotherapy or its combination therapy with ribavirin, 600-800 mg QD, according to hemoglobin levels (n=199). Treatment experienced patients were eligible for this study.
RESULTS: Sustained virological response (SVR) was significantly higher in patients who received ribavirin (51% vs. 38% P=0.02). In multivariate regression, OR of ribavirin for prediction of SVR was 2.2 (95% CI 1.24-3.91). The SVR was significantly higher in the ribavirin group in subgroups of patients with more than 24 years of age, elevated ALT, ferritin<2006 ng/mL, previous treatment failure, genotype 1, positive history of splenectomy, fibrosis score of 0-4 HAI and viral load<600,000 IU/mL. Treatment discontinuations due to the safety concerns were comparable between the treatment groups (6.5 and 8%). Furthermore, transfusion intervals were almost halved in patients who received low dose ribavirin.
CONCLUSION: According to the present study, adult thalassemia patients with HCV infection can be treated successfully with low dose ribavirin. Hence, we strongly advise combination therapy in thalassemia patients with aforementioned clinical characteristics. Moreover, ribavirin does not seem to be beneficial in thalassemia patients below 18 years of age.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145858 [PubMed - as supplied by publisher]
Source
Role of a cirrhosis risk score for the early prediction of fibrosis progression in hepatitis C patients with minimal liver disease
J Hepatol. 2010 Nov 23. [Epub ahead of print]
Trépo E, Potthoff A, Pradat P, Bakshi R, Young B, Lagier R, Moreno C, Verset L, Cross R, Degré D, Lemmers A, Gustot T, Berthillon P, Rosenberg W, Trépo C, Sninsky J, Adler M, Wedemeyer H.
Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium.
Abstract
BACKGROUND AND AIMS: Fibrosis progression in patients with chronic hepatitis C (CHC) is highly variable. A Cirrhosis Risk Score (CRS) based on seven genetic variants has been recently developed for identifying patients at risk for cirrhosis. The objective of this study was to assess the role of the CRS for the early prediction of fibrosis progression in CHC patients with mild liver fibrosis. In addition, we evaluated the potential benefit, for prediction accuracy, of a recently described non-invasive fibrosis staging assay, the Enhanced Liver Fibrosis (ELF) test.
METHODS: Two separate cohorts of HCV patients (Brussels, Belgium/Hannover, Germany) were retrospectively analyzed. Only patients with a fibrosis Ishak or METAVIR score of F0-F1 at baseline were included. Patients were classified as progressors if they showed an increase >=2 fibrosis stages at the second histological evaluation after a follow-up >=5 years. The CRS was calculated locally. Genotyping was performed by PCR and oligonucleotide ligation with the resulting signal detected with a Luminex® 200TM and computer analysis.
RESULTS: In Brussels, 12/25 patients progressed (48%); similarly in Hannover, 16/31 (52%) patients progressed. In both sample sets, the CRS was significantly associated with fibrosis progression (p=0.050 in Brussels; p=0.018 in Hannover). The ELF test was only a significant predictor in Hannover (p=0.015). In multivariate analysis the CRS remained the only variable associated with fibrosis progression (Odds-ratio= 2.23, 95%CI 1.21-4.11 p=0.01).
CONCLUSIONS: Although conducted on a limited number of patients, this study in two independent centres confirms that the CRS predicts fibrosis progression in initially mild CHC.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145859 [PubMed - as supplied by publisher]
Source
Trépo E, Potthoff A, Pradat P, Bakshi R, Young B, Lagier R, Moreno C, Verset L, Cross R, Degré D, Lemmers A, Gustot T, Berthillon P, Rosenberg W, Trépo C, Sninsky J, Adler M, Wedemeyer H.
Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium.
Abstract
BACKGROUND AND AIMS: Fibrosis progression in patients with chronic hepatitis C (CHC) is highly variable. A Cirrhosis Risk Score (CRS) based on seven genetic variants has been recently developed for identifying patients at risk for cirrhosis. The objective of this study was to assess the role of the CRS for the early prediction of fibrosis progression in CHC patients with mild liver fibrosis. In addition, we evaluated the potential benefit, for prediction accuracy, of a recently described non-invasive fibrosis staging assay, the Enhanced Liver Fibrosis (ELF) test.
METHODS: Two separate cohorts of HCV patients (Brussels, Belgium/Hannover, Germany) were retrospectively analyzed. Only patients with a fibrosis Ishak or METAVIR score of F0-F1 at baseline were included. Patients were classified as progressors if they showed an increase >=2 fibrosis stages at the second histological evaluation after a follow-up >=5 years. The CRS was calculated locally. Genotyping was performed by PCR and oligonucleotide ligation with the resulting signal detected with a Luminex® 200TM and computer analysis.
RESULTS: In Brussels, 12/25 patients progressed (48%); similarly in Hannover, 16/31 (52%) patients progressed. In both sample sets, the CRS was significantly associated with fibrosis progression (p=0.050 in Brussels; p=0.018 in Hannover). The ELF test was only a significant predictor in Hannover (p=0.015). In multivariate analysis the CRS remained the only variable associated with fibrosis progression (Odds-ratio= 2.23, 95%CI 1.21-4.11 p=0.01).
CONCLUSIONS: Although conducted on a limited number of patients, this study in two independent centres confirms that the CRS predicts fibrosis progression in initially mild CHC.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145859 [PubMed - as supplied by publisher]
Source
Predictors and effects of alcohol use on liver function among young HCV-infected injection drug users in a behavioral intervention
J Hepatol. 2010 Nov 24. [Epub ahead of print]
Drumright LN, Hagan H, Thomas DL, Latka MH, Golub ET, Garfein RS, Clapp JD, Campbell JV, Bonner S, Kapadia F, Thiel TK, Strathdee SA.
At the time of work on study: University of California, San Diego, Department of Medicine, Division of Global Public Health, La Jolla, CA.
Abstract
BACKGROUND & AIMS: Hepatitis C virus (HCV) screening can provide opportunities to reduce disease progression through counseling against alcohol use, but empirical data on this issue are sparse. We determined the efficacy of a behavioral intervention in reducing alcohol use among young, HCV-infected injection drug users (IDUs) (n=355) and assessed whether changes in liver enzymes were associated with changes in alcohol consumption.
METHODS: Both the intervention and attention-control groups were counseled to avoid alcohol use, but the intervention group received enhanced counseling. Logistic regression, ANOVA, and continuous time Markov models were used to identify factors associated with alcohol use, changes in mean ALT and AST levels and change in alcohol use post-intervention.
RESULTS: Six months post-intervention, alcohol abstinence increased 22.7% in both groups, with no difference by intervention arm. Transition from alcohol use to abstinence was associated with a decrease in liver enzymes, with a marginally greater decrease in the intervention group (p=0.05 for ALT; p=0.06 for AST). In multivariate Markov models, those who used marijuana transitioned from alcohol abstinence to consumption more rapidly than non-users (RR=3.11); those who were homeless transitioned more slowly to alcohol abstinence (RR=0.47); and those who had ever received a clinical diagnosis of liver disease transitioned more rapidly to abstinence (RR=1.88).
CONCLUSIONS: Although, behavioral counseling to reduce alcohol consumption among HCV-infected IDUs had a modest effect, reductions in alcohol consumption were associated with marked improvements in liver function. Interventions to reduce alcohol use among HCV-infected IDUs may benefit from being integrated into clinical care and monitoring of HCV infection.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145862 [PubMed - as supplied by publisher]
Source
Drumright LN, Hagan H, Thomas DL, Latka MH, Golub ET, Garfein RS, Clapp JD, Campbell JV, Bonner S, Kapadia F, Thiel TK, Strathdee SA.
At the time of work on study: University of California, San Diego, Department of Medicine, Division of Global Public Health, La Jolla, CA.
Abstract
BACKGROUND & AIMS: Hepatitis C virus (HCV) screening can provide opportunities to reduce disease progression through counseling against alcohol use, but empirical data on this issue are sparse. We determined the efficacy of a behavioral intervention in reducing alcohol use among young, HCV-infected injection drug users (IDUs) (n=355) and assessed whether changes in liver enzymes were associated with changes in alcohol consumption.
METHODS: Both the intervention and attention-control groups were counseled to avoid alcohol use, but the intervention group received enhanced counseling. Logistic regression, ANOVA, and continuous time Markov models were used to identify factors associated with alcohol use, changes in mean ALT and AST levels and change in alcohol use post-intervention.
RESULTS: Six months post-intervention, alcohol abstinence increased 22.7% in both groups, with no difference by intervention arm. Transition from alcohol use to abstinence was associated with a decrease in liver enzymes, with a marginally greater decrease in the intervention group (p=0.05 for ALT; p=0.06 for AST). In multivariate Markov models, those who used marijuana transitioned from alcohol abstinence to consumption more rapidly than non-users (RR=3.11); those who were homeless transitioned more slowly to alcohol abstinence (RR=0.47); and those who had ever received a clinical diagnosis of liver disease transitioned more rapidly to abstinence (RR=1.88).
CONCLUSIONS: Although, behavioral counseling to reduce alcohol consumption among HCV-infected IDUs had a modest effect, reductions in alcohol consumption were associated with marked improvements in liver function. Interventions to reduce alcohol use among HCV-infected IDUs may benefit from being integrated into clinical care and monitoring of HCV infection.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21145862 [PubMed - as supplied by publisher]
Source
Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy
J Hepatol. 2010 Dec 8. [Epub ahead of print]
Oze T, Hiramatsu N, Yakushijin T, Mochizuki K, Oshita M, Hagiwara H, Mita E, Ito T, Fukui H, Inui Y, Hijioka T, Inada M, Kaytayama K, Tamura S, Yoshihara H, Inoue A, Imai Y, Kato M, Miyagi T, Yoshida Y, Tatsumi T, Kiso S, Kanto T, Kasahara A, Takehara T, Hayashi N.
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Japan.
Abstract
BACKGROUND & AIMS: This study investigated the efficacy and adverse effects of pegylated interferon (Peg-IFN) plus ribavirin therapy in aged patients with chronic hepatitis C (CH-C).
METHODS: A total of 1040 naïve patients with CH-C (genotype 1, n=759; genotype 2, n=281), of whom 240 (23%) over 65years old (y.o.), were treated with Peg-IFN alfa-2b plus ribavirin and assessed after being classified into five categories, according to age.
RESULTS: The discontinuance rate was higher for patients over 70 y.o. (36%), the most common reason being anemia. In the presence of genotype 1, the SVR rate was similar (42-46%) among patients under 65 y.o. and declined (26-29%) among patients over 65 y.o. For patients over 65 y.o., being male (Odds ratio, OR, 3.5, p=0.035) and EVR (OR, 83.3, p<0.001) were significant factors for SVR, in multivariate analysis. The Peg-IFN dose was related to EVR, and when EVR was attained, 76-86% of patients over 65 y.o. achieved SVR. SVR was not achieved (0/35, 0/38, respectively) if a 1-log decrease and a 2-log decrease were not attained at week 4 and week 8, respectively. In the presence of genotype 2, the SVR rate was similar (70-71%) among patients under 70 y.o. and declined among patients over 70 y.o. (43%).
CONCLUSIONS: Aged patients up to 65 y.o. with genotype 1 and 70 y.o. with genotype 2 can be candidates for pegylated interferon (Peg-IFN) plus ribavirin therapy. The response-guided therapy can be applied for aged patients with genotype 1.
Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PMID: 21145907 [PubMed - as supplied by publisher]
Source
Oze T, Hiramatsu N, Yakushijin T, Mochizuki K, Oshita M, Hagiwara H, Mita E, Ito T, Fukui H, Inui Y, Hijioka T, Inada M, Kaytayama K, Tamura S, Yoshihara H, Inoue A, Imai Y, Kato M, Miyagi T, Yoshida Y, Tatsumi T, Kiso S, Kanto T, Kasahara A, Takehara T, Hayashi N.
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Japan.
Abstract
BACKGROUND & AIMS: This study investigated the efficacy and adverse effects of pegylated interferon (Peg-IFN) plus ribavirin therapy in aged patients with chronic hepatitis C (CH-C).
METHODS: A total of 1040 naïve patients with CH-C (genotype 1, n=759; genotype 2, n=281), of whom 240 (23%) over 65years old (y.o.), were treated with Peg-IFN alfa-2b plus ribavirin and assessed after being classified into five categories, according to age.
RESULTS: The discontinuance rate was higher for patients over 70 y.o. (36%), the most common reason being anemia. In the presence of genotype 1, the SVR rate was similar (42-46%) among patients under 65 y.o. and declined (26-29%) among patients over 65 y.o. For patients over 65 y.o., being male (Odds ratio, OR, 3.5, p=0.035) and EVR (OR, 83.3, p<0.001) were significant factors for SVR, in multivariate analysis. The Peg-IFN dose was related to EVR, and when EVR was attained, 76-86% of patients over 65 y.o. achieved SVR. SVR was not achieved (0/35, 0/38, respectively) if a 1-log decrease and a 2-log decrease were not attained at week 4 and week 8, respectively. In the presence of genotype 2, the SVR rate was similar (70-71%) among patients under 70 y.o. and declined among patients over 70 y.o. (43%).
CONCLUSIONS: Aged patients up to 65 y.o. with genotype 1 and 70 y.o. with genotype 2 can be candidates for pegylated interferon (Peg-IFN) plus ribavirin therapy. The response-guided therapy can be applied for aged patients with genotype 1.
Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PMID: 21145907 [PubMed - as supplied by publisher]
Source
Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection
J Hepatol. 2010 Dec 10. [Epub ahead of print]
Lange CM, Moradpour D, Doehring A, Lehr HA, Müllhaupt B, Bibert S, Bochud PY, Antonino AT, Pascual M, Farnik H, Shi Y, Bechstein WO, Moench C, Hansmann ML, Sarrazin C, Lötsch J, Zeuzem S, Hofmann WP.
Medizinische Klinik 1, Germany; Centre Hospitalier Universitaire Vaudois, University of Lausanne, Rue Bugnon 46, CH-1010 Lausanne, Switzerland.
Abstract
BACKGROUND AND AIM: Recent studies described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection.
METHODS: Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of which were treated with pegylated interferon-α(PEG-IFN-α) and ribavirin. IL28B genetic polymorphisms were correlated with the natural course and treatment outcome of recurrent hepatitis C.
RESULTS: Patients requiring liver transplantation due to end-stage chronic hepatitis C appeared to be selected towards the adverse genotypes rs12979860CT/TT compared to non-transplanted HCV-infected patients (p=0.046). Patients with the donor genotype rs12979860CC had higher peak ALT and HCV RNA serum concentrations than those with CT/TT (p=0.04 and 0.06, respectively). No associations were observed between ALT / HCV RNA serum concentrations and recipient genotypes (p>0.3). More important, donor IL28B rs12979860 CC vs. CT/TT genotypes were associated with rapid, complete early, and sustained virologic response (RVR, cEVR, SVR) to treatment with PEG-IFN-α and ribavirin (p=0.003, 0.0012, 0.008, respectively), but weaker associations of recipient genotypes with RVR, cEVR and SVR were observed as well (p=0.0046, 0.115, 0.118, respectively).
CONCLUSIONS: We provide evidence for a dominant, but not exclusive impact of the donor rather than the recipient IL28B genetic background on the natural course and treatment outcome of HCV liver graft reinfection.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21147186 [PubMed - as supplied by publisher]
Source
Lange CM, Moradpour D, Doehring A, Lehr HA, Müllhaupt B, Bibert S, Bochud PY, Antonino AT, Pascual M, Farnik H, Shi Y, Bechstein WO, Moench C, Hansmann ML, Sarrazin C, Lötsch J, Zeuzem S, Hofmann WP.
Medizinische Klinik 1, Germany; Centre Hospitalier Universitaire Vaudois, University of Lausanne, Rue Bugnon 46, CH-1010 Lausanne, Switzerland.
Abstract
BACKGROUND AND AIM: Recent studies described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection.
METHODS: Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of which were treated with pegylated interferon-α(PEG-IFN-α) and ribavirin. IL28B genetic polymorphisms were correlated with the natural course and treatment outcome of recurrent hepatitis C.
RESULTS: Patients requiring liver transplantation due to end-stage chronic hepatitis C appeared to be selected towards the adverse genotypes rs12979860CT/TT compared to non-transplanted HCV-infected patients (p=0.046). Patients with the donor genotype rs12979860CC had higher peak ALT and HCV RNA serum concentrations than those with CT/TT (p=0.04 and 0.06, respectively). No associations were observed between ALT / HCV RNA serum concentrations and recipient genotypes (p>0.3). More important, donor IL28B rs12979860 CC vs. CT/TT genotypes were associated with rapid, complete early, and sustained virologic response (RVR, cEVR, SVR) to treatment with PEG-IFN-α and ribavirin (p=0.003, 0.0012, 0.008, respectively), but weaker associations of recipient genotypes with RVR, cEVR and SVR were observed as well (p=0.0046, 0.115, 0.118, respectively).
CONCLUSIONS: We provide evidence for a dominant, but not exclusive impact of the donor rather than the recipient IL28B genetic background on the natural course and treatment outcome of HCV liver graft reinfection.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21147186 [PubMed - as supplied by publisher]
Source
IL28B inhibits Hepatitis C virus replication through the JAK-STAT pathway
J Hepatol. 2010 Dec 10. [Epub ahead of print]
Zhang L, Jilg N, Shao RX, Lin W, Fusco DN, Zhao H, Goto K, Peng LF, Chen WC, Chung RT.
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Abstract
BACKGROUND AND AIMS: The combination of pegylated interferon (IFN) α and ribavirin (RBV) is standard therapy for patients with chronic HCV infection. However, it produces a sustained virologic response (SVR) in only half of treated individuals and is associated with significant side effects. Recently several single-nucleotide polymorphisms (SNPs) near the IL28B locus, also known as IFNλ3, were identified to be strong predictors of SVR in patients receiving PEG-IFN and RBV. We sought to determine whether IL28B was capable of inhibiting HCV replication and to determine the pathway by which IL28B exhibits anti-HCV activity.
METHODS: Using the full-length HCV replicon OR6 and the infectious HCV clones JFH1 and Jc1, we assessed the anti-HCV effect of IL28B on HCV and characterized the key steps of the JAK-STAT pathway by real time PCR, luciferase assay, and Western blot. Finally, we evaluated the anti-HCV effect of IL28B in the presence of JAK-STAT pathway inhibitors such as blocking antibodies, a pharmacological inhibitor and siRNAs.
RESULTS: We found that IL28B inhibits HCV replication in a dose- and time- dependent manner. Like IFNα, IL28B induces the phosphorylation of STAT1 and STAT2, ISRE-driven transcription, and expression of known ISGs. The anti-HCV effects of IL28A, IL28B and IL29 were abrogated by an IL10R2 blocking antibody, a pharmacological inhibitor of JAK1/TYK2, and by siRNA against IL28R1, STAT1, STAT2 and IRF9.
CONCLUSIONS: Our data demonstrate that IL28A, IL28B and IL29 signal through the JAK-STAT pathway to inhibit HCV. These data suggest possible applications of new approaches in HCV treatment.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21147189 [PubMed - as supplied by publisher]
Source
Zhang L, Jilg N, Shao RX, Lin W, Fusco DN, Zhao H, Goto K, Peng LF, Chen WC, Chung RT.
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Abstract
BACKGROUND AND AIMS: The combination of pegylated interferon (IFN) α and ribavirin (RBV) is standard therapy for patients with chronic HCV infection. However, it produces a sustained virologic response (SVR) in only half of treated individuals and is associated with significant side effects. Recently several single-nucleotide polymorphisms (SNPs) near the IL28B locus, also known as IFNλ3, were identified to be strong predictors of SVR in patients receiving PEG-IFN and RBV. We sought to determine whether IL28B was capable of inhibiting HCV replication and to determine the pathway by which IL28B exhibits anti-HCV activity.
METHODS: Using the full-length HCV replicon OR6 and the infectious HCV clones JFH1 and Jc1, we assessed the anti-HCV effect of IL28B on HCV and characterized the key steps of the JAK-STAT pathway by real time PCR, luciferase assay, and Western blot. Finally, we evaluated the anti-HCV effect of IL28B in the presence of JAK-STAT pathway inhibitors such as blocking antibodies, a pharmacological inhibitor and siRNAs.
RESULTS: We found that IL28B inhibits HCV replication in a dose- and time- dependent manner. Like IFNα, IL28B induces the phosphorylation of STAT1 and STAT2, ISRE-driven transcription, and expression of known ISGs. The anti-HCV effects of IL28A, IL28B and IL29 were abrogated by an IL10R2 blocking antibody, a pharmacological inhibitor of JAK1/TYK2, and by siRNA against IL28R1, STAT1, STAT2 and IRF9.
CONCLUSIONS: Our data demonstrate that IL28A, IL28B and IL29 signal through the JAK-STAT pathway to inhibit HCV. These data suggest possible applications of new approaches in HCV treatment.
Copyright © 2010. Published by Elsevier B.V.
PMID: 21147189 [PubMed - as supplied by publisher]
Source
Meeting vaccination quality measures for hepatitis A and B virus in patients with chronic hepatitis C infection
Hepatology. 2010 Oct 6. [Epub ahead of print]
Kramer JR, Hachem CY, Kanwal F, Mei M, El-Serag HB.
Houston VA Health Services Research #38; Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX.
Abstract
Coinfection with hepatitis A virus (HAV) or hepatitis B virus (HBV) in patients with chronic hepatitis C virus (HCV) is associated with increased morbidity and mortality. The Center for Medicare and Medicaid Services has identified HAV and HBV vaccination as a priority area for quality measurement in HCV. It is unclear to what extent patients with HCV meet these recommendations. We used national data from the Department of Veterans Affairs HCV Clinical Case Registry to evaluate the prevalence and predictors of meeting the quality measure (QM) of receiving vaccination or documented immunity to HAV and HBV in patients with chronic HCV. We identified 88,456 patients who had overall vaccination rates of 21.9% and 20.7% for HBV and HAV, respectively. The QM rates were 57.0% and 45.5% for HBV and HAV, respectively. Patients who were nonwhite or who had elevated alanine aminotransferase levels, cirrhosis, or human immunodeficiency virus were more likely to meet the HBV QM. Factors related to HCV care were also determinants of meeting the HBV QM. These factors included receiving a specialist consult, genotype testing, or HCV treatment. Patients who were older, had psychosis, and had a higher comorbidity score were less likely to meet the HBV QM. With a few exceptions, similar variables were related to meeting the HAV QM. The incidence of superinfection with acute HBV and HAV was low, but it was significantly lower in patients who received vaccination than in those who did not. Conclusion: Quality measure rates for HAV and HBV are suboptimal for patients with chronic HCV. In addition, several patient-related factors and receiving HCV-related care are associated with a higher likelihood of meeting QMs. (HEPATOLOGY 2010;).
PMID: 21157783 [PubMed - as supplied by publisher]
Source
Kramer JR, Hachem CY, Kanwal F, Mei M, El-Serag HB.
Houston VA Health Services Research #38; Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX.
Abstract
Coinfection with hepatitis A virus (HAV) or hepatitis B virus (HBV) in patients with chronic hepatitis C virus (HCV) is associated with increased morbidity and mortality. The Center for Medicare and Medicaid Services has identified HAV and HBV vaccination as a priority area for quality measurement in HCV. It is unclear to what extent patients with HCV meet these recommendations. We used national data from the Department of Veterans Affairs HCV Clinical Case Registry to evaluate the prevalence and predictors of meeting the quality measure (QM) of receiving vaccination or documented immunity to HAV and HBV in patients with chronic HCV. We identified 88,456 patients who had overall vaccination rates of 21.9% and 20.7% for HBV and HAV, respectively. The QM rates were 57.0% and 45.5% for HBV and HAV, respectively. Patients who were nonwhite or who had elevated alanine aminotransferase levels, cirrhosis, or human immunodeficiency virus were more likely to meet the HBV QM. Factors related to HCV care were also determinants of meeting the HBV QM. These factors included receiving a specialist consult, genotype testing, or HCV treatment. Patients who were older, had psychosis, and had a higher comorbidity score were less likely to meet the HBV QM. With a few exceptions, similar variables were related to meeting the HAV QM. The incidence of superinfection with acute HBV and HAV was low, but it was significantly lower in patients who received vaccination than in those who did not. Conclusion: Quality measure rates for HAV and HBV are suboptimal for patients with chronic HCV. In addition, several patient-related factors and receiving HCV-related care are associated with a higher likelihood of meeting QMs. (HEPATOLOGY 2010;).
PMID: 21157783 [PubMed - as supplied by publisher]
Source
December 17, 2010
Progression of initially mild hepatic fibrosis in patients with chronic hepatitis C infection
J Viral Hepat. 2011 Jan;18(1):17-22. doi: 10.1111/j.1365-2893.2009.01262.x.
Williams MJ, Lang-Lenton M; on behalf of the Trent HCV Study Group.
Nottingham Digestive Diseases Centre, Nottingham University Hospital, Nottingham, UK.
Abstract
Summary. A significant number of patients with chronic hepatitis C infection have minimal fibrosis at presentation. Although the short-term outlook for such patients is good, there are limited data available on long-term progression. We assessed the risk of fibrosis progression in 282 patients with chronic hepatitis C with Ishak stage 0 or 1 fibrosis on initial liver biopsy. Progression of fibrosis stage occurred in 118 patients (42%) over a median interval of 52.5 months. Thirteen (5%) progressed to severe (Ishak stage 4 or more) fibrosis. Progression was significantly associated with both age at initial biopsy [odds ratio (OR) for progression of 1.31 per 10 year increase in age] and median alanine transaminase (ALT) levels during follow-up (OR of 1.06 per 10 IU/L increase). There was no significant association with gender, histological inflammatory grade, hepatic steatosis or body mass index. We conclude that hepatitis C with initially mild fibrosis does progress in a substantial proportion of patients and should not be viewed as a benign disease. Early antiviral therapy should be considered in older patients and those with high ALT levels.
© 2010 Blackwell Publishing Ltd.
PMID: 20088889 [PubMed - as supplied by publisher]
Source
Williams MJ, Lang-Lenton M; on behalf of the Trent HCV Study Group.
Nottingham Digestive Diseases Centre, Nottingham University Hospital, Nottingham, UK.
Abstract
Summary. A significant number of patients with chronic hepatitis C infection have minimal fibrosis at presentation. Although the short-term outlook for such patients is good, there are limited data available on long-term progression. We assessed the risk of fibrosis progression in 282 patients with chronic hepatitis C with Ishak stage 0 or 1 fibrosis on initial liver biopsy. Progression of fibrosis stage occurred in 118 patients (42%) over a median interval of 52.5 months. Thirteen (5%) progressed to severe (Ishak stage 4 or more) fibrosis. Progression was significantly associated with both age at initial biopsy [odds ratio (OR) for progression of 1.31 per 10 year increase in age] and median alanine transaminase (ALT) levels during follow-up (OR of 1.06 per 10 IU/L increase). There was no significant association with gender, histological inflammatory grade, hepatic steatosis or body mass index. We conclude that hepatitis C with initially mild fibrosis does progress in a substantial proportion of patients and should not be viewed as a benign disease. Early antiviral therapy should be considered in older patients and those with high ALT levels.
© 2010 Blackwell Publishing Ltd.
PMID: 20088889 [PubMed - as supplied by publisher]
Source
Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C
J Viral Hepat. 2011 Jan;18(1):23-31. doi: 10.1111/j.1365-2893.2009.01263.x.
Parkes J, Guha IN, Roderick P, Harris S, Cross R, Manos MM, Irving W, Zaitoun A, Wheatley M, Ryder S, Rosenberg W.
Public Health Sciences & Medical Statistics, University of Southampton, Southampton Nottingham Digestive Diseases Centre Biomedical Research Unit, University of Nottingham iQur Ltd, Southampton General Hospital, Southampton, UK Kaiser Permanente Division of Research; Oakland, CA, USA Division of Microbiology, University Hospital, Queen's Medical Centre, Nottingham Department of Histopathology, University Hospital Queens Medical Centre, Nottingham Division of Gastroenterology, Queens Medical Centre, Nottingham; Centre for Hepatology, University College London, London, UK.
Abstract
Summary. Assessment of liver fibrosis is important in determining prognosis and evaluating interventions. Due to limitations of accuracy and patient hazard of liver biopsy, non-invasive methods have been sought to provide information on liver fibrosis, including the European liver fibrosis (ELF) test, shown to have good diagnostic accuracy for the detection of moderate and severe fibrosis. Access to independent cohorts of patients has provided an opportunity to explore if this test could be simplified. This paper reports the simplification of the ELF test and its ability to identity severity of liver fibrosis in external validation studies in patients with chronic hepatitis C (CHC). Paired biopsy and serum samples from 347 naïve patients with CHC in three independent cohorts were analysed. Diagnostic performance characteristics were derived (AUROC, sensitivity and specificity, predictive values), and clinical utility modelling performed to determine the proportion of biopsies that could have been avoided if ELF test was used in this patient group. It was possible to simplify the original ELF test without loss of performance and the new algorithm is reported. The simplified ELF test was able to predict severe fibrosis [pooled AUROC of 0.85 (95% CI 0.81-0.89)] and using clinical utility modelling to predict severe fibrosis (Ishak stages 4-6; METAVIR stages 3 and 4) 81% of biopsies could have been avoided (65% correctly). Issues of spectrum effect in diagnostic test evaluations are discussed. In chronic hepatitis C a simplified ELF test can detect severe liver fibrosis with good accuracy.
© 2010 Blackwell Publishing Ltd.
PMID: 20196799 [PubMed - as supplied by publisher]
Source
Parkes J, Guha IN, Roderick P, Harris S, Cross R, Manos MM, Irving W, Zaitoun A, Wheatley M, Ryder S, Rosenberg W.
Public Health Sciences & Medical Statistics, University of Southampton, Southampton Nottingham Digestive Diseases Centre Biomedical Research Unit, University of Nottingham iQur Ltd, Southampton General Hospital, Southampton, UK Kaiser Permanente Division of Research; Oakland, CA, USA Division of Microbiology, University Hospital, Queen's Medical Centre, Nottingham Department of Histopathology, University Hospital Queens Medical Centre, Nottingham Division of Gastroenterology, Queens Medical Centre, Nottingham; Centre for Hepatology, University College London, London, UK.
Abstract
Summary. Assessment of liver fibrosis is important in determining prognosis and evaluating interventions. Due to limitations of accuracy and patient hazard of liver biopsy, non-invasive methods have been sought to provide information on liver fibrosis, including the European liver fibrosis (ELF) test, shown to have good diagnostic accuracy for the detection of moderate and severe fibrosis. Access to independent cohorts of patients has provided an opportunity to explore if this test could be simplified. This paper reports the simplification of the ELF test and its ability to identity severity of liver fibrosis in external validation studies in patients with chronic hepatitis C (CHC). Paired biopsy and serum samples from 347 naïve patients with CHC in three independent cohorts were analysed. Diagnostic performance characteristics were derived (AUROC, sensitivity and specificity, predictive values), and clinical utility modelling performed to determine the proportion of biopsies that could have been avoided if ELF test was used in this patient group. It was possible to simplify the original ELF test without loss of performance and the new algorithm is reported. The simplified ELF test was able to predict severe fibrosis [pooled AUROC of 0.85 (95% CI 0.81-0.89)] and using clinical utility modelling to predict severe fibrosis (Ishak stages 4-6; METAVIR stages 3 and 4) 81% of biopsies could have been avoided (65% correctly). Issues of spectrum effect in diagnostic test evaluations are discussed. In chronic hepatitis C a simplified ELF test can detect severe liver fibrosis with good accuracy.
© 2010 Blackwell Publishing Ltd.
PMID: 20196799 [PubMed - as supplied by publisher]
Source
WHAT KINDS OF DOCTORS TREAT LIVER DISEASE?
Written by Melissa Palmer, MD
Melissa Palmer, MD is the author of " Dr. Melissa Palmer's Guide of Hepatitis and Liver Disease". (Published 2004. Penguin Putnam).
There are many different kinds of doctors who evaluate and treat people with liver disorders. First, there is the family physician or internist. These doctors are also referred to as primary care physicians (PCPs). They are often the first ones to discover that something is wrong with the liver. From there, the patient is customarily referred to a specialist—either a gastroenterologist, hepatologist, or infectious disease specialist—for further evaluation and treatment. This specialist may be in a practice located at an academic institution or in a private practice located in a community setting. The difference between the various types of doctors a patient with liver disease encounters may sometimes be confusing. Hopefully, this section will clarify these differences in order to eliminate any future confusion.
The Medical Doctor (MD)
Medical Doctors (MDs) are physicians who have successfully completed four years of medical school training. After graduating from medical school, these doctors must complete a minimum of one additional year of training in a hospital in what is known as an internship. They must then pass a state-licensing exam in order to practice medicine in that state. After obtaining their license, they have the right to practice medicine in that state. However, many doctors choose to continue their training in a hospital by undergoing a residency—typically an additional two years.
After completing their residency, these doctors must take an exam in order to become board certified in a specialty, such as family medicine or internal medicine. Doctors may practice medicine whether or not they pass this exam. Doctors who become family doctors or internists have general knowledge in all areas of medicine including the heart, lungs, kidneys, stomach, intestines, and liver. At this time, a doctor may decide to undergo additional specialty training, known as a fellowship, in a specific area of internal medicine, such as gastroenterology, hepatology, or infectious diseases, in order to become an expert in these areas.
The Doctor of Osteopathy (DO)
Doctors of osteopathy (DOs) are commonly referred to as osteopaths. These are doctors who graduated from a four-year osteopathic school. They must also complete a one-year internship in a hospital in order to be eligible to obtain a license to practice medicine. Osteopaths can also choose to undergo an additional two-year residency, and may thereafter undergo specialty training in a specific area of medicine.
Osteopaths tend to focus on treating “the body as a whole,” particularly on the body’s ability to heal itself. Osteopaths typically center their treatment on the musculoskeletal system, the muscles and bones, often using techniques such as bone manipulation and a form of massage.
The Family Physician
A family physician is a doctor—either an MD or a DO—who has been trained to prevent, diagnose, and treat medical conditions in people of all ages. The family physician takes care of the general health of the patient and his entire family. Their training is not limited to internal medicine, but includes some training in psychiatry, obstetrics, gynecology, and surgery. These are the “Marcus Welby” doctors, seemingly able to handle almost any general problem.
There is a separate board certification examination specifically for family practitioners. This is known as the family practice boards. Specializing in family practice medicine requires an additional three years’ training beyond medical school. The amount of exposure to, and degree of expertise in liver disease varies among family practitioners. However, family physicians have not undergone additional specialized training in liver disease.
The Internist
An internist is a doctor—an MD or a DO—who is trained to prevent, diagnose, and treat medical conditions in adolescents and adults, including the elderly. Internists have received some basic training in subspecialty areas of internal medicine, including gastroenterology, hepatology, and infectious diseases. Internists are trained to treat both straightforward and complex problems of the internal organs. They are also trained in emergency medicine and critical care medicine. There is a separate board certification examination specifically for internists. It is known as the internal medicine boards. Specializing in internal medicine requires an additional three years’ training beyond medical school.
The amount of exposure to, and degree of expertise in liver disease varies among internists. Internists have the option of continuing their training in a subspecialty of internal medicine. This requires applying for, and being accepted into, a fellowship in the subspecialty of their choice. gastroenterology, hepatology, and infectious diseases are among the many subspecialties of internal medicine.
The Gastroenterologist
A gastroenterologist is an internist who has completed specialty training in the treatment of digestive disorders. Digestive disorders include disorders of the esophagus, stomach, small and large intestines, pancreas, gallbladder, and liver. In order to become board certified in gastroenterology, the doctor must first become board certified in internal medicine. In order to become eligible to even take the examination for board certification in gastroenterology, a gastrointestinal (GI) fellowship lasting an additional two to three years beyond an internal medicine residency must be completed.
During the course of their two to three years of training in gastroenterology, some gastroenterologists have little exposure to patients with liver disease. On the other hand, some gastroenterologists have a great deal of exposure to patients with liver disease during the course of their gastroenterology specialty training. Thus, the level of experience and expertise among gastroenterologists in diagnosing and treating liver disease varies greatly. It is important for the patient to determine the gastroenterologist’s level of expertise in liver disease prior to establishing a long-term medical relationship with this type of doctor.
The Hepatologist
A hepatologist is the most experienced and qualified type of doctor to treat people with liver disease. Since there is currently no separate board certification examination in the field of hepatology, there is no official definition of a hepatologist. However, there are specialized training programs for doctors who are focused solely on liver disease. These are known as hepatology fellowships and typically last from one to two years. Over the course of a hepatology fellowship, a doctor receives comprehensive training in the diagnosis and treatment of liver disease. This specialty training typically includes extensive exposure to all liver diseases, including those that are rare and infrequently seen. This intense training in liver disease is rarely matched in a gastroenterology fellowship.
A physician who successfully completes a hepatology fellowship is considered a hepatologist. Most hepatologists, although not all, are also gastroenterologists. These doctors have successfully completed both a hepatology and a gastroenterology fellowship. Occasionally, gastroenterologists who have not completed a fellowship in hepatology nonetheless focus their medical practice primarily on the diagnosis and treatment of people with liver disease. While these physicians do not have a separate diploma in the field of liver disease, they may also be considered hepatologists.
For many reasons, it is to the patient’s advantage to choose a hepatologist to treat his liver disease. The patient can be virtually assured that the hepatologist will have substantial experience in the diagnosis and treatment of the full range of liver diseases. Furthermore, hepatologists are likely to be the first to learn about the most up-to-date therapies—both FDA-approved and experimental—and to incorporate them into their practices. However, whether someone chooses to see a gastroenterologist or a hepatologist, it is important to find a doctor who is willing to work with him as an equal partner in the healing process.
Infectious Disease Specialists
An infectious disease specialist is an internist who has completed a specialty fellowship in infectious diseases of all types. Many infectious disease specialists treat people with liver disease caused by infectious - such as hepatitis B and C (both of which are caused by viruses). During the course of their two years of training in infectious diseases, some infectious disease specialists have little exposure to patients with viral hepatitis. On the other hand, some infectious disease specialists receive a great deal of exposure to patients with viral hepatitis during the course of their specialty training. Thus, the level of expertise among infectious disease specialists in diagnosing and treating viral hepatitis varies greatly. It is important for the patient to determine the infectious disease specialist’s level of expertise in treating hepatitis B or C prior to establishing a long-term medical relationship with this type of doctor. It should be stressed that infectious disease doctors have no special expertise treating liver diseases that are not caused by infections – such as alcoholic liver disease or autoimmune hepatitis.
Academic Physicians Versus Private Practitioners
People searching for a doctor should be aware of the differences between academic physicians and private practitioners. Each type of doctor has pros and cons that must be carefully weighed by the patient as part of the process of choosing a physician.
The Academic Physician
An academic physician is a doctor who has accepted a faculty position on staff at a hospital. Often, though not always, the hospital will be associated with a medical school. These doctors spend a portion of their time teaching medical students and physicians-in-training (interns, residents, and fellows) about their specialty—in this case hepatology. Also, some academic physicians spend a considerable percentage of their time conducting research, as opposed to treating patients. Although some of this research is performed in a laboratory, some is within the context of clinical trials involving patients. (See Chapter 11 of my book for a discussion of clinical trials.)
These physicians are usually, but not always, board certified in their specialty, and some have contributed significantly to the advancement of the medical profession in their specialty. However, this is not always the case. Academic physicians carry a title such as assistant professor, associate professor, or professor. This title is based on a number of factors, including, but not limited to, how long they have been practicing in their specialty, their leadership skills, their teaching skills and the contributions made by them in their specialty. No one should ever assume that the qualifications of a given academic physician are superior to those of a given private practitioner merely based on the academic physician’s title or employment by a hospital. This may even hold true of the department chairman.
Academic physicians are generally expected to stay abreast of the newest developments in their field. Such a physician may have initiated or prompted the investigation of a new drug or may have played a significant role in the development of a new medical procedure. Frequently, but not always, academic physicians are involved in conducting investigational trials on the most promising experimental drugs. However, the requirements of entering a study at an academic center may be very rigid and typically involve a risk that the patient will be given a placebo (dummy drug).
Doctors at an academic institution usually allot some time to patient care. However, since these physicians must also teach, the patient will sometimes be evaluated and treated primarily by a doctor-in-training rather than the more experienced faculty member he was expecting. Although these doctor trainees must discuss the patient with the academic physician, the patient will have no assurance of ever meeting with the academic physician, sometimes the patient will only briefly meet with the academic doctor whose credentials prompted his visit in the first place. This may occur on the initial consultation and/or on subsequent visits. Thus, the patient may experience, but cannot count on a close personal relationship with this doctor. Therefore, it is important for a patient making an appointment with a physician who is on staff at a hospital to inquire whether he will be seeing the doctor in a clinic setting or in some type of private office. And, whether he will be seeing the doctor he is requesting the appointment with, opposed to his associates or staff, both for the initial consultation and follow-up visits.
Finally, since academic physicians are typically based within a hospital, their office hours are often limited. Rarely, if ever, will these physicians make themselves available for routine appointments after 5:00 pm, before 8:00 am, or on weekends. And since these doctors have so many other duties in the hospital, such as meetings, teaching, and lecturing, typically only two or three days at most will be devoted to seeing patients, and then only for a limited number of hours. The result of such limited hours is that typically the patient will only be able to book an appointment several weeks, if not months, in advance. Furthermore, hospital-based physicians are typically away from their practice many weeks out of the year attending meetings and lecturing.
The Private Practitioner
A private practitioner is a physician who typically focuses his career on patient care. Usually, but not always, private practitioners take care of people who are admitted to local hospitals in their communities. That is, these private practitioners have either admitting or consulting privileges at one or more local hospitals. Some private practitioners may also be affiliated with an academic institution, where they also treat patients and occasionally teach. And, some private practitioners do not see patients in a hospital setting at all but only in their office for consultations.
Private practitioner physicians may be in solo practice, wherein only one doctor is running the practice; in a partnership, wherein two or more physicians share the responsibilities of the practice; or in a group practice, wherein several doctors are affiliated across an array of different medical specialties. As compared with at an academic setting within a large hospital, a personal relationship with the physician is more likely to develop in a private-practice setting. (Although this is not always the case). If the physician is not a solo practitioner, the patient should inquire whether he will be seen by the same physician on each visit. Similarly, all patients in the process of choosing a physician should inquire whether they will be seen by an actual doctor, as opposed to a nurse or physician’s assistant (P.A.) on each visit.
Private practitioners typically have much longer and more flexible office hours than physicians who are hospital staff members. Thus, early morning, as well as evening, and weekend hours are often available. Of course, the actual hours of availability vary considerably among private practitioners. Also, as compared with hospital-based physicians, private practitioners are less likely to be away from their offices for extended periods of time. Thus, it is possible to obtain an appointment with a highly qualified hepatologist in private practice much more quickly (usually within a few weeks) than with an academic hepatologist of similar stature.
A person doesn’t necessarily have to be treated at an academic institution in order to enroll in a clinical trial of an experimental drug. Some private practitioners conduct clinical studies as part of their practice, in the same manner as would an academic physician. However, this is not especially common and generally applies only to the most knowledgeable privately practicing hepatologists. This is an important area to inquire about prior to making an appointment with the doctor. Typically, studies run in a private practitioner’s office are less rigid in terms of criteria for including or excluding subjects and are less likely to involve the use of a placebo as compared with those conducted at an academic institution. It is important to thoroughly research the credentials of the physician conducting the study, whether the study is conducted in a private practice setting or at an academic institution. This will be discussed in further detail in Chapter 11.
Finally, many people with liver disease incorrectly assume that, if they are treated by an academic physician who is affiliated with a transplant center, this will automatically increase their chances of obtaining a new liver, should one be required. This is a total misconception, as all people are subject to identical rules, regulations, and criteria for liver transplantation—regardless of whether the patient is being treated within an academic or private practice setting. (See chapter xx for more about liver transplantation).
WHAT TO LOOK FOR IN A SPECIALIST
Now that you are familiar with the different kinds of doctors, the next step is to find out about the specialist you have chosen and how he runs his office.
So, what questions should be asked to determine the doctors experience treating people with liver disease?
Determining The Doctor’s Experience With Liver Disease
It is essential to find a doctor who has a significant amount of experience in taking care of people who have liver disease. Information about hepatitis and liver disease rapidly changes. Thus, unless the doctor deals with these diseases multiple times a day it is unlikely that he will be up-to date with information. Even most textbooks are two to three years out-of-date by the time they are published. In this regard, the patient should pose some basic questions to the doctor. See the sample questions that follow. Also, there is no guarantee that the doctor will be totally forthcoming about his level of experience. It’s very important to remember that just because the doctor’s business card or door sign says liver disease, it shouldn’t be assumed that his practice focuses on liver disease. The printer and the sign maker do not verify the doctor’s qualifications and credentials.
- Did your specialty training include a liver fellowship?
As discussed above, a doctor may have trained in the general specialty of gastroenterology, which includes some training in liver disease, or the doctor may have additional training specifically in liver disease. Doctors typically, but not always, hang their diplomas that they are awarded at the completion of their training on the wall. Therefore, simply looking at the doctor’s wall to see if there are two separate diplomas – one for liver disease and the other for gastroenterology will answer this question in many instances.
• ‑Approximately what percentage of your practice is devoted to liver disease, and about how many liver disease patients are you presently treating?
Some doctors have a very large practice but treat very few individuals with liver disease. Other doctors have a relatively small practice, but it may be one that is devoted primarily to taking care of people with liver disease. And some doctors—despite being well known in the field of hepatology—have not actually treated many people with liver disease. These doctors, who often work at large, well-respected hospitals, have devoted their careers to liver disease research rather than patient care.
• Are you involved in liver disease research?
It is advisable to ask the doctor whether he has participated in or is currently conducting research devoted to liver disease. For example, a doctor may be involved in experimental trials to evaluate a promising new form of diet or drug therapy for liver disease or may be involved in evaluating a new method of diagnosing liver disease. A doctor involved in such investigations will afford the patient the opportunity not only to learn firsthand about the most up-to-date therapies, but also may enable the patient to begin using a promising form of therapy before it becomes readily available to the public.
• Have you written any articles on liver disease? Have you written or contributed to any books on liver disease?
A patient should feel free to inquire about the doctor’s medical research experience and also about whether the doctor has authored any publications on liver disease. Many of the most knowledgeable hepatologists have published articles in any well-respected peer-review medical publications, such as Hepatology, Gastro-enterology, or Seminars in Liver Disease. This can be independently checked by accessing medline on the Internet (see Appendix for website address) or by asking for a copy of the article. Doctors are usually more than happy to comply with such a request. Remember, however, that articles appearing in medical publications are written for other physicians and other members of the medical community. These articles will, therefore, contain technical medical terminology. Some doctors have written articles on liver disease for the general public. These may appear in local newspapers, general circulation magazines, specialty publications -such as “Hepatitis” magazine, or publications such as the American Liver Foundation newsletters and pamphlets.
Some of the doctors who are the most dedicated to liver disease have demonstrated their dedication by writing book chapters, book forwards, or entire books on the subject of liver disease – either for the medical or lay community. The patient should feel free to inquire about any of these publications.
• What is your knowledgeability regarding alternatives to conventional medical therapies?
While a liver specialist is primarily involved in prescribing mainstream medical treatments, he should also be knowledgeable about the available alternatives to conventional medical therapy. Extensive evaluation of any alternative treatment is essential before its effectiveness can be assessed. How familiar is the doctor with the alternative therapy in question? How is the doctor basing his recommendations as to the alternative in question? How many of the doctor’s patients tried this alternative treatment, and what were the results?
If a doctor is going to treat your liver disease, it is important that he be knowledgeable as to the most popular alternative treatments for liver disease. While the doctor may not necessarily recommend their usage, it is important that he be conversant with their pros and cons.
- How many people with liver disease have you treated?
It is important to know how experienced the doctor is in treating patients with liver disease. However, while you may be tempted to ask the doctor his age or how long he has been in practice, these questions are of questionable usefulness. Though most people would prefer not to be treated by a doctor who has just completed specialty training, the actual amount of years in practice may not be a reliable indicator of the doctor’s experience with liver disease. For example, a doctor who has been in practice for thirty years may treat only ten individuals with liver disease each week. While another doctor, who may have been in practice for ten years, treats thirty people with liver disease each week. Who is more qualified? The answer is they both may be sufficiently qualified. The bottom line is that the age of the physician and the actual number of years he has been in practice are not reliable criteria by which to judge a doctor’s level of experience.
THE DOCTOR’S OFFICE AND STAFF
In addition to the qualifications of the doctor, there are several important factors which a prospective patient should consider when choosing a liver specialist. It is important to search for a practice in which the doctor has made many amends to make the practice convenient, available and private. This section discusses some additional issues to consider when finding a doctor to treat your liver disease.
Office Staff
Often, the patient can get a baseline impression of the doctor by observing how the office is run. Take note of whether the office staff seems to be knowledgeable about liver disease. A person telephoning the office may not always be able to contact the doctor immediately. Does the doctor have a nurse, medical assistant, or office manager who can promptly and accurately answer questions in the doctor’s absence?
Office Availability
What is the availability of the doctor and the doctor’s staff? How many days a week is the office open? Are the doctor’s hours flexible? Are evening and weekend appointments available? How long must the patient wait to get an appointment? A doctor may not have an appointment available the same day a patient calls, but no matter how busy the doctor’s practice is (even in the busiest of practices), a patient should be able to schedule an appointment within 3 or 4 weeks—at most.
How long does the patient have to wait once in the doctor’s office? If on every visit, the patient is left waiting for more than two hours in the waiting room, then there is something wrong with the doctor’s method of scheduling. But a long wait on occasion should not be cause for concern. Emergencies sometimes arise and can result in delays.
Office Privacy
It is important to be treated by a medical practice that respects your privacy. In fact, it’s the law. Is the nurse’s and office reception area enclosed with a window or door, or is it open thereby allowing patients’ names and personal information to be overheard? Do the doctor or his staff discuss other patients’ information (i.e. on the phone) while in your presence? Can you rely on the doctor and his staff to take the necessary steps to protect your medical information? Is the doctor’s practice in compliance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA)?
What is HIPAA?
HIPAA was developed by the Department of Health and Human Services (HHS). This law applies uniformly to all areas of the United States effective as of April 15, 2003. These laws are a national standard. No doctor’s office or hospital in any area of the country is exempt from this law. The HIPAA law is designed to protect the security and confidentiality of patients’ protected health information (PHI) whether it is on paper, in computers or communicated orally. PHI is any information that the doctor’s office possesses about the patient that identifies the patient and relates to their past, current and future physical and/or mental health condition and the health care products and services that have been provided. Under this law your medical records and conversations with the doctor and doctor’s staff are not readily available to anyone without your written authorization.
All doctors’ offices must provide written notice to their patients describing their rights under this law. Patients typically will be asked to sign, initial or otherwise acknowledge that they received this notice. Furthermore, a notice must also be posted in the doctors’ office describing the basic features of this law. An office which does not display a HIPAA notice is in violation of their patients’ privacy rights and is subject to both civil and criminal penalties. The same applies to an office that does not provide you with a written notice describing your rights under HIPAA.
Office Services
People with liver disease generally need frequent assessment of their blood work. Therefore, it is important to find out whether blood will be drawn at the doctor’s office or whether the patient will be sent to a laboratory to have blood drawn. Obviously, it is a great convenience to have blood drawn in the doctor’s office at the time of the visit.
Often the patient with liver disease will need evaluation of his digestive system for a variety of reasons. The evaluation will typically include an upper endoscopy and a colonoscopy. An upper endoscopy is a flexible tube with a light at the end and is performed to evaluate the esophagus for possible esophageal varices, and the stomach for possible ulcers or infection. A colonoscopy is a flexible tube with a light at the end of it performed to evaluate the lower intestines (colon), for polyps or rectal bleeding, for example. Some doctors perform these tests in the comfort, privacy, and convenience of their office. Other doctors perform these tests at the local hospital, which is invariably more time consuming for the patient, as well as less convenient.
Who Will The Patient Actually Be Seeing?
It is crucial for the patient to find out whether he will be seeing the doctor on the initial, as well as subsequent visits, or a nurse, physician’s assistant (P.A.), or medical assistant (M.A.). You want to know who is actually going to be treating you. For many doctors, their standard procedure is to only conduct the initial evaluation of the patient. All subsequent visits, phone calls or other contacts with the patient are handled by a doctor’s representative – i.e. nurse, medical assistant, or physician assistant. These doctors’ helpers are commonly referred to as “physician extenders”. In such practices, the doctor is directly involved with the patient’s care only in the event of a serious complication. Baring a serious complication, the management of the patient is mostly left in the hands of the physician extender. However, in many practices, every patient is managed personally by the doctor. In such practices, the doctor himself will perform all examinations of the patient, (both initial and subsequent), will personally evaluate the patient’s response to therapy, and will personally make all treatment decisions - both major and minor. In this type of practice, the physician that you have chosen - after researching his level of expertise and experience in liver disease, will be the individual who is treating you.
Finally, find out how many doctors there are in the practice and whether you will be seeing the same doctor at each visit. It is in the best interest of the patient to establish a relationship with one doctor. This way, the doctor’s familiarity with the patient’s medical history and special needs will be maximized. This is likely to lead to the highest rate of success in treatment of the patient’s liver disease.
THE WAYS DOCTORS HELP PATIENTS OUTSIDE THEIR PRACTICES
Treating each person individually is the standard way a doctor helps patients get better. But there are additional ways that a doctor can help people—ways in which he can reach out to large groups of people with liver disease and to their loved ones all at once.
If a doctor spends his spare time involved in activities relating to liver disease, such as writing articles, lecturing, making radio or television appearances, creating instructional videos, or running a website devoted to liver disease, it’s pretty obvious that this doctor is dedicating his career, as well as his free time and spare energy, to helping people with liver disease. Patients should not hesitate to ask their doctors if they are involved in any of these worthy activities.
Publications
A doctor who writes articles on liver disease can reach a large number of people. The article can be contributed to a local newspaper, a health-related magazine, or the newsletter or brochure of a support group or a nonprofit organization devoted to liver disease, such as the American Liver Foundation (ALF) or Hepatitis Foundation International (HFI). Similarly, many pharmaceutical companies involved in the treatment of liver disease have literature concerning the disease and its treatment. The patient should find out if the doctor has contributed to any of these publications. Doctors who have had articles published will often have copies available at their offices that the patient can take home to read.
Lecturing
Does the doctor give lectures on liver disease, either within the local community or nationally? Lectures are regularly sponsored by nonprofit organizations such as ALF or HFI. The general public is normally invited to attend these lectures, either free of charge or for a very minimal fee. A knowledgeable doctor should be able to inform the patient of the date and location of scheduled lectures in the community or nearby areas. The patient should find out if the doctor is invited to speak at these lectures. A doctor who is involved in lecturing to the public will gladly tell the patient when the next lecture is scheduled, so that the patient may attend if he wishes. Or the doctor will describe to the patient the most recent lecture that he has given.
Media Appearances
The media is a means by which the doctor can reach out to many people with liver disease and their loved ones all at the same time. By communicating to the public through the media, the doctor is able to spread information about liver disease to thousands, if not millions, of people. Health topics are frequently discussed on news programs and talk shows. Often, local or cable television stations devote entire programs to liver disease, and radio programs often have short segments related to health topics. The patient should find out if the doctor has appeared on television or radio shows concerning liver disease, or if the doctor has participated in the production of any videotapes devoted to liver disease. A doctor who has appeared on television, radio, or videotape will probably be able to provide the patient with a taped copy of the show, or at the very least, provide information about how to obtain a copy.
Internet Websites
There are numerous liver-related websites on the Internet. The patient should find out if the doctor is involved in running one of these websites. The doctor should be able to direct the patient to some informative, accurate Internet websites related to liver disease. This topic will be discussed in more detail later in this chapter on page xx.
Associations and Foundations
Methods for the diagnosis and treatment of liver disease change rapidly on an ongoing basis. It is important to be treated by a doctor who is familiar with the most up-to-date developments. There are many professional organizations that keep doctors abreast of the most recent information on liver disease. The most prominent of these organizations in the field of liver disease is the American Association for the Study of Liver Disease (AASLD). A doctor who has been elected to membership in the AASLD is most likely to be actively involved in liver disease. The AASLD is an association of physicians and scientists who are dedicated to the advancement and application of knowledge of liver disease.
There are also numerous lay (non-professional) organizations that are dedicated to increasing the awareness of liver disease. Perhaps the best-known of these is the American Liver Foundation (ALF) is a voluntary nonprofit organization whose membership consists of doctors, patients, and any other individuals interested in liver disease. ALF’s major goals include educating the public about liver disease and fostering the prevention and treatment of liver disease. A doctor may be involved with ALF to varying degrees, ranging from being a member to running a support group to lecturing to the public on a topic pertaining to liver disease. Doctors who have demonstrated exceptional dedication to the cause of helping individuals with liver disease are often invited to serve as a board member of ALF, either at the national or local level. A patient can contact ALF to inquire about a doctor’s level of activity in this organization.
INSURANCE AND HMO PLANS
A full discussion of insurance plans, including HMOs, POSs and PPOs, is beyond the scope of this book. However, the patient should be aware of one very important point concerning insurance plans, which is described in the following scenario: After Tom’s exhausting search, he finally found a specialist that he wanted to consult with. However, when he checked in his insurance book, to his great disappointment, the specialist’s name was nowhere to be found! Now what?
All patients should be aware that most insurance plans will pay for a visit to a doctor who is not included in their plan, if—and this is an important if—the doctor offers special or unique services that no other doctor in the plan offers. For example, some liver specialists offer a wealth of experience treating people with liver disease, which greatly exceeds that of any other doctors who are currently listed on the plan, or they are offering treatment options that are not available through any of the other doctors on the plan. In these circumstances, an appeal letter or even a phone call to the appropriate insurance company representative explaining the dilemma often results in the patient being granted coverage for a consultation with the desired specialist. Also, the patient may want to ask the doctor personally if he would consider joining his health plan.
LIVER DISEASE SPECIALISTS AND THE INTERNET
The Internet may be considered a double-edged sword when it comes to liver disease. It is an ocean of both information and misinformation. Surf with caution. The number of Internet websites continues to grow at an explosive rate. Despite the relative newness of the Internet, there are already over one hundred Internet websites devoted to liver disease and hepatitis. It can be difficult for the layperson to determine which information is correct and which information is not. It is most important for the patient using the Internet to determine who is sponsoring the website.
Is a pharmaceutical company maintaining the website? For example, Schering-Plough, Roche, and Intermune, three major drug companies that manufacture and distribute pharmaceuticals used in the prevention or treatment of liver disease all maintain Internet websites. Each of these websites contains useful information, but, keep in mind that these companies also are promoting their product. Is it a well-respected hepatologist who maintains the website? For example, I maintain a regularly updated Internet website, and there are a number of other excellent hepatologists who also maintain websites devoted to liver disease. Or, is it a health-care professional who is not a hepatologist? Does a well-established not-for-profit organization maintain the website? For example, ALF and HFI, in addition to many other groups maintain helpful websites. Is it a knowledgeable patient eager to help others who maintains the site? Or is it a not-so-knowledgeable patient who is giving false and possibly dangerous information? Be careful. (See Appendix for some helpful website addresses.)
Some websites provide referrals to doctors who purportedly specialize in liver disease. Unfortunately, it is often impossible to ascertain what criteria were used in selecting the referred doctors. Some sites merely require a doctor to pay a fee in order to be listed. While it may be difficult to obtain accurate information from searching the Internet, one generality may be relied on: If the doctor has a website devoted to liver disease, it is likely his practice is focused on taking care of people with liver disease.
CONSULTING WITH THE SPECIALIST
Now that the patient has located a specialist, there are a few tips to follow, which will help make the appointment as smooth and efficient as possible for both the patient and the doctor. It is normal to be nervous about seeing a specialist. So much new and crucial information will be provided to the patient during this visit. It is to be expected that after the initial consultation is over, the patient will not recall a significant amount of what the doctor has said. For this reason, the patient should try to have a relative or close friend along for the consultation. Prior to the visit, the patient should make a list of all of the questions that he wants answered during this visit. The patient should bring this list to the consultation and should not leave the doctor’s office until every question has been satisfactorily answered. It’s perfectly okay to take short notes while the doctor is talking and to check off each question after the doctor has answered it. If necessary, the patient should request that the doctor write down unfamiliar technical medical terms used during the conversation.
The patient can make the initial consultation more productive for the specialist by bringing all prior records from other doctors to the visit. This will better enable the doctor to promptly and accurately assess the patient’s condition on the initial visit. It is especially important to bring the doctor copies of all previously performed blood work, imaging studies, and liver biopsy reports or slides. Doing so will not only assist the doctor, but it can sometimes eliminate the necessity of repeating the tests and/or biopsy.
Remember, all prior records, reports, and slides legally belong to the patient. These records should never be difficult for the patient to obtain. However, most doctors’ offices, hospitals, and medical facilities require a written request authorizing the release of the records to another doctor or hospital. Often there is a fee. Be aware that the maximum fee that by law can be charged for medical records is seventy-five cents per page.
Finally, the patient should always bring the doctor a list of all medications, including over-the-counter medications, vitamins, dietary supplements, and/or herbal remedies, that he is taking. The more comprehensive the information the patient provides, the more accurate the specialist’s advice will be.
FINDING SECOND OPINIONS
If a patient is not comfortable with the advice he receives from a specialist, it is advisable to seek another opinion. Always make sure that a second opinion is provided by a doctor whose knowledge of liver disease is superior to, or at least equal to, that of the first specialist. However, patients should keep multiple opinions in perspective. Under no circumstances should patients ever make it their objective to shop around for opinions until they hear the diagnosis or prognosis that they are looking for. A game plan of this nature could only cause a serious illness to be left neglected, untreated, or treated inappropriately. It is natural for anyone to hope to hear that there is nothing wrong and that a liver biopsy and treatment aren’t necessary. In some cases, these statements may in fact be accurate; however, if the patient has seen two or three well-respected liver specialists, all of whom concur that something is wrong, the patient must accept that he has a chronic illness that may require treatment.
Source
Melissa Palmer, MD is the author of " Dr. Melissa Palmer's Guide of Hepatitis and Liver Disease". (Published 2004. Penguin Putnam).
There are many different kinds of doctors who evaluate and treat people with liver disorders. First, there is the family physician or internist. These doctors are also referred to as primary care physicians (PCPs). They are often the first ones to discover that something is wrong with the liver. From there, the patient is customarily referred to a specialist—either a gastroenterologist, hepatologist, or infectious disease specialist—for further evaluation and treatment. This specialist may be in a practice located at an academic institution or in a private practice located in a community setting. The difference between the various types of doctors a patient with liver disease encounters may sometimes be confusing. Hopefully, this section will clarify these differences in order to eliminate any future confusion.
The Medical Doctor (MD)
Medical Doctors (MDs) are physicians who have successfully completed four years of medical school training. After graduating from medical school, these doctors must complete a minimum of one additional year of training in a hospital in what is known as an internship. They must then pass a state-licensing exam in order to practice medicine in that state. After obtaining their license, they have the right to practice medicine in that state. However, many doctors choose to continue their training in a hospital by undergoing a residency—typically an additional two years.
After completing their residency, these doctors must take an exam in order to become board certified in a specialty, such as family medicine or internal medicine. Doctors may practice medicine whether or not they pass this exam. Doctors who become family doctors or internists have general knowledge in all areas of medicine including the heart, lungs, kidneys, stomach, intestines, and liver. At this time, a doctor may decide to undergo additional specialty training, known as a fellowship, in a specific area of internal medicine, such as gastroenterology, hepatology, or infectious diseases, in order to become an expert in these areas.
The Doctor of Osteopathy (DO)
Doctors of osteopathy (DOs) are commonly referred to as osteopaths. These are doctors who graduated from a four-year osteopathic school. They must also complete a one-year internship in a hospital in order to be eligible to obtain a license to practice medicine. Osteopaths can also choose to undergo an additional two-year residency, and may thereafter undergo specialty training in a specific area of medicine.
Osteopaths tend to focus on treating “the body as a whole,” particularly on the body’s ability to heal itself. Osteopaths typically center their treatment on the musculoskeletal system, the muscles and bones, often using techniques such as bone manipulation and a form of massage.
The Family Physician
A family physician is a doctor—either an MD or a DO—who has been trained to prevent, diagnose, and treat medical conditions in people of all ages. The family physician takes care of the general health of the patient and his entire family. Their training is not limited to internal medicine, but includes some training in psychiatry, obstetrics, gynecology, and surgery. These are the “Marcus Welby” doctors, seemingly able to handle almost any general problem.
There is a separate board certification examination specifically for family practitioners. This is known as the family practice boards. Specializing in family practice medicine requires an additional three years’ training beyond medical school. The amount of exposure to, and degree of expertise in liver disease varies among family practitioners. However, family physicians have not undergone additional specialized training in liver disease.
The Internist
An internist is a doctor—an MD or a DO—who is trained to prevent, diagnose, and treat medical conditions in adolescents and adults, including the elderly. Internists have received some basic training in subspecialty areas of internal medicine, including gastroenterology, hepatology, and infectious diseases. Internists are trained to treat both straightforward and complex problems of the internal organs. They are also trained in emergency medicine and critical care medicine. There is a separate board certification examination specifically for internists. It is known as the internal medicine boards. Specializing in internal medicine requires an additional three years’ training beyond medical school.
The amount of exposure to, and degree of expertise in liver disease varies among internists. Internists have the option of continuing their training in a subspecialty of internal medicine. This requires applying for, and being accepted into, a fellowship in the subspecialty of their choice. gastroenterology, hepatology, and infectious diseases are among the many subspecialties of internal medicine.
The Gastroenterologist
A gastroenterologist is an internist who has completed specialty training in the treatment of digestive disorders. Digestive disorders include disorders of the esophagus, stomach, small and large intestines, pancreas, gallbladder, and liver. In order to become board certified in gastroenterology, the doctor must first become board certified in internal medicine. In order to become eligible to even take the examination for board certification in gastroenterology, a gastrointestinal (GI) fellowship lasting an additional two to three years beyond an internal medicine residency must be completed.
During the course of their two to three years of training in gastroenterology, some gastroenterologists have little exposure to patients with liver disease. On the other hand, some gastroenterologists have a great deal of exposure to patients with liver disease during the course of their gastroenterology specialty training. Thus, the level of experience and expertise among gastroenterologists in diagnosing and treating liver disease varies greatly. It is important for the patient to determine the gastroenterologist’s level of expertise in liver disease prior to establishing a long-term medical relationship with this type of doctor.
The Hepatologist
A hepatologist is the most experienced and qualified type of doctor to treat people with liver disease. Since there is currently no separate board certification examination in the field of hepatology, there is no official definition of a hepatologist. However, there are specialized training programs for doctors who are focused solely on liver disease. These are known as hepatology fellowships and typically last from one to two years. Over the course of a hepatology fellowship, a doctor receives comprehensive training in the diagnosis and treatment of liver disease. This specialty training typically includes extensive exposure to all liver diseases, including those that are rare and infrequently seen. This intense training in liver disease is rarely matched in a gastroenterology fellowship.
A physician who successfully completes a hepatology fellowship is considered a hepatologist. Most hepatologists, although not all, are also gastroenterologists. These doctors have successfully completed both a hepatology and a gastroenterology fellowship. Occasionally, gastroenterologists who have not completed a fellowship in hepatology nonetheless focus their medical practice primarily on the diagnosis and treatment of people with liver disease. While these physicians do not have a separate diploma in the field of liver disease, they may also be considered hepatologists.
For many reasons, it is to the patient’s advantage to choose a hepatologist to treat his liver disease. The patient can be virtually assured that the hepatologist will have substantial experience in the diagnosis and treatment of the full range of liver diseases. Furthermore, hepatologists are likely to be the first to learn about the most up-to-date therapies—both FDA-approved and experimental—and to incorporate them into their practices. However, whether someone chooses to see a gastroenterologist or a hepatologist, it is important to find a doctor who is willing to work with him as an equal partner in the healing process.
Infectious Disease Specialists
An infectious disease specialist is an internist who has completed a specialty fellowship in infectious diseases of all types. Many infectious disease specialists treat people with liver disease caused by infectious - such as hepatitis B and C (both of which are caused by viruses). During the course of their two years of training in infectious diseases, some infectious disease specialists have little exposure to patients with viral hepatitis. On the other hand, some infectious disease specialists receive a great deal of exposure to patients with viral hepatitis during the course of their specialty training. Thus, the level of expertise among infectious disease specialists in diagnosing and treating viral hepatitis varies greatly. It is important for the patient to determine the infectious disease specialist’s level of expertise in treating hepatitis B or C prior to establishing a long-term medical relationship with this type of doctor. It should be stressed that infectious disease doctors have no special expertise treating liver diseases that are not caused by infections – such as alcoholic liver disease or autoimmune hepatitis.
Academic Physicians Versus Private Practitioners
People searching for a doctor should be aware of the differences between academic physicians and private practitioners. Each type of doctor has pros and cons that must be carefully weighed by the patient as part of the process of choosing a physician.
The Academic Physician
An academic physician is a doctor who has accepted a faculty position on staff at a hospital. Often, though not always, the hospital will be associated with a medical school. These doctors spend a portion of their time teaching medical students and physicians-in-training (interns, residents, and fellows) about their specialty—in this case hepatology. Also, some academic physicians spend a considerable percentage of their time conducting research, as opposed to treating patients. Although some of this research is performed in a laboratory, some is within the context of clinical trials involving patients. (See Chapter 11 of my book for a discussion of clinical trials.)
These physicians are usually, but not always, board certified in their specialty, and some have contributed significantly to the advancement of the medical profession in their specialty. However, this is not always the case. Academic physicians carry a title such as assistant professor, associate professor, or professor. This title is based on a number of factors, including, but not limited to, how long they have been practicing in their specialty, their leadership skills, their teaching skills and the contributions made by them in their specialty. No one should ever assume that the qualifications of a given academic physician are superior to those of a given private practitioner merely based on the academic physician’s title or employment by a hospital. This may even hold true of the department chairman.
Academic physicians are generally expected to stay abreast of the newest developments in their field. Such a physician may have initiated or prompted the investigation of a new drug or may have played a significant role in the development of a new medical procedure. Frequently, but not always, academic physicians are involved in conducting investigational trials on the most promising experimental drugs. However, the requirements of entering a study at an academic center may be very rigid and typically involve a risk that the patient will be given a placebo (dummy drug).
Doctors at an academic institution usually allot some time to patient care. However, since these physicians must also teach, the patient will sometimes be evaluated and treated primarily by a doctor-in-training rather than the more experienced faculty member he was expecting. Although these doctor trainees must discuss the patient with the academic physician, the patient will have no assurance of ever meeting with the academic physician, sometimes the patient will only briefly meet with the academic doctor whose credentials prompted his visit in the first place. This may occur on the initial consultation and/or on subsequent visits. Thus, the patient may experience, but cannot count on a close personal relationship with this doctor. Therefore, it is important for a patient making an appointment with a physician who is on staff at a hospital to inquire whether he will be seeing the doctor in a clinic setting or in some type of private office. And, whether he will be seeing the doctor he is requesting the appointment with, opposed to his associates or staff, both for the initial consultation and follow-up visits.
Finally, since academic physicians are typically based within a hospital, their office hours are often limited. Rarely, if ever, will these physicians make themselves available for routine appointments after 5:00 pm, before 8:00 am, or on weekends. And since these doctors have so many other duties in the hospital, such as meetings, teaching, and lecturing, typically only two or three days at most will be devoted to seeing patients, and then only for a limited number of hours. The result of such limited hours is that typically the patient will only be able to book an appointment several weeks, if not months, in advance. Furthermore, hospital-based physicians are typically away from their practice many weeks out of the year attending meetings and lecturing.
The Private Practitioner
A private practitioner is a physician who typically focuses his career on patient care. Usually, but not always, private practitioners take care of people who are admitted to local hospitals in their communities. That is, these private practitioners have either admitting or consulting privileges at one or more local hospitals. Some private practitioners may also be affiliated with an academic institution, where they also treat patients and occasionally teach. And, some private practitioners do not see patients in a hospital setting at all but only in their office for consultations.
Private practitioner physicians may be in solo practice, wherein only one doctor is running the practice; in a partnership, wherein two or more physicians share the responsibilities of the practice; or in a group practice, wherein several doctors are affiliated across an array of different medical specialties. As compared with at an academic setting within a large hospital, a personal relationship with the physician is more likely to develop in a private-practice setting. (Although this is not always the case). If the physician is not a solo practitioner, the patient should inquire whether he will be seen by the same physician on each visit. Similarly, all patients in the process of choosing a physician should inquire whether they will be seen by an actual doctor, as opposed to a nurse or physician’s assistant (P.A.) on each visit.
Private practitioners typically have much longer and more flexible office hours than physicians who are hospital staff members. Thus, early morning, as well as evening, and weekend hours are often available. Of course, the actual hours of availability vary considerably among private practitioners. Also, as compared with hospital-based physicians, private practitioners are less likely to be away from their offices for extended periods of time. Thus, it is possible to obtain an appointment with a highly qualified hepatologist in private practice much more quickly (usually within a few weeks) than with an academic hepatologist of similar stature.
A person doesn’t necessarily have to be treated at an academic institution in order to enroll in a clinical trial of an experimental drug. Some private practitioners conduct clinical studies as part of their practice, in the same manner as would an academic physician. However, this is not especially common and generally applies only to the most knowledgeable privately practicing hepatologists. This is an important area to inquire about prior to making an appointment with the doctor. Typically, studies run in a private practitioner’s office are less rigid in terms of criteria for including or excluding subjects and are less likely to involve the use of a placebo as compared with those conducted at an academic institution. It is important to thoroughly research the credentials of the physician conducting the study, whether the study is conducted in a private practice setting or at an academic institution. This will be discussed in further detail in Chapter 11.
Finally, many people with liver disease incorrectly assume that, if they are treated by an academic physician who is affiliated with a transplant center, this will automatically increase their chances of obtaining a new liver, should one be required. This is a total misconception, as all people are subject to identical rules, regulations, and criteria for liver transplantation—regardless of whether the patient is being treated within an academic or private practice setting. (See chapter xx for more about liver transplantation).
WHAT TO LOOK FOR IN A SPECIALIST
Now that you are familiar with the different kinds of doctors, the next step is to find out about the specialist you have chosen and how he runs his office.
So, what questions should be asked to determine the doctors experience treating people with liver disease?
Determining The Doctor’s Experience With Liver Disease
It is essential to find a doctor who has a significant amount of experience in taking care of people who have liver disease. Information about hepatitis and liver disease rapidly changes. Thus, unless the doctor deals with these diseases multiple times a day it is unlikely that he will be up-to date with information. Even most textbooks are two to three years out-of-date by the time they are published. In this regard, the patient should pose some basic questions to the doctor. See the sample questions that follow. Also, there is no guarantee that the doctor will be totally forthcoming about his level of experience. It’s very important to remember that just because the doctor’s business card or door sign says liver disease, it shouldn’t be assumed that his practice focuses on liver disease. The printer and the sign maker do not verify the doctor’s qualifications and credentials.
- Did your specialty training include a liver fellowship?
As discussed above, a doctor may have trained in the general specialty of gastroenterology, which includes some training in liver disease, or the doctor may have additional training specifically in liver disease. Doctors typically, but not always, hang their diplomas that they are awarded at the completion of their training on the wall. Therefore, simply looking at the doctor’s wall to see if there are two separate diplomas – one for liver disease and the other for gastroenterology will answer this question in many instances.
• ‑Approximately what percentage of your practice is devoted to liver disease, and about how many liver disease patients are you presently treating?
Some doctors have a very large practice but treat very few individuals with liver disease. Other doctors have a relatively small practice, but it may be one that is devoted primarily to taking care of people with liver disease. And some doctors—despite being well known in the field of hepatology—have not actually treated many people with liver disease. These doctors, who often work at large, well-respected hospitals, have devoted their careers to liver disease research rather than patient care.
• Are you involved in liver disease research?
It is advisable to ask the doctor whether he has participated in or is currently conducting research devoted to liver disease. For example, a doctor may be involved in experimental trials to evaluate a promising new form of diet or drug therapy for liver disease or may be involved in evaluating a new method of diagnosing liver disease. A doctor involved in such investigations will afford the patient the opportunity not only to learn firsthand about the most up-to-date therapies, but also may enable the patient to begin using a promising form of therapy before it becomes readily available to the public.
• Have you written any articles on liver disease? Have you written or contributed to any books on liver disease?
A patient should feel free to inquire about the doctor’s medical research experience and also about whether the doctor has authored any publications on liver disease. Many of the most knowledgeable hepatologists have published articles in any well-respected peer-review medical publications, such as Hepatology, Gastro-enterology, or Seminars in Liver Disease. This can be independently checked by accessing medline on the Internet (see Appendix for website address) or by asking for a copy of the article. Doctors are usually more than happy to comply with such a request. Remember, however, that articles appearing in medical publications are written for other physicians and other members of the medical community. These articles will, therefore, contain technical medical terminology. Some doctors have written articles on liver disease for the general public. These may appear in local newspapers, general circulation magazines, specialty publications -such as “Hepatitis” magazine, or publications such as the American Liver Foundation newsletters and pamphlets.
Some of the doctors who are the most dedicated to liver disease have demonstrated their dedication by writing book chapters, book forwards, or entire books on the subject of liver disease – either for the medical or lay community. The patient should feel free to inquire about any of these publications.
• What is your knowledgeability regarding alternatives to conventional medical therapies?
While a liver specialist is primarily involved in prescribing mainstream medical treatments, he should also be knowledgeable about the available alternatives to conventional medical therapy. Extensive evaluation of any alternative treatment is essential before its effectiveness can be assessed. How familiar is the doctor with the alternative therapy in question? How is the doctor basing his recommendations as to the alternative in question? How many of the doctor’s patients tried this alternative treatment, and what were the results?
If a doctor is going to treat your liver disease, it is important that he be knowledgeable as to the most popular alternative treatments for liver disease. While the doctor may not necessarily recommend their usage, it is important that he be conversant with their pros and cons.
- How many people with liver disease have you treated?
It is important to know how experienced the doctor is in treating patients with liver disease. However, while you may be tempted to ask the doctor his age or how long he has been in practice, these questions are of questionable usefulness. Though most people would prefer not to be treated by a doctor who has just completed specialty training, the actual amount of years in practice may not be a reliable indicator of the doctor’s experience with liver disease. For example, a doctor who has been in practice for thirty years may treat only ten individuals with liver disease each week. While another doctor, who may have been in practice for ten years, treats thirty people with liver disease each week. Who is more qualified? The answer is they both may be sufficiently qualified. The bottom line is that the age of the physician and the actual number of years he has been in practice are not reliable criteria by which to judge a doctor’s level of experience.
THE DOCTOR’S OFFICE AND STAFF
In addition to the qualifications of the doctor, there are several important factors which a prospective patient should consider when choosing a liver specialist. It is important to search for a practice in which the doctor has made many amends to make the practice convenient, available and private. This section discusses some additional issues to consider when finding a doctor to treat your liver disease.
Office Staff
Often, the patient can get a baseline impression of the doctor by observing how the office is run. Take note of whether the office staff seems to be knowledgeable about liver disease. A person telephoning the office may not always be able to contact the doctor immediately. Does the doctor have a nurse, medical assistant, or office manager who can promptly and accurately answer questions in the doctor’s absence?
Office Availability
What is the availability of the doctor and the doctor’s staff? How many days a week is the office open? Are the doctor’s hours flexible? Are evening and weekend appointments available? How long must the patient wait to get an appointment? A doctor may not have an appointment available the same day a patient calls, but no matter how busy the doctor’s practice is (even in the busiest of practices), a patient should be able to schedule an appointment within 3 or 4 weeks—at most.
How long does the patient have to wait once in the doctor’s office? If on every visit, the patient is left waiting for more than two hours in the waiting room, then there is something wrong with the doctor’s method of scheduling. But a long wait on occasion should not be cause for concern. Emergencies sometimes arise and can result in delays.
Office Privacy
It is important to be treated by a medical practice that respects your privacy. In fact, it’s the law. Is the nurse’s and office reception area enclosed with a window or door, or is it open thereby allowing patients’ names and personal information to be overheard? Do the doctor or his staff discuss other patients’ information (i.e. on the phone) while in your presence? Can you rely on the doctor and his staff to take the necessary steps to protect your medical information? Is the doctor’s practice in compliance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA)?
What is HIPAA?
HIPAA was developed by the Department of Health and Human Services (HHS). This law applies uniformly to all areas of the United States effective as of April 15, 2003. These laws are a national standard. No doctor’s office or hospital in any area of the country is exempt from this law. The HIPAA law is designed to protect the security and confidentiality of patients’ protected health information (PHI) whether it is on paper, in computers or communicated orally. PHI is any information that the doctor’s office possesses about the patient that identifies the patient and relates to their past, current and future physical and/or mental health condition and the health care products and services that have been provided. Under this law your medical records and conversations with the doctor and doctor’s staff are not readily available to anyone without your written authorization.
All doctors’ offices must provide written notice to their patients describing their rights under this law. Patients typically will be asked to sign, initial or otherwise acknowledge that they received this notice. Furthermore, a notice must also be posted in the doctors’ office describing the basic features of this law. An office which does not display a HIPAA notice is in violation of their patients’ privacy rights and is subject to both civil and criminal penalties. The same applies to an office that does not provide you with a written notice describing your rights under HIPAA.
Office Services
People with liver disease generally need frequent assessment of their blood work. Therefore, it is important to find out whether blood will be drawn at the doctor’s office or whether the patient will be sent to a laboratory to have blood drawn. Obviously, it is a great convenience to have blood drawn in the doctor’s office at the time of the visit.
Often the patient with liver disease will need evaluation of his digestive system for a variety of reasons. The evaluation will typically include an upper endoscopy and a colonoscopy. An upper endoscopy is a flexible tube with a light at the end and is performed to evaluate the esophagus for possible esophageal varices, and the stomach for possible ulcers or infection. A colonoscopy is a flexible tube with a light at the end of it performed to evaluate the lower intestines (colon), for polyps or rectal bleeding, for example. Some doctors perform these tests in the comfort, privacy, and convenience of their office. Other doctors perform these tests at the local hospital, which is invariably more time consuming for the patient, as well as less convenient.
Who Will The Patient Actually Be Seeing?
It is crucial for the patient to find out whether he will be seeing the doctor on the initial, as well as subsequent visits, or a nurse, physician’s assistant (P.A.), or medical assistant (M.A.). You want to know who is actually going to be treating you. For many doctors, their standard procedure is to only conduct the initial evaluation of the patient. All subsequent visits, phone calls or other contacts with the patient are handled by a doctor’s representative – i.e. nurse, medical assistant, or physician assistant. These doctors’ helpers are commonly referred to as “physician extenders”. In such practices, the doctor is directly involved with the patient’s care only in the event of a serious complication. Baring a serious complication, the management of the patient is mostly left in the hands of the physician extender. However, in many practices, every patient is managed personally by the doctor. In such practices, the doctor himself will perform all examinations of the patient, (both initial and subsequent), will personally evaluate the patient’s response to therapy, and will personally make all treatment decisions - both major and minor. In this type of practice, the physician that you have chosen - after researching his level of expertise and experience in liver disease, will be the individual who is treating you.
Finally, find out how many doctors there are in the practice and whether you will be seeing the same doctor at each visit. It is in the best interest of the patient to establish a relationship with one doctor. This way, the doctor’s familiarity with the patient’s medical history and special needs will be maximized. This is likely to lead to the highest rate of success in treatment of the patient’s liver disease.
THE WAYS DOCTORS HELP PATIENTS OUTSIDE THEIR PRACTICES
Treating each person individually is the standard way a doctor helps patients get better. But there are additional ways that a doctor can help people—ways in which he can reach out to large groups of people with liver disease and to their loved ones all at once.
If a doctor spends his spare time involved in activities relating to liver disease, such as writing articles, lecturing, making radio or television appearances, creating instructional videos, or running a website devoted to liver disease, it’s pretty obvious that this doctor is dedicating his career, as well as his free time and spare energy, to helping people with liver disease. Patients should not hesitate to ask their doctors if they are involved in any of these worthy activities.
Publications
A doctor who writes articles on liver disease can reach a large number of people. The article can be contributed to a local newspaper, a health-related magazine, or the newsletter or brochure of a support group or a nonprofit organization devoted to liver disease, such as the American Liver Foundation (ALF) or Hepatitis Foundation International (HFI). Similarly, many pharmaceutical companies involved in the treatment of liver disease have literature concerning the disease and its treatment. The patient should find out if the doctor has contributed to any of these publications. Doctors who have had articles published will often have copies available at their offices that the patient can take home to read.
Lecturing
Does the doctor give lectures on liver disease, either within the local community or nationally? Lectures are regularly sponsored by nonprofit organizations such as ALF or HFI. The general public is normally invited to attend these lectures, either free of charge or for a very minimal fee. A knowledgeable doctor should be able to inform the patient of the date and location of scheduled lectures in the community or nearby areas. The patient should find out if the doctor is invited to speak at these lectures. A doctor who is involved in lecturing to the public will gladly tell the patient when the next lecture is scheduled, so that the patient may attend if he wishes. Or the doctor will describe to the patient the most recent lecture that he has given.
Media Appearances
The media is a means by which the doctor can reach out to many people with liver disease and their loved ones all at the same time. By communicating to the public through the media, the doctor is able to spread information about liver disease to thousands, if not millions, of people. Health topics are frequently discussed on news programs and talk shows. Often, local or cable television stations devote entire programs to liver disease, and radio programs often have short segments related to health topics. The patient should find out if the doctor has appeared on television or radio shows concerning liver disease, or if the doctor has participated in the production of any videotapes devoted to liver disease. A doctor who has appeared on television, radio, or videotape will probably be able to provide the patient with a taped copy of the show, or at the very least, provide information about how to obtain a copy.
Internet Websites
There are numerous liver-related websites on the Internet. The patient should find out if the doctor is involved in running one of these websites. The doctor should be able to direct the patient to some informative, accurate Internet websites related to liver disease. This topic will be discussed in more detail later in this chapter on page xx.
Associations and Foundations
Methods for the diagnosis and treatment of liver disease change rapidly on an ongoing basis. It is important to be treated by a doctor who is familiar with the most up-to-date developments. There are many professional organizations that keep doctors abreast of the most recent information on liver disease. The most prominent of these organizations in the field of liver disease is the American Association for the Study of Liver Disease (AASLD). A doctor who has been elected to membership in the AASLD is most likely to be actively involved in liver disease. The AASLD is an association of physicians and scientists who are dedicated to the advancement and application of knowledge of liver disease.
There are also numerous lay (non-professional) organizations that are dedicated to increasing the awareness of liver disease. Perhaps the best-known of these is the American Liver Foundation (ALF) is a voluntary nonprofit organization whose membership consists of doctors, patients, and any other individuals interested in liver disease. ALF’s major goals include educating the public about liver disease and fostering the prevention and treatment of liver disease. A doctor may be involved with ALF to varying degrees, ranging from being a member to running a support group to lecturing to the public on a topic pertaining to liver disease. Doctors who have demonstrated exceptional dedication to the cause of helping individuals with liver disease are often invited to serve as a board member of ALF, either at the national or local level. A patient can contact ALF to inquire about a doctor’s level of activity in this organization.
INSURANCE AND HMO PLANS
A full discussion of insurance plans, including HMOs, POSs and PPOs, is beyond the scope of this book. However, the patient should be aware of one very important point concerning insurance plans, which is described in the following scenario: After Tom’s exhausting search, he finally found a specialist that he wanted to consult with. However, when he checked in his insurance book, to his great disappointment, the specialist’s name was nowhere to be found! Now what?
All patients should be aware that most insurance plans will pay for a visit to a doctor who is not included in their plan, if—and this is an important if—the doctor offers special or unique services that no other doctor in the plan offers. For example, some liver specialists offer a wealth of experience treating people with liver disease, which greatly exceeds that of any other doctors who are currently listed on the plan, or they are offering treatment options that are not available through any of the other doctors on the plan. In these circumstances, an appeal letter or even a phone call to the appropriate insurance company representative explaining the dilemma often results in the patient being granted coverage for a consultation with the desired specialist. Also, the patient may want to ask the doctor personally if he would consider joining his health plan.
LIVER DISEASE SPECIALISTS AND THE INTERNET
The Internet may be considered a double-edged sword when it comes to liver disease. It is an ocean of both information and misinformation. Surf with caution. The number of Internet websites continues to grow at an explosive rate. Despite the relative newness of the Internet, there are already over one hundred Internet websites devoted to liver disease and hepatitis. It can be difficult for the layperson to determine which information is correct and which information is not. It is most important for the patient using the Internet to determine who is sponsoring the website.
Is a pharmaceutical company maintaining the website? For example, Schering-Plough, Roche, and Intermune, three major drug companies that manufacture and distribute pharmaceuticals used in the prevention or treatment of liver disease all maintain Internet websites. Each of these websites contains useful information, but, keep in mind that these companies also are promoting their product. Is it a well-respected hepatologist who maintains the website? For example, I maintain a regularly updated Internet website, and there are a number of other excellent hepatologists who also maintain websites devoted to liver disease. Or, is it a health-care professional who is not a hepatologist? Does a well-established not-for-profit organization maintain the website? For example, ALF and HFI, in addition to many other groups maintain helpful websites. Is it a knowledgeable patient eager to help others who maintains the site? Or is it a not-so-knowledgeable patient who is giving false and possibly dangerous information? Be careful. (See Appendix for some helpful website addresses.)
Some websites provide referrals to doctors who purportedly specialize in liver disease. Unfortunately, it is often impossible to ascertain what criteria were used in selecting the referred doctors. Some sites merely require a doctor to pay a fee in order to be listed. While it may be difficult to obtain accurate information from searching the Internet, one generality may be relied on: If the doctor has a website devoted to liver disease, it is likely his practice is focused on taking care of people with liver disease.
CONSULTING WITH THE SPECIALIST
Now that the patient has located a specialist, there are a few tips to follow, which will help make the appointment as smooth and efficient as possible for both the patient and the doctor. It is normal to be nervous about seeing a specialist. So much new and crucial information will be provided to the patient during this visit. It is to be expected that after the initial consultation is over, the patient will not recall a significant amount of what the doctor has said. For this reason, the patient should try to have a relative or close friend along for the consultation. Prior to the visit, the patient should make a list of all of the questions that he wants answered during this visit. The patient should bring this list to the consultation and should not leave the doctor’s office until every question has been satisfactorily answered. It’s perfectly okay to take short notes while the doctor is talking and to check off each question after the doctor has answered it. If necessary, the patient should request that the doctor write down unfamiliar technical medical terms used during the conversation.
The patient can make the initial consultation more productive for the specialist by bringing all prior records from other doctors to the visit. This will better enable the doctor to promptly and accurately assess the patient’s condition on the initial visit. It is especially important to bring the doctor copies of all previously performed blood work, imaging studies, and liver biopsy reports or slides. Doing so will not only assist the doctor, but it can sometimes eliminate the necessity of repeating the tests and/or biopsy.
Remember, all prior records, reports, and slides legally belong to the patient. These records should never be difficult for the patient to obtain. However, most doctors’ offices, hospitals, and medical facilities require a written request authorizing the release of the records to another doctor or hospital. Often there is a fee. Be aware that the maximum fee that by law can be charged for medical records is seventy-five cents per page.
Finally, the patient should always bring the doctor a list of all medications, including over-the-counter medications, vitamins, dietary supplements, and/or herbal remedies, that he is taking. The more comprehensive the information the patient provides, the more accurate the specialist’s advice will be.
FINDING SECOND OPINIONS
If a patient is not comfortable with the advice he receives from a specialist, it is advisable to seek another opinion. Always make sure that a second opinion is provided by a doctor whose knowledge of liver disease is superior to, or at least equal to, that of the first specialist. However, patients should keep multiple opinions in perspective. Under no circumstances should patients ever make it their objective to shop around for opinions until they hear the diagnosis or prognosis that they are looking for. A game plan of this nature could only cause a serious illness to be left neglected, untreated, or treated inappropriately. It is natural for anyone to hope to hear that there is nothing wrong and that a liver biopsy and treatment aren’t necessary. In some cases, these statements may in fact be accurate; however, if the patient has seen two or three well-respected liver specialists, all of whom concur that something is wrong, the patient must accept that he has a chronic illness that may require treatment.
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