01/10/11 - 07:18 AM EST
Bristol-Myers Squibb Company (NYSE:BMY) and Pharmasset (NASDAQ: VRUS) announced today that the companies have entered into a clinical collaboration agreement to evaluate the utility of BMS-790052, Bristol-Myers Squibb’s NS5A replication complex inhibitor, in combination with PSI-7977, Pharmasset’s nucleotide polymerase inhibitor, for the treatment of chronic hepatitis C virus (HCV).
This proof of concept study will evaluate the potential to achieve sustained viral response 24 weeks post treatment with an oral, once-daily treatment regimen in patients across HCV genotypes. Specifically, the study will assess the safety, pharmacokinetics and pharmacodynamics of BMS-790052 in combination with PSI-7977, with and without ribavirin, in treatment-naïve patients chronically infected with HCV genotypes 1, 2, and 3. The study is planned to start in the first half of 2011. This collaboration represents the first cross-company collaboration combining two oral agents to address a significant unmet medical need in the treatment of HCV.
“Bristol-Myers Squibb is committed to the goal of helping patients prevail over hepatitis C by investigating multiple therapeutic platforms,” said Brian Daniels, senior vice president, Development. “We are pleased to partner with Pharmasset on this important study to advance the scientific understanding of the potential for an all-oral regimen to treat hepatitis C. Conducting this study highlights Bristol-Myers Squibb’s ability to collaborate with other companies to develop innovative combination therapies in areas of high unmet need.”
”We are excited to be working with Bristol-Myers Squibb and to be investigating PSI-7977 with a different class of direct acting antivirals,” stated Michelle Berrey, MD, MPH, Chief Medical Officer. “This collaboration represents one of many approaches we are pursuing with our portfolio of nucleoside/tide analogs that include both interferon free and interferon sparing regimens. We believe the development of an all oral treatment regimen represents an important evolution in the treatment of HCV.”
Source
January 10, 2011
Vertex Announces Key Business Objectives To Support Planned Launch of Telaprevir in Hepatitis C and Continued Progress in Other Serious Diseases
January 09, 2011 09:34 PM Eastern Time
- Hepatitis C: Submission of New Drug Application complete for telaprevir-
- Cystic Fibrosis: First Phase 3 data for VX-770 expected in first quarter 2011-
- Additional ongoing trials in HCV, CF, epilepsy and rheumatoid arthritis-
- Vertex enters 2011 with cash and cash equivalents position of more than $1 billion-
SAN FRANCISCO--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (NASDAQ: VRTX) today announced its 2011 business objectives in conjunction with the 29th Annual J.P. Morgan Healthcare Conference in San Francisco. Matthew Emmens, Chairman, President and Chief Executive Officer of Vertex, will discuss these objectives as part of a live webcast presentation, which will be available on Vertex's website, http://www.vrtx.com/, on Monday, January 10 at 9:30 a.m. PT (12:30 p.m. ET).
“2011 will be a landmark year for Vertex as we prepare for the expected launch of telaprevir in hepatitis C and advance other new therapies in development," said Mr. Emmens.
“Our commercial team is in place and prepared for the planned launch of telaprevir this year. We believe that telaprevir will dramatically change the treatment of hepatitis C and establish Vertex as a company capable of discovering, developing and launching transformative medicines to treat serious diseases.
"We are in a unique position, as just behind telaprevir is VX-770, a medicine in development that aims to treat the underlying cause of cystic fibrosis. We will soon obtain data from the Phase 3 registration program of VX-770 that may support the planned submission of a New Drug Application to the FDA in the second half of this year.
“We also expect to receive important data from multiple ongoing Phase 2 trials this year, including those evaluating new combination regimens for hepatitis C and cystic fibrosis, which may provide further development opportunities,” Mr. Emmens concluded.
Hepatitis C: Preparing for Launch of Telaprevir
Submission of New Drug Application Completed in November 2010 with Request for Priority Review
• On November 22, 2010, Vertex completed the submission of its New Drug Application (NDA) for telaprevir to the United States Food and Drug Administration (FDA). A response from the FDA regarding the company’s request for Priority Review of the telaprevir NDA is expected this month. The FDA’s goal for completion of its review for NDA submissions granted Priority Review status is six months from the NDA submission date.
• In December 2010, Vertex’s collaborator, Janssen-Cilag International NV, submitted a Marketing Authorization Application (MAA) for telaprevir to the European Medicines Agency (EMA). The EMA accepted telaprevir for accelerated assessment, which is granted to new medicines of major public health interest.
• To support the planned launch of telaprevir, Vertex has hired more than 200 new employees into its expanding commercial function. The sales and commercial leadership team is in place, and more than 100 field-based employees have been hired to date and are prepared to support the future use of telaprevir across the United States following the planned launch.
Phase 3b Study of Twice-daily Dosing of Telaprevir to Support Supplemental NDA by end of 2012
• Patient enrollment is ongoing in a Phase 3b clinical trial to evaluate twice-daily dosing of telaprevir (1,125 mg; BID) compared to three-times-daily dosing of telaprevir (750 mg; q8h) in combination with pegylated-interferon and ribavirin for people with genotype 1 hepatitis C. The study, known as OPTIMIZE, is the first Phase 3 study to evaluate twice-daily dosing of a protease inhibitor for the treatment of hepatitis C. The study does not include a control arm of pegylated-interferon and ribavirin alone.
• Sustained viral response (SVR or viral cure) data from OPTIMIZE are expected as early as 2012, which could potentially support the submission of a supplemental NDA for twice-daily (BID) dosing of telaprevir by the end of 2012.
Cystic Fibrosis: Phase 3 Registration Program for VX-770 Nears Completion
VX-770 NDA Submission Planned for Second Half of 2011
• Three trials of the novel cystic fibrosis transmembrane conductance regulator protein (CFTR) potentiator VX-770 are fully enrolled and ongoing as part of a global Phase 3 registration program focused on patients with the G551D mutation. The G551D mutation is present in approximately four percent of people with CF.
• The first Phase 3 data for VX-770 are expected in the first quarter of 2011 and will come from the Phase 3 STRIVE trial in people aged 12 and older with at least one copy of the G551D mutation. Data from the Phase 2 DISCOVER trial, which was primarily a safety study that enrolled people aged 12 and older with two copies of the F508del mutation, are also expected in the first quarter of 2011.
• Data from the Phase 3 ENVISION trial in people aged six to 11 with at least one copy of the G551D mutation are expected in mid-2011.
• If positive, the results from the Phase 3 program for VX-770 could support the submission of an NDA for VX-770 in the second half of 2011.
Opportunities to Further Advance Future Treatment of Hepatitis C and Cystic Fibrosis
Interim Data from Phase 2 Study of Telaprevir and VX-222 Expected in First Quarter of 2011
• Vertex is conducting a Phase 2 clinical trial evaluating multiple 12-week, response-guided regimens of telaprevir dosed in combination with its lead investigational HCV polymerase inhibitor, VX-222. The study currently includes three treatment arms. Two of the treatment arms are fully enrolled and are evaluating four-drug combinations of telaprevir (1,125 mg; BID), VX-222 (400 mg or 100 mg; BID), Pegasys® (pegylated-interferon alfa-2a) and Copegus® (ribavirin). Approximately two-thirds of the people in the four-drug treatment arms have received eight weeks or more of treatment. More than one-third of patients have received 10 weeks or more of treatment, with some people having completed all 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 three-drug treatment arm 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 anticipated to begin in the first quarter of 2011.
Additional Trials of Telaprevir to Advance Leadership Position in Hepatitis C
• Vertex and Tibotec also plan to conduct several additional clinical trials of telaprevir in 2011 that aim to expand the future patient population for telaprevir-based regimens. These trials include:
◦ Phase 3 HCV/Human Immunodeficiency Virus Co-Infection Trial: Vertex recently completed enrollment in a Phase 2 clinical trial of telaprevir-based regimens in people who are infected with genotype 1 hepatitis C virus and the human immunodeficiency virus (HIV), also known as HCV-HIV co-infection. If positive, results from this trial could support the planned initiation of a Phase 3 study of telaprevir-based regimens in people co-infected with HCV and HIV in 2011. The Phase 3 trial will be designed to generate data that, if positive, could support the submission of a supplemental NDA for this population.
◦ Phase 2 Short-Duration Treatment Study: Also in 2011, Vertex and Tibotec plan to initiate a clinical trial to evaluate the role of telaprevir as part of hepatitis C treatment regimens involving less than six total months of therapy. One part of the trial may evaluate a telaprevir-based treatment regimen as short as 12 total weeks in duration for certain subsets of patients.
◦ Phase 2 Post-Transplant Study: Vertex recently completed a drug-drug interaction study of telaprevir with immunosuppressive agents commonly used following a liver transplant. Based on results from this study, Vertex and Tibotec plan to initiate in 2011 a Phase 2 study of telaprevir-based regimens in people with recurrent hepatitis C following a liver transplant.
Combination of Two CFTR Modulators for the Treatment of People with the Most Common Mutation of Cystic Fibrosis
• Vertex is conducting a Phase 2a clinical trial to evaluate multiple combination regimens of its lead CFTR Modulators - VX-770, a CFTR potentiator, and VX-809, a CFTR corrector - in people with the most common mutation of CF, known as F508del. Enrollment is ongoing in Part One of the trial, which is designed to evaluate VX-809 (200 mg), or placebo, dosed alone for 14 days and in combination with VX-770 (150 mg or 250 mg), or placebo, for 7 days. Vertex expects to obtain interim data from Part One of the trial in the first half of 2011.
Additional Phase 2 Trials and Continued Productivity in Research for Other Serious Diseases
Data from Phase 2 Trials in Epilepsy and Rheumatoid Arthritis Expected in 2011
• Vertex recently completed a Phase 2 trial of the novel caspase-1 inhibitor VX-765 in people with epilepsy. The double-blind, randomized, placebo-controlled trial was designed to evaluate the safety, tolerability and clinical activity of VX-765. The primary endpoints of the trial were safety and tolerability. Analyses of the data are ongoing and Vertex expects to announce top-line data from the trial in the first quarter of 2011.
• In the first quarter of 2011, Vertex expects to complete enrollment in an ongoing Phase 2 proof-of-concept clinical trial of the JAK3 inhibitor VX-509 in people with moderate to severe rheumatoid arthritis. In the third quarter of 2011, Vertex expects to obtain clinical data, including measurements of safety, tolerability and clinical efficacy, as measured by American College of Rheumatology scores (ACR) and Disease Activity Scores (DAS).
Continued Investment in Research to Support Discovery of Future Medicines
• Vertex continues to focus its research efforts in the areas of infectious diseases, including viral infections - such as influenza - and bacterial infections, inflammatory diseases, cancer and neurological disorders, including pain. Vertex expects additional development candidates for the treatment of one or more of these diseases to emerge from research in 2011.
As of December 31, 2010, Vertex had more than $1 billion in cash, cash equivalents and marketable securities. The company also recently entered into a $100 million commercial line of credit from Bank of America for a term of 18 months.
Vertex anticipates a GAAP net loss for 2010, including certain charges, of approximately $750 million. Vertex anticipates a 2010 non-GAAP loss, excluding certain charges, of approximately $600 million.
Vertex will report full-year 2010 financial results on February 3, 2011.
Non-GAAP Financial Measures
In this press release, Vertex's financial results are provided both in accordance with accounting principles generally accepted in the United States (GAAP) and using certain non-GAAP financial measures. In particular, Vertex provides guidance for its full-year 2010 loss, excluding stock-based compensation expense, restructuring expense and expenses related to certain September 2009 financial transactions, which results in a non-GAAP financial measure. These results are provided as a complement to results provided in accordance with GAAP because management believes these non-GAAP financial measures help indicate underlying trends in Vertex's business and are important in comparing current results with prior period results. Management also uses these non-GAAP financial measures to establish budgets and operational goals that are communicated internally and externally to manage the Vertex's business and to evaluate its performance.
Safe Harbor Statement
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including the statements made by Mr. Emmens in the second through fifth paragraphs of the press release, and statements regarding (i) Vertex’s planned launch of telaprevir in 2011; (ii) the expectation that the first Phase 3 data for VX-770 will be available in the first quarter of 2011; (iii) the expectation that Vertex will obtain a response from the FDA regarding its request for Priority Review in January 2011 and the FDA’s goal for completion of its review of NDA submissions granted Priority Review; (iv) the preparedness of the field-based employees to support the future use of telaprevir; (v) the timing of SVR data from OPTIMIZE and the potential Supplemental NDA for telaprevir; (vi) the status of the VX-770 registration program and the possibility that if the results from the Phase 3 program are positive the company could submit an NDA for VX-770 in the second half of 2011; (vii) expectations regarding the timing of data from the Phase 2 studies of (a) telaprevir and VX-222, (b) VX-770 and VX-809, (c) VX-765 and (d) VX-509; (viii) the anticipation that enrollment in the three-drug treatment arm of the VX-222/telaprevir clinical trial will begin in the first quarter of 2011; (ix) planned clinical trials of telaprevir that aim to expand the future patient population and the potential for these trials to support further trials and/or a supplemental NDA; (x) the expectation that additional development candidates will emerge in 2011; and (xi) the anticipation that Vertex’s projected GAAP and non-GAAP 2010 annual loss and year-end cash, cash equivalents and marketable securities balance will be as set forth above. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the outcomes for each of its planned clinical trials and studies may not be favorable, that regulatory authorities may require supplemental clinical trials in order to support the registration of telaprevir and/or VX-770, that planned or potential clinical trials may be delayed or may not be conducted, that the company may not be able to successfully develop telaprevir, VX-770, VX-509, VX-765 or combination therapies involving telaprevir and VX-222 or VX-770 and VX-809, that the company's expectations regarding its 2010 GAAP and non-GAAP net loss may be incorrect, 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/. The company disclaims any obligation to update the information contained in this press release as new information becomes available.
Webcast
Vertex Pharmaceuticals will webcast its corporate presentation at the 29th Annual J.P. Morgan Healthcare Conference on January 10, 2011 at 9:30 a.m. PT (12:30 p.m. ET). A link to the live webcast will be available via Vertex's website, http://www.vrtx.com/, in the Events & Presentations section. An archived webcast of the presentation will be available on Vertex's website through January 24, 2011.
About Vertex
Vertex creates new possibilities in medicine. Our team aims to discover and develop innovative therapies so people with serious diseases can lead better lives.
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.
Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.
For more information and to view Vertex’s press releases, please visit http://www.vrtx.com/.
(VRTX - GEN)
Contacts
Vertex:
Investors:
Michael Partridge, 617-444-6108 (at J.P. Morgan Healthcare Conference: 617-767-6108)
or
Lora Pike, 617-444-6755
Matthew Osborne, 617-444-6057
or
Media: 617-444-6992
Zachry Barber (at J.P. Morgan Healthcare Conference: 617-767-9533)
Source
- Hepatitis C: Submission of New Drug Application complete for telaprevir-
- Cystic Fibrosis: First Phase 3 data for VX-770 expected in first quarter 2011-
- Additional ongoing trials in HCV, CF, epilepsy and rheumatoid arthritis-
- Vertex enters 2011 with cash and cash equivalents position of more than $1 billion-
SAN FRANCISCO--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (NASDAQ: VRTX) today announced its 2011 business objectives in conjunction with the 29th Annual J.P. Morgan Healthcare Conference in San Francisco. Matthew Emmens, Chairman, President and Chief Executive Officer of Vertex, will discuss these objectives as part of a live webcast presentation, which will be available on Vertex's website, http://www.vrtx.com/, on Monday, January 10 at 9:30 a.m. PT (12:30 p.m. ET).
“2011 will be a landmark year for Vertex as we prepare for the expected launch of telaprevir in hepatitis C and advance other new therapies in development," said Mr. Emmens.
“Our commercial team is in place and prepared for the planned launch of telaprevir this year. We believe that telaprevir will dramatically change the treatment of hepatitis C and establish Vertex as a company capable of discovering, developing and launching transformative medicines to treat serious diseases.
"We are in a unique position, as just behind telaprevir is VX-770, a medicine in development that aims to treat the underlying cause of cystic fibrosis. We will soon obtain data from the Phase 3 registration program of VX-770 that may support the planned submission of a New Drug Application to the FDA in the second half of this year.
“We also expect to receive important data from multiple ongoing Phase 2 trials this year, including those evaluating new combination regimens for hepatitis C and cystic fibrosis, which may provide further development opportunities,” Mr. Emmens concluded.
Hepatitis C: Preparing for Launch of Telaprevir
Submission of New Drug Application Completed in November 2010 with Request for Priority Review
• On November 22, 2010, Vertex completed the submission of its New Drug Application (NDA) for telaprevir to the United States Food and Drug Administration (FDA). A response from the FDA regarding the company’s request for Priority Review of the telaprevir NDA is expected this month. The FDA’s goal for completion of its review for NDA submissions granted Priority Review status is six months from the NDA submission date.
• In December 2010, Vertex’s collaborator, Janssen-Cilag International NV, submitted a Marketing Authorization Application (MAA) for telaprevir to the European Medicines Agency (EMA). The EMA accepted telaprevir for accelerated assessment, which is granted to new medicines of major public health interest.
• To support the planned launch of telaprevir, Vertex has hired more than 200 new employees into its expanding commercial function. The sales and commercial leadership team is in place, and more than 100 field-based employees have been hired to date and are prepared to support the future use of telaprevir across the United States following the planned launch.
Phase 3b Study of Twice-daily Dosing of Telaprevir to Support Supplemental NDA by end of 2012
• Patient enrollment is ongoing in a Phase 3b clinical trial to evaluate twice-daily dosing of telaprevir (1,125 mg; BID) compared to three-times-daily dosing of telaprevir (750 mg; q8h) in combination with pegylated-interferon and ribavirin for people with genotype 1 hepatitis C. The study, known as OPTIMIZE, is the first Phase 3 study to evaluate twice-daily dosing of a protease inhibitor for the treatment of hepatitis C. The study does not include a control arm of pegylated-interferon and ribavirin alone.
• Sustained viral response (SVR or viral cure) data from OPTIMIZE are expected as early as 2012, which could potentially support the submission of a supplemental NDA for twice-daily (BID) dosing of telaprevir by the end of 2012.
Cystic Fibrosis: Phase 3 Registration Program for VX-770 Nears Completion
VX-770 NDA Submission Planned for Second Half of 2011
• Three trials of the novel cystic fibrosis transmembrane conductance regulator protein (CFTR) potentiator VX-770 are fully enrolled and ongoing as part of a global Phase 3 registration program focused on patients with the G551D mutation. The G551D mutation is present in approximately four percent of people with CF.
• The first Phase 3 data for VX-770 are expected in the first quarter of 2011 and will come from the Phase 3 STRIVE trial in people aged 12 and older with at least one copy of the G551D mutation. Data from the Phase 2 DISCOVER trial, which was primarily a safety study that enrolled people aged 12 and older with two copies of the F508del mutation, are also expected in the first quarter of 2011.
• Data from the Phase 3 ENVISION trial in people aged six to 11 with at least one copy of the G551D mutation are expected in mid-2011.
• If positive, the results from the Phase 3 program for VX-770 could support the submission of an NDA for VX-770 in the second half of 2011.
Opportunities to Further Advance Future Treatment of Hepatitis C and Cystic Fibrosis
Interim Data from Phase 2 Study of Telaprevir and VX-222 Expected in First Quarter of 2011
• Vertex is conducting a Phase 2 clinical trial evaluating multiple 12-week, response-guided regimens of telaprevir dosed in combination with its lead investigational HCV polymerase inhibitor, VX-222. The study currently includes three treatment arms. Two of the treatment arms are fully enrolled and are evaluating four-drug combinations of telaprevir (1,125 mg; BID), VX-222 (400 mg or 100 mg; BID), Pegasys® (pegylated-interferon alfa-2a) and Copegus® (ribavirin). Approximately two-thirds of the people in the four-drug treatment arms have received eight weeks or more of treatment. More than one-third of patients have received 10 weeks or more of treatment, with some people having completed all 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 three-drug treatment arm 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 anticipated to begin in the first quarter of 2011.
Additional Trials of Telaprevir to Advance Leadership Position in Hepatitis C
• Vertex and Tibotec also plan to conduct several additional clinical trials of telaprevir in 2011 that aim to expand the future patient population for telaprevir-based regimens. These trials include:
◦ Phase 3 HCV/Human Immunodeficiency Virus Co-Infection Trial: Vertex recently completed enrollment in a Phase 2 clinical trial of telaprevir-based regimens in people who are infected with genotype 1 hepatitis C virus and the human immunodeficiency virus (HIV), also known as HCV-HIV co-infection. If positive, results from this trial could support the planned initiation of a Phase 3 study of telaprevir-based regimens in people co-infected with HCV and HIV in 2011. The Phase 3 trial will be designed to generate data that, if positive, could support the submission of a supplemental NDA for this population.
◦ Phase 2 Short-Duration Treatment Study: Also in 2011, Vertex and Tibotec plan to initiate a clinical trial to evaluate the role of telaprevir as part of hepatitis C treatment regimens involving less than six total months of therapy. One part of the trial may evaluate a telaprevir-based treatment regimen as short as 12 total weeks in duration for certain subsets of patients.
◦ Phase 2 Post-Transplant Study: Vertex recently completed a drug-drug interaction study of telaprevir with immunosuppressive agents commonly used following a liver transplant. Based on results from this study, Vertex and Tibotec plan to initiate in 2011 a Phase 2 study of telaprevir-based regimens in people with recurrent hepatitis C following a liver transplant.
Combination of Two CFTR Modulators for the Treatment of People with the Most Common Mutation of Cystic Fibrosis
• Vertex is conducting a Phase 2a clinical trial to evaluate multiple combination regimens of its lead CFTR Modulators - VX-770, a CFTR potentiator, and VX-809, a CFTR corrector - in people with the most common mutation of CF, known as F508del. Enrollment is ongoing in Part One of the trial, which is designed to evaluate VX-809 (200 mg), or placebo, dosed alone for 14 days and in combination with VX-770 (150 mg or 250 mg), or placebo, for 7 days. Vertex expects to obtain interim data from Part One of the trial in the first half of 2011.
Additional Phase 2 Trials and Continued Productivity in Research for Other Serious Diseases
Data from Phase 2 Trials in Epilepsy and Rheumatoid Arthritis Expected in 2011
• Vertex recently completed a Phase 2 trial of the novel caspase-1 inhibitor VX-765 in people with epilepsy. The double-blind, randomized, placebo-controlled trial was designed to evaluate the safety, tolerability and clinical activity of VX-765. The primary endpoints of the trial were safety and tolerability. Analyses of the data are ongoing and Vertex expects to announce top-line data from the trial in the first quarter of 2011.
• In the first quarter of 2011, Vertex expects to complete enrollment in an ongoing Phase 2 proof-of-concept clinical trial of the JAK3 inhibitor VX-509 in people with moderate to severe rheumatoid arthritis. In the third quarter of 2011, Vertex expects to obtain clinical data, including measurements of safety, tolerability and clinical efficacy, as measured by American College of Rheumatology scores (ACR) and Disease Activity Scores (DAS).
Continued Investment in Research to Support Discovery of Future Medicines
• Vertex continues to focus its research efforts in the areas of infectious diseases, including viral infections - such as influenza - and bacterial infections, inflammatory diseases, cancer and neurological disorders, including pain. Vertex expects additional development candidates for the treatment of one or more of these diseases to emerge from research in 2011.
As of December 31, 2010, Vertex had more than $1 billion in cash, cash equivalents and marketable securities. The company also recently entered into a $100 million commercial line of credit from Bank of America for a term of 18 months.
Vertex anticipates a GAAP net loss for 2010, including certain charges, of approximately $750 million. Vertex anticipates a 2010 non-GAAP loss, excluding certain charges, of approximately $600 million.
Vertex will report full-year 2010 financial results on February 3, 2011.
Non-GAAP Financial Measures
In this press release, Vertex's financial results are provided both in accordance with accounting principles generally accepted in the United States (GAAP) and using certain non-GAAP financial measures. In particular, Vertex provides guidance for its full-year 2010 loss, excluding stock-based compensation expense, restructuring expense and expenses related to certain September 2009 financial transactions, which results in a non-GAAP financial measure. These results are provided as a complement to results provided in accordance with GAAP because management believes these non-GAAP financial measures help indicate underlying trends in Vertex's business and are important in comparing current results with prior period results. Management also uses these non-GAAP financial measures to establish budgets and operational goals that are communicated internally and externally to manage the Vertex's business and to evaluate its performance.
Safe Harbor Statement
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including the statements made by Mr. Emmens in the second through fifth paragraphs of the press release, and statements regarding (i) Vertex’s planned launch of telaprevir in 2011; (ii) the expectation that the first Phase 3 data for VX-770 will be available in the first quarter of 2011; (iii) the expectation that Vertex will obtain a response from the FDA regarding its request for Priority Review in January 2011 and the FDA’s goal for completion of its review of NDA submissions granted Priority Review; (iv) the preparedness of the field-based employees to support the future use of telaprevir; (v) the timing of SVR data from OPTIMIZE and the potential Supplemental NDA for telaprevir; (vi) the status of the VX-770 registration program and the possibility that if the results from the Phase 3 program are positive the company could submit an NDA for VX-770 in the second half of 2011; (vii) expectations regarding the timing of data from the Phase 2 studies of (a) telaprevir and VX-222, (b) VX-770 and VX-809, (c) VX-765 and (d) VX-509; (viii) the anticipation that enrollment in the three-drug treatment arm of the VX-222/telaprevir clinical trial will begin in the first quarter of 2011; (ix) planned clinical trials of telaprevir that aim to expand the future patient population and the potential for these trials to support further trials and/or a supplemental NDA; (x) the expectation that additional development candidates will emerge in 2011; and (xi) the anticipation that Vertex’s projected GAAP and non-GAAP 2010 annual loss and year-end cash, cash equivalents and marketable securities balance will be as set forth above. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the outcomes for each of its planned clinical trials and studies may not be favorable, that regulatory authorities may require supplemental clinical trials in order to support the registration of telaprevir and/or VX-770, that planned or potential clinical trials may be delayed or may not be conducted, that the company may not be able to successfully develop telaprevir, VX-770, VX-509, VX-765 or combination therapies involving telaprevir and VX-222 or VX-770 and VX-809, that the company's expectations regarding its 2010 GAAP and non-GAAP net loss may be incorrect, 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/. The company disclaims any obligation to update the information contained in this press release as new information becomes available.
Webcast
Vertex Pharmaceuticals will webcast its corporate presentation at the 29th Annual J.P. Morgan Healthcare Conference on January 10, 2011 at 9:30 a.m. PT (12:30 p.m. ET). A link to the live webcast will be available via Vertex's website, http://www.vrtx.com/, in the Events & Presentations section. An archived webcast of the presentation will be available on Vertex's website through January 24, 2011.
About Vertex
Vertex creates new possibilities in medicine. Our team aims to discover and develop innovative therapies so people with serious diseases can lead better lives.
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.
Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.
For more information and to view Vertex’s press releases, please visit http://www.vrtx.com/.
(VRTX - GEN)
Contacts
Vertex:
Investors:
Michael Partridge, 617-444-6108 (at J.P. Morgan Healthcare Conference: 617-767-6108)
or
Lora Pike, 617-444-6755
Matthew Osborne, 617-444-6057
or
Media: 617-444-6992
Zachry Barber (at J.P. Morgan Healthcare Conference: 617-767-9533)
Source
January 9, 2011
New Study in San Francisco Aims to Improve HIV Care for Aging Population
January 7, 2011
Researchers at the University of California in San Francisco (UCSF) have launched a study to discover the best comprehensive care methods for people living with HIV as they get older. In a news article by the university about the project, the study’s leaders explain they will be integrating the expertise of specialists in geriatric medicine with that of infectious disease experts to address the fact that HIV-positive people are experiencing age-related problems at a younger age than HIV-negative people.
“I know I’m getting older,” Lou Grosso, a 57-year-old UCSF HIV clinic patient, said in the article. “So is that why I have the aches and pains and memory issues? Or is it because I have been taking all those antiretroviral drug cocktails that have been keeping me alive all these years? I never thought I would live this long to ask these questions.”
These are some of the issues that the new study aims to answer, as well as how to choose the best care models for people with age-related problems. At present, doctors really don’t know how best to manage aging HIV-positive patients.
Are the same comprehensive care guidelines used for HIV-negative people appropriate? Currently, there are no easy answers to that question.
“Conditions that you might normally see in patients in their 60s or 70s are showing up in HIV patients who are only in their 40s and 50s,” said Brad Hare, MD, Grosso’s doctor and medical director of the UCSF Positive Health Program at San Francisco General Hospital.
Hare explains that he and a colleague, Malcolm John, MD, who heads UCSF’s comprehensive HIV care clinic, will use the study funds to identify which screening tests should be conducted to monitor for diseases of aging, along with when they should be used. The study will also explore the value of bringing in nutritionists and pharmacists as essential members of the care team.
John stresses that they will also be looking beyond the physical manifestations of HIV disease. Specialists in psychology and social support will also be involved.
UCSF’s Positive Care Center, one of the country’s model integrated care programs, will serve as the template upon which to study the best care strategies for people as they age.
“It’s our legacy and responsibility at UC to be leaders in research and caring for people with HIV,” Hare concluded.
Source
Researchers at the University of California in San Francisco (UCSF) have launched a study to discover the best comprehensive care methods for people living with HIV as they get older. In a news article by the university about the project, the study’s leaders explain they will be integrating the expertise of specialists in geriatric medicine with that of infectious disease experts to address the fact that HIV-positive people are experiencing age-related problems at a younger age than HIV-negative people.
“I know I’m getting older,” Lou Grosso, a 57-year-old UCSF HIV clinic patient, said in the article. “So is that why I have the aches and pains and memory issues? Or is it because I have been taking all those antiretroviral drug cocktails that have been keeping me alive all these years? I never thought I would live this long to ask these questions.”
These are some of the issues that the new study aims to answer, as well as how to choose the best care models for people with age-related problems. At present, doctors really don’t know how best to manage aging HIV-positive patients.
Are the same comprehensive care guidelines used for HIV-negative people appropriate? Currently, there are no easy answers to that question.
“Conditions that you might normally see in patients in their 60s or 70s are showing up in HIV patients who are only in their 40s and 50s,” said Brad Hare, MD, Grosso’s doctor and medical director of the UCSF Positive Health Program at San Francisco General Hospital.
Hare explains that he and a colleague, Malcolm John, MD, who heads UCSF’s comprehensive HIV care clinic, will use the study funds to identify which screening tests should be conducted to monitor for diseases of aging, along with when they should be used. The study will also explore the value of bringing in nutritionists and pharmacists as essential members of the care team.
John stresses that they will also be looking beyond the physical manifestations of HIV disease. Specialists in psychology and social support will also be involved.
UCSF’s Positive Care Center, one of the country’s model integrated care programs, will serve as the template upon which to study the best care strategies for people as they age.
“It’s our legacy and responsibility at UC to be leaders in research and caring for people with HIV,” Hare concluded.
Source
Cirrhosis Is Present in Most Patients With Hepatitis B and Hepatocellular Carcinoma
Clinical Gastroenterology and Hepatology
Volume 9, Issue 1 , Pages 64-70, January 2011
Ju Dong Yang, W. Ray Kim, Ritika Coelho, Teresa A. Mettler, Joanne T. Benson, Schuyler O. Sanderson, Terry M. Therneau, Bohyun Kim, Lewis R. Roberts
Abstract
Background & Aims
There are few data available about the prevalence or effects of cirrhosis in patients with hepatocellular carcinoma (HCC) from viral hepatitis. We compared patients with HCC and hepatitis B virus (HBV) or hepatitis C virus (HCV) infections to determine the proportions of cirrhosis in each group, virologic and tumor characteristics, and overall survival.
Methods
This analysis included patients with HBV (n = 64) or HCV (n = 118) infection who were diagnosed with HCC at the Mayo Clinic in Rochester, Minnesota from 1994–2008; groups were matched for age and sex. The diagnosis of cirrhosis was based on histology and, if histologic information was insufficient or unavailable, clinical indicators that included ascites or varices, thrombocytopenia or splenomegaly, and radiographic configuration of cirrhosis. Virologic characteristics, tumor stage, and patient survival were also assessed.
Results
The prevalence of histologic cirrhosis was 88% among patients with HBV infection and 93% among those with HCV infection (P = .46). When the most inclusive criteria for cirrhosis were applied, cirrhosis was present in 94% of patients with HBV and 97% with HCV (P = .24). Among HCV patients, 5.2% were negative for HCV RNA after antiviral treatment; 63.4% of HBV patients had HBV DNA <2000 IU/mL with or without treatment. Patients with HBV tended to have less surveillance and more advanced stages of HCC, without differences in survival from those with HCV infection (P = .75).
Conclusions
Most patients with HCC and chronic viral hepatitis had evidence of cirrhosis, including those with HBV infection and those without active viral replication.
Keywords: Liver Cancer, Liver Disease, Virology, Survival
Source
Volume 9, Issue 1 , Pages 64-70, January 2011
Ju Dong Yang, W. Ray Kim, Ritika Coelho, Teresa A. Mettler, Joanne T. Benson, Schuyler O. Sanderson, Terry M. Therneau, Bohyun Kim, Lewis R. Roberts
Abstract
Background & Aims
There are few data available about the prevalence or effects of cirrhosis in patients with hepatocellular carcinoma (HCC) from viral hepatitis. We compared patients with HCC and hepatitis B virus (HBV) or hepatitis C virus (HCV) infections to determine the proportions of cirrhosis in each group, virologic and tumor characteristics, and overall survival.
Methods
This analysis included patients with HBV (n = 64) or HCV (n = 118) infection who were diagnosed with HCC at the Mayo Clinic in Rochester, Minnesota from 1994–2008; groups were matched for age and sex. The diagnosis of cirrhosis was based on histology and, if histologic information was insufficient or unavailable, clinical indicators that included ascites or varices, thrombocytopenia or splenomegaly, and radiographic configuration of cirrhosis. Virologic characteristics, tumor stage, and patient survival were also assessed.
Results
The prevalence of histologic cirrhosis was 88% among patients with HBV infection and 93% among those with HCV infection (P = .46). When the most inclusive criteria for cirrhosis were applied, cirrhosis was present in 94% of patients with HBV and 97% with HCV (P = .24). Among HCV patients, 5.2% were negative for HCV RNA after antiviral treatment; 63.4% of HBV patients had HBV DNA <2000 IU/mL with or without treatment. Patients with HBV tended to have less surveillance and more advanced stages of HCC, without differences in survival from those with HCV infection (P = .75).
Conclusions
Most patients with HCC and chronic viral hepatitis had evidence of cirrhosis, including those with HBV infection and those without active viral replication.
Keywords: Liver Cancer, Liver Disease, Virology, Survival
Source
Thrombocytopenia in chronic hepatitis C
J Gastrointestin Liver Dis. 2010 Dec;19(4):381-5.
Olariu M, Olariu C, Olteanu D.
National Institute of Infectious Diseases "Prof.Dr.Matei Balş" Bucharest,Romania; Email: ol_mihai@yahoo.com.
Abstract
BACKGROUND AND AIMS: Thrombocytopenia in patients with chronic hepatitis C may be the result of several factors: bone marrow inhibition, the decrease of liver thrombopoietin production and an autoimmune mechanism. Clinical variables such as age, gender, severity of liver disease and degree of viremia could influence the severity of platelet reduction. The goal of this study is to determine the prevalent mechanism of thrombocytopenia in patients with chronic hepatitis C and the clinical predictors of its severity.
METHODS: Eighty-one patients with chronic hepatitis C and thrombocytopenia were included. The viral inhibition on the bone marrow (central mechanism) was studied by performing bone marrow biopsy from the iliac crest. The presence of antiplatelet antibodies by ELISA assessed the peripheral mechanism. The clinical predictors included in the analysis were: age, gender, ALT level, liver fibrosis stage and HCV RNA.
RESULTS: Coexistence of a central and peripheral mechanism was found in the vast majority (93.3%) of patients with severe thrombocytopenia (< 100,000/microL) and in most patients (61.53%) with moderate thrombocytopenia (100,000- 125,000/microL). In patients with less severe thrombocytopenia (126,000-149,000/microL), autoimmune destruction was the sole mechanism (85%). Thrombocytopenia was significantly associated with ALT values, viral load and stage of fibrosis.
CONCLUSIONS: Our data demonstrates that chronic hepatitis C is associated with a variable degree of thrombocytopenia. As the disease advances, the platelet count decreases and, in most cases, both mechanisms are involved. The stage of fibrosis is one of the major determinants of thrombocytopenia.
PMID: 21188328 [PubMed - in process]
Source
Olariu M, Olariu C, Olteanu D.
National Institute of Infectious Diseases "Prof.Dr.Matei Balş" Bucharest,Romania; Email: ol_mihai@yahoo.com.
Abstract
BACKGROUND AND AIMS: Thrombocytopenia in patients with chronic hepatitis C may be the result of several factors: bone marrow inhibition, the decrease of liver thrombopoietin production and an autoimmune mechanism. Clinical variables such as age, gender, severity of liver disease and degree of viremia could influence the severity of platelet reduction. The goal of this study is to determine the prevalent mechanism of thrombocytopenia in patients with chronic hepatitis C and the clinical predictors of its severity.
METHODS: Eighty-one patients with chronic hepatitis C and thrombocytopenia were included. The viral inhibition on the bone marrow (central mechanism) was studied by performing bone marrow biopsy from the iliac crest. The presence of antiplatelet antibodies by ELISA assessed the peripheral mechanism. The clinical predictors included in the analysis were: age, gender, ALT level, liver fibrosis stage and HCV RNA.
RESULTS: Coexistence of a central and peripheral mechanism was found in the vast majority (93.3%) of patients with severe thrombocytopenia (< 100,000/microL) and in most patients (61.53%) with moderate thrombocytopenia (100,000- 125,000/microL). In patients with less severe thrombocytopenia (126,000-149,000/microL), autoimmune destruction was the sole mechanism (85%). Thrombocytopenia was significantly associated with ALT values, viral load and stage of fibrosis.
CONCLUSIONS: Our data demonstrates that chronic hepatitis C is associated with a variable degree of thrombocytopenia. As the disease advances, the platelet count decreases and, in most cases, both mechanisms are involved. The stage of fibrosis is one of the major determinants of thrombocytopenia.
PMID: 21188328 [PubMed - in process]
Source
Vitamins B status and antioxidative defense in patients with chronic hepatitis B or hepatitis C virus infection
European Journal of Nutrition
DOI: 10.1007/s00394-010-0156-1
Published Online 24 December 2010
Original Contribution
Chun-che Lin, Wen-hu Liu, Zhi-hong Wang and Mei-chin Yin
Abstract
Background & Aims
The impact of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection upon B vitamins status and antioxidative defense in infected patients was examined.
Methods
Dietary record and blood levels of B vitamins and oxidative stress–associated biomarkers were determined for 195 healthy controls, 132 HBV, and 114 HCV patients.
Results
HBV-infected patients had significantly higher levels of total cholesterol, free fatty acids (FFA), and lower ghrelin level (p < 0.05); and HCV-infected patients had significantly higher Ishak inflammation score and lactate dehydrogenase activity (p < 0.05). HBV patients had significantly lower red blood cell (RBC) vitamins B2 and B6 levels, and HCV infection significantly decreased vitamins B2, B6 and folate levels in RBC and/or plasma (p < 0.05). Correlation coefficients of RBC vitamin B2 versus serum FFA in HBV patients, RBC vitamins B2 and B6 versus HCV RNA and Ishak inflammation score, and plasma vitamin B6 vs Ishak inflammation score in HCV patients were <−0.5. HBV-infected patients had significantly higher oxidized glutathione level and lower glutathione peroxidase activity (p < 0.05), but HCV patients had significantly lower superoxide dismutase and catalase activities (p < 0.05).
Conclusion
HBV or HCV infection enhanced oxidative stress and lowered B vitamins in circulation. In order to avoid other healthy risk, nutrition status should be monitored and limitation or supplementation of certain nutrients might be helpful for HBV- or HCV-infected patients.
Keywords Hepatitis B virus – Hepatitis C virus – B vitamins – Oxidative stress – Lipid metabolism
Source
DOI: 10.1007/s00394-010-0156-1
Published Online 24 December 2010
Original Contribution
Chun-che Lin, Wen-hu Liu, Zhi-hong Wang and Mei-chin Yin
Abstract
Background & Aims
The impact of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection upon B vitamins status and antioxidative defense in infected patients was examined.
Methods
Dietary record and blood levels of B vitamins and oxidative stress–associated biomarkers were determined for 195 healthy controls, 132 HBV, and 114 HCV patients.
Results
HBV-infected patients had significantly higher levels of total cholesterol, free fatty acids (FFA), and lower ghrelin level (p < 0.05); and HCV-infected patients had significantly higher Ishak inflammation score and lactate dehydrogenase activity (p < 0.05). HBV patients had significantly lower red blood cell (RBC) vitamins B2 and B6 levels, and HCV infection significantly decreased vitamins B2, B6 and folate levels in RBC and/or plasma (p < 0.05). Correlation coefficients of RBC vitamin B2 versus serum FFA in HBV patients, RBC vitamins B2 and B6 versus HCV RNA and Ishak inflammation score, and plasma vitamin B6 vs Ishak inflammation score in HCV patients were <−0.5. HBV-infected patients had significantly higher oxidized glutathione level and lower glutathione peroxidase activity (p < 0.05), but HCV patients had significantly lower superoxide dismutase and catalase activities (p < 0.05).
Conclusion
HBV or HCV infection enhanced oxidative stress and lowered B vitamins in circulation. In order to avoid other healthy risk, nutrition status should be monitored and limitation or supplementation of certain nutrients might be helpful for HBV- or HCV-infected patients.
Keywords Hepatitis B virus – Hepatitis C virus – B vitamins – Oxidative stress – Lipid metabolism
Source
The relationship between liver disease stage and liver fibrosis: a tangled web
Authors: Germani, Giacomo 1; Burroughs, Andrew K 1; Dhillon, Amar P 2
Source: Histopathology, Volume 57, Number 6, December 2010 , pp. 773-784(12)
Publisher: Wiley-Blackwell
Abstract:
The structural consequences of chronic liver disease are described as a series of liver disease `stages' with scarring and architectural change that eventually destroys and replaces the normal lobular structure of the liver. Fibrosis (`excess collagen') and stage have been confused in histological staging systems. Fibrosis is part of increasing liver disease stage, but fibrosis and stage are different. Staging liver disease is important in routine histopathological assessment. Measurement of liver fibrosis is another process. The collagenous proportion of a liver biopsy [collagen proportionate area (CPA)] correlates with hepatic venous pressure gradient (HVPG), which is of recognized prognostic value. CPA at 1 year post-transplantation in hepatitis C virus-infected patients predicts subsequent clinical decompensation. CPA in cirrhotic patients predicts decompensation more accurately than staging or HVPG. The `cirrhosis' stage category has poor prognostic power, and CPA effectively substages cirrhosis. CPA improves the description of liver disease stage. Proper validation of antifibrotic treatments and `non-invasive markers of liver fibrosis' requires measurement of liver fibrosis (and not liver biopsy stage scores). It is unacceptable for the words `fibrosis' and `score' to remain next to each other. There are benefits to properly understanding liver fibrosis and liver disease stage and properly assessing each of them.
Keywords: liver; fibrosis; stage; collagen proportionate area; image analysis
Source
Source: Histopathology, Volume 57, Number 6, December 2010 , pp. 773-784(12)
Publisher: Wiley-Blackwell
Abstract:
The structural consequences of chronic liver disease are described as a series of liver disease `stages' with scarring and architectural change that eventually destroys and replaces the normal lobular structure of the liver. Fibrosis (`excess collagen') and stage have been confused in histological staging systems. Fibrosis is part of increasing liver disease stage, but fibrosis and stage are different. Staging liver disease is important in routine histopathological assessment. Measurement of liver fibrosis is another process. The collagenous proportion of a liver biopsy [collagen proportionate area (CPA)] correlates with hepatic venous pressure gradient (HVPG), which is of recognized prognostic value. CPA at 1 year post-transplantation in hepatitis C virus-infected patients predicts subsequent clinical decompensation. CPA in cirrhotic patients predicts decompensation more accurately than staging or HVPG. The `cirrhosis' stage category has poor prognostic power, and CPA effectively substages cirrhosis. CPA improves the description of liver disease stage. Proper validation of antifibrotic treatments and `non-invasive markers of liver fibrosis' requires measurement of liver fibrosis (and not liver biopsy stage scores). It is unacceptable for the words `fibrosis' and `score' to remain next to each other. There are benefits to properly understanding liver fibrosis and liver disease stage and properly assessing each of them.
Keywords: liver; fibrosis; stage; collagen proportionate area; image analysis
Source
Metabolic syndrome found in 52 percent of patients after liver transplantation
Published: Thursday, January 6, 2011 - 10:11
Researchers from Israel have determined that more than half of liver transplant recipients develop post-transplantation metabolic syndrome (PTMS), placing them at greater risk for cardiovascular disease. Prior to transplantation only 5% of the patients were diagnosed with metabolic syndrome, but rates of obesity, hypertriglyceridemia, hypertension, and diabetes were significantly higher post transplantation. Full details of this retrospective-prevalence study are available in the January 2011 issue of Liver Transplantation, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases. Metabolic syndrome, which is comprised of obesity, hypertension, hyperglycemia, and dyslipidemia, is commonly seen in patients following liver transplantation and is double the rate reported for the general population. Prior studies have found that immunosuppressive medications including calcineurin inhibitors and corticosteroids; modifiable lifestyle choices such as food intake, which can contribute to weight gain and insulin resistance; and the underlying liver disease itself (chronic hepatitis C virus infection and nonalcoholic fatty liver disease), all play a significant role in the development of metabolic syndrome.
In order to determine the prevalence and risk factors associated with PTMS, Professor Ziv Ben Ari and colleagues from the Liver Transplant Unit at Rabin Medical Center—the largest such unit in Israel—reviewed the files of 252 patients who received a liver transplant between 1985 and 2007. Researchers analyzed pre- and post-transplant clinical and laboratory data, including height, weight, waist circumference, presence of diabetes, hypertension, or hyperlipidemia, and prescribed medications (immunosuppressive, anti-hypertensive, hypoglycemic, and lipid-lowering drugs).
Researchers diagnosed PTMS when at least three of the following criteria were met: increased waist circumference, elevated fasting serum triglycerides, elevated blood pressure, abnormally high fasting serum glucose, high BMI and low high-density lipoprotein-cholesterol. Major vascular events were defined as transient ischemic attack, cerebrovascular accident, acute coronary syndrome, and myocardial infarction. Coronary events were identified by coronary angiography or coronary revascularization.
"We found significantly higher rates of obesity, hypertriglyceridemia, hypertension, diabetes and low HDL cholesterol, in patients following liver transplantation," said Professor Ben Ari. Researchers determined that PTMS patients were older and heavier than those in the non-PTMS group, and had a higher rate of pre-transplant chronic hepatitis C virus infection.
Further analysis showed significant independent predictors of PTMS were age, pre-transplant nonalcoholic fatty liver disease, BMI, diabetes, and triglycerides. Patients with PTMS also experienced more major vascular and cardiac events following their transplants than those without PTMS (15% versus 5%). "PTMS is associated with cardiovascular morbidity but not mortality, and it may be predicted by pre-transplantation conditions," concluded Professor Ben Ari.
In an editorial also published this month in Liver Transplantation, Michael Charlton, MD, FRCP, from the Mayo Clinic Transplant Center commented, "Professor Ben Ari and colleagues provide new evidence of the increasingly high prevalence and important associated outcomes of PTMS. Well designed, prospective studies are needed to validate these new observations and to establish optimal strategies for the diagnosis, prevention and management of post-transplant metabolic syndrome."
Source: Wiley-Blackwell
Soure
Researchers from Israel have determined that more than half of liver transplant recipients develop post-transplantation metabolic syndrome (PTMS), placing them at greater risk for cardiovascular disease. Prior to transplantation only 5% of the patients were diagnosed with metabolic syndrome, but rates of obesity, hypertriglyceridemia, hypertension, and diabetes were significantly higher post transplantation. Full details of this retrospective-prevalence study are available in the January 2011 issue of Liver Transplantation, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases. Metabolic syndrome, which is comprised of obesity, hypertension, hyperglycemia, and dyslipidemia, is commonly seen in patients following liver transplantation and is double the rate reported for the general population. Prior studies have found that immunosuppressive medications including calcineurin inhibitors and corticosteroids; modifiable lifestyle choices such as food intake, which can contribute to weight gain and insulin resistance; and the underlying liver disease itself (chronic hepatitis C virus infection and nonalcoholic fatty liver disease), all play a significant role in the development of metabolic syndrome.
In order to determine the prevalence and risk factors associated with PTMS, Professor Ziv Ben Ari and colleagues from the Liver Transplant Unit at Rabin Medical Center—the largest such unit in Israel—reviewed the files of 252 patients who received a liver transplant between 1985 and 2007. Researchers analyzed pre- and post-transplant clinical and laboratory data, including height, weight, waist circumference, presence of diabetes, hypertension, or hyperlipidemia, and prescribed medications (immunosuppressive, anti-hypertensive, hypoglycemic, and lipid-lowering drugs).
Researchers diagnosed PTMS when at least three of the following criteria were met: increased waist circumference, elevated fasting serum triglycerides, elevated blood pressure, abnormally high fasting serum glucose, high BMI and low high-density lipoprotein-cholesterol. Major vascular events were defined as transient ischemic attack, cerebrovascular accident, acute coronary syndrome, and myocardial infarction. Coronary events were identified by coronary angiography or coronary revascularization.
"We found significantly higher rates of obesity, hypertriglyceridemia, hypertension, diabetes and low HDL cholesterol, in patients following liver transplantation," said Professor Ben Ari. Researchers determined that PTMS patients were older and heavier than those in the non-PTMS group, and had a higher rate of pre-transplant chronic hepatitis C virus infection.
Further analysis showed significant independent predictors of PTMS were age, pre-transplant nonalcoholic fatty liver disease, BMI, diabetes, and triglycerides. Patients with PTMS also experienced more major vascular and cardiac events following their transplants than those without PTMS (15% versus 5%). "PTMS is associated with cardiovascular morbidity but not mortality, and it may be predicted by pre-transplantation conditions," concluded Professor Ben Ari.
In an editorial also published this month in Liver Transplantation, Michael Charlton, MD, FRCP, from the Mayo Clinic Transplant Center commented, "Professor Ben Ari and colleagues provide new evidence of the increasingly high prevalence and important associated outcomes of PTMS. Well designed, prospective studies are needed to validate these new observations and to establish optimal strategies for the diagnosis, prevention and management of post-transplant metabolic syndrome."
Source: Wiley-Blackwell
Soure
The natural history of interferon-alpha induced thyroiditis in chronic hepatitis C patients: A long term study
Published on: 2011-01-08
Autoimmune thyroid disease is a common complication of patients with chronic hepatitis C undergoing combination pegylated interferon-alpha and ribavirin treatment. A small proportion develops interferon-induced thyroiditis of which the long term natural history is unknown and how it compares with de novo thyroiditis.
The aim of the study is to determine the natural history of thyroid disease including antibody profile in this particular setting 36 months from the completion of therapy.
Methods: A cohort of 18 hepatitis C patients (mean age 45 +/- 8 years (standard deviation)) who developed exclusively thyroiditis in this setting was followed every 12 months after the completion of therapy for 36 months. Investigations included thyrotropin, free tetra-iodothyronine, free tri-iodothyronine levels and thyroid autoantibodies.
Results: None of the patients developed any long term thyroid disease.
Two patients had a prolonged hypothyroid phase of the thyroiditis early after the completion of treatment but recovered fully. The remaining 16 patients remained euthyroid.
Similarly, thyroid autoantibodies all declined and returned to reference range.
Conclusions: The long term natural history in this small series of interferon induced thyroiditis was benign. If a larger series confirms a similar outcome then there is no long term residual effect on thyroid function and follow-up testing would not be warranted.
Author: Huy TranTracey JonesElizabeth IannaGlenn Reeves
Credits/Source: Thyroid Research 2011, 4:2
Source
Autoimmune thyroid disease is a common complication of patients with chronic hepatitis C undergoing combination pegylated interferon-alpha and ribavirin treatment. A small proportion develops interferon-induced thyroiditis of which the long term natural history is unknown and how it compares with de novo thyroiditis.
The aim of the study is to determine the natural history of thyroid disease including antibody profile in this particular setting 36 months from the completion of therapy.
Methods: A cohort of 18 hepatitis C patients (mean age 45 +/- 8 years (standard deviation)) who developed exclusively thyroiditis in this setting was followed every 12 months after the completion of therapy for 36 months. Investigations included thyrotropin, free tetra-iodothyronine, free tri-iodothyronine levels and thyroid autoantibodies.
Results: None of the patients developed any long term thyroid disease.
Two patients had a prolonged hypothyroid phase of the thyroiditis early after the completion of treatment but recovered fully. The remaining 16 patients remained euthyroid.
Similarly, thyroid autoantibodies all declined and returned to reference range.
Conclusions: The long term natural history in this small series of interferon induced thyroiditis was benign. If a larger series confirms a similar outcome then there is no long term residual effect on thyroid function and follow-up testing would not be warranted.
Author: Huy TranTracey JonesElizabeth IannaGlenn Reeves
Credits/Source: Thyroid Research 2011, 4:2
Source
January 8, 2011
HCV and HIV Coinfection
Current Hepatitis Reports
DOI: 10.1007/s11901-010-0080-
Published Online 05 January 2011
Vincent Soriano, Eugenia Vispo, Luz Martin-Carbonero and Pablo Barreiro
Abstract
Chronic hepatitis C (CHC) is estimated to affect about 20% of the 34 million individuals currently living with HIV worldwide, with greater rates (~ 75%) in intravenous drug users or persons exposed to blood products. Individuals who are coinfected with HIV and hepatitis C virus (HCV) show an accelerated course of liver disease, with faster progression to cirrhosis and its clinical complications. The combination of pegylated interferon plus ribavirin given for 6–18 months leads to sustained HCV clearance in no more than half of HIV-HCV coinfected patients. Thus, new direct anti-HCV drugs are eagerly awaited for this population. Appropriate diagnosis and monitoring of CHC, including the use of noninvasive tools for assessing liver fibrosis (eg, elastometry) as well as provision of therapy guided by early viral kinetics and IL28B genotyping, are improving the management of CHC in HIV-infected persons.
Keywords Hepatitis C – HIV – Coinfection – Liver – Interferon – Ribavirin – Direct-acting antivirals – IL28B
Source
DOI: 10.1007/s11901-010-0080-
Published Online 05 January 2011
Vincent Soriano, Eugenia Vispo, Luz Martin-Carbonero and Pablo Barreiro
Abstract
Chronic hepatitis C (CHC) is estimated to affect about 20% of the 34 million individuals currently living with HIV worldwide, with greater rates (~ 75%) in intravenous drug users or persons exposed to blood products. Individuals who are coinfected with HIV and hepatitis C virus (HCV) show an accelerated course of liver disease, with faster progression to cirrhosis and its clinical complications. The combination of pegylated interferon plus ribavirin given for 6–18 months leads to sustained HCV clearance in no more than half of HIV-HCV coinfected patients. Thus, new direct anti-HCV drugs are eagerly awaited for this population. Appropriate diagnosis and monitoring of CHC, including the use of noninvasive tools for assessing liver fibrosis (eg, elastometry) as well as provision of therapy guided by early viral kinetics and IL28B genotyping, are improving the management of CHC in HIV-infected persons.
Keywords Hepatitis C – HIV – Coinfection – Liver – Interferon – Ribavirin – Direct-acting antivirals – IL28B
Source
A Comparison of Prognosis between Patients with Hepatitis B and C Virus-related Hepatocellular Carcinoma Undergoing Resection Surgery
World Journal of Surgery
DOI: 10.1007/s00268-010-0928-z
Published Online 05 January 2011
Wei-Yu Kao, Chien-Wei Su, Gar-Yang Chau, Wing-Yiu Lui, Chew-Wun Wu and Jaw-Ching Wu
Abstract
Background
The impact of viral factors on the prognosis of hepatocellular carcinoma (HCC) remains controversial because of heterogeneous populations included in previous reports. This study aims to compare clinicopathologic features and prognoses between patients with hepatitis B- and hepatitis C-related HCC who underwent resection surgery.
Methods
We enrolled 609 patients with positive serum hepatitis B virus (HBV) surface antigen (HBsAg) and negative serum antibody against hepatitis C virus (anti-HCV) as the B-HCC group and 206 patients with negative serum HBsAg and positive anti-HCV as the C-HCC group. The overall survival rates and cumulative recurrence rates were compared between these two groups.
Results
B-HCC patients were significantly younger, predominantly male, had better liver functional reserve, but more advanced tumor stage than C-HCC patients. After a median follow-up period of 40.6 months, 427 patients had died. Furthermore, 501 patients had tumor recurrence after surgery. The postoperative overall survival rates (p = 0.640) and recurrence rates (p = 0.387) of the two groups were comparable. However, the overall survival rate was higher in the B-HCC group than in the C-HCC group in the cases of transplantable HCC (p = 0.021) and Barcelona-Clinic Liver Cancer stage A HCC (p = 0.040).
Conclusions
Viral etiologies were not apparent in determining outcomes of HCC patients who underwent resection due to heterogeneous studied populations. In early-stage HCC, B-HCC patients had better outcomes than C-HCC patients did because of better liver reserve and less hepatic inflammation.
Source
DOI: 10.1007/s00268-010-0928-z
Published Online 05 January 2011
Wei-Yu Kao, Chien-Wei Su, Gar-Yang Chau, Wing-Yiu Lui, Chew-Wun Wu and Jaw-Ching Wu
Abstract
Background
The impact of viral factors on the prognosis of hepatocellular carcinoma (HCC) remains controversial because of heterogeneous populations included in previous reports. This study aims to compare clinicopathologic features and prognoses between patients with hepatitis B- and hepatitis C-related HCC who underwent resection surgery.
Methods
We enrolled 609 patients with positive serum hepatitis B virus (HBV) surface antigen (HBsAg) and negative serum antibody against hepatitis C virus (anti-HCV) as the B-HCC group and 206 patients with negative serum HBsAg and positive anti-HCV as the C-HCC group. The overall survival rates and cumulative recurrence rates were compared between these two groups.
Results
B-HCC patients were significantly younger, predominantly male, had better liver functional reserve, but more advanced tumor stage than C-HCC patients. After a median follow-up period of 40.6 months, 427 patients had died. Furthermore, 501 patients had tumor recurrence after surgery. The postoperative overall survival rates (p = 0.640) and recurrence rates (p = 0.387) of the two groups were comparable. However, the overall survival rate was higher in the B-HCC group than in the C-HCC group in the cases of transplantable HCC (p = 0.021) and Barcelona-Clinic Liver Cancer stage A HCC (p = 0.040).
Conclusions
Viral etiologies were not apparent in determining outcomes of HCC patients who underwent resection due to heterogeneous studied populations. In early-stage HCC, B-HCC patients had better outcomes than C-HCC patients did because of better liver reserve and less hepatic inflammation.
Source
HIV and Hepatitis C Co-infection: Guideline and Commentary
Douglas G. Fish, MD
Posted: 01/05/2011
HIV and Hepatitis C: Expert Commentary
Approximately 15% to 30% of people with HIV are estimated to be co-infected with hepatitis C virus (HCV) in the United States, and up to 90% of those with HIV secondary to injection drug use are co-infected.1,2 Chronic liver disease from co-infection, including cirrhosis and hepatocellular carcinoma, leads to significant morbidity and mortality.
Most patients who are co-infected with hepatitis C are diagnosed with chronic disease. This is diagnosed when the hepatitis C antibody is reactive and subsequent viral load (RNA) testing is positive. Acute hepatitis C is less common and can be associated with spontaneous clearance. Estimates of spontaneous clearance rates are lower, however, among persons with HIV than in those who are mono-infected.3 Rates of perinatal transmission of hepatitis C are approximately 20% for HIV-infected mothers co-infected with hepatitis C, considerably more than for HCV mono-infected mothers.4
Substantial progress has been made in the treatment of hepatitis C, and more patients are having sustained virologic responses (SVRs) with combination weekly pegylated interferon and twice-daily oral ribavirin therapy. Most of these patients with SVR are thought to be cured of their hepatitis C. Clinical trials involving co-infected patients have informed treatment guidelines, including those of the New York State Department of Health AIDS Institute.5
Pegylated interferon and ribavirin have greatly improved treatment responses, especially for persons with HCV genotypes 2 and 3. Updated recommendations in these guidelines (see the following sections of this document) include annual HCV antibody testing for persons with continued high-risk behaviors, such as injection drug use and multiple sexual partners; quantitative viral load testing to confirm a reactive HCV antibody result on enzyme-linked immunosorbent assay (ELISA) or enzyme immunoassay (EIA); and consultation with a mental health professional when prescribing anti-HCV therapy for persons with mental health disorders. A section on baseline assessment has been added (Section 8: Hepatitis C Treatment and Treatment Monitoring), along with a table on treatment recommendations based on liver biopsy results (Table 4) and updates on algorithms for the diagnosis of hepatitis C (Figure 1) and for guiding therapeutic decisions on the basis of HCV RNA responses to treatment (Figure 2).
In summary, we should now be looking for reasons to treat our HIV/HCV co-infected patients, as opposed to looking for reasons not to treat. The therapeutic pipeline for newer anti-HCV therapies -- such as telaprevir, an oral protease inhibitor -- is rich, and these therapies will have to be studied in co-infected populations for safety, tolerability, efficacy, and pharmacokinetic interactions with available antiretroviral medications.
Related Resources
• Hepatitis A Virus
• Hepatitis B Virus
• Hepatitis C Virus
References
1.Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients co-infected with human immunodeficiency virus: A cross-sectional analysis of the U.S. Adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34:831-837.
2.Centers for Disease Control and Prevention. Recommendations for the prevention and control of hepatitis C virus (HCV) infection and HCV related disease. MMWR Recomm Rep. 1998;47(RR-19):1-39.
3.Piasecki BA, Lewis JD, Reddy KR, et al. Influence of alcohol use, race, and viral co-infections on spontaneous HCV clearance in a U.S. veteran population. Hepatology. 2004;40:892-899.
4.National Institutes of Health. NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements. 2002;19:1-46.
5.Medical Care Criteria Committee. Hepatitis C. New York State Department of Health AIDS Institute. Available at: http://www.hivguidelines.org/clinical-guidelines/ Accessed October 27, 2010.
Hepatitis C Virus: Guideline for Care
Editor's Note: This guideline was prepared and published by the New York State Department of Health AIDS Institute HIV Clinical Guidelines Program. It has been republished here. Please note that recommendations are assigned an evidence-based rating and use the rating scheme developed by the Department of Health and Human Services.
What's New in the Latest Update (May 2010)
Significant revisions [to this guideline] include the following:
• An annual HCV antibody test is now recommended for HIV-infected patients who have continued high-risk behaviors but are seronegative for HCV; such individuals include:
◦ Injection drug users
◦ Men who have sex with men (MSM) and don't use barrier protection
◦ Anyone with multiple sexual partners
• Quantitative HCV RNA viral load testing is now recommended for HIV-infected patients:
◦ To confirm a reactive HCV ELISA antibody screen
◦ To exclude HCV infection in those who are seronegative for HCV but have risk factors for HCV exposure and unexplained liver disease, including increased serum liver enzymes
• A table has been added that lists the tests for measuring HCV RNA (see Table 1)
• Figure 1. HCV Testing Algorithm for HIV-Infected Patients has been updated
• Assessment for anti-HCV therapy is now recommended for HIV-infected patients with acute HCV infection (see Section 6: Deciding Whether to Treat HCV in HIV-Infected Patients)
• Sections on assessment of mental health disorders and alcohol and substance use have been added (see Section 5: Evaluation and Initial Management of Confirmed Hepatitis C Infection)
• A new section has been added on ongoing evaluation of patients when anti-HCV therapy is deferred (see Section 7: Ongoing Evaluation of Patients in Whom Anti-HCV Treatment Is Deferred)
• A new section has been added that outlines baseline assessments and counseling at initiation of therapy (see Section 8: Hepatitis C Treatment and Treatment Monitoring)
• Consultation with a psychiatrist is now recommended when prescribing anti-HCV therapy for HIV-infected patients with mental health disorders
• Figure 2. Initial Anti-HCV Therapy for HIV/HCV Co-infected Patients has been updated and now recommends determining whether or not to continue anti-HCV treatment after week 12 by assessing for virologic response according to quantitative HCV RNA
• A table has been added that outlines strategies for managing side effects of anti-HCV therapy (see Table 7)
Introduction
Hepatitis C virus (HCV) is a common cause of death from liver disease among the HIV-infected population.[1] Approximately 15% to 30% of people with HIV are estimated to be co-infected with HCV in the United States.[2] The rate is much higher among patients infected with HIV through injection drug use (approximately 70% to 90%) or individuals with hemophilia who received factor concentrates before 1987.[3] Data collected from the ACTG A5001 cohort demonstrate that HIV/HCV co-infected patients visit the emergency department more frequently, are hospitalized more often, and have longer hospital stays than HIV mono-infected patients.[4] Other studies have established HCV-related end-stage liver disease as a leading cause of in-hospital mortality among HIV-infected patients.[5-7]
Therapy for HCV has become increasingly successful. However, anti-HCV therapy is complex, particularly in the presence of HIV, and requires many treatment considerations, as well as careful monitoring.
Key Point
The similar routes of exposure for HIV and HCV place patients with either infection at risk for HIV/HCV co-infection.
Natural History of Hepatitis C Virus
HCV and HIV are both RNA viruses but belong to different viral families (Flaviviridae and Retroviridae, respectively) and have very different life cycles.[8] Like HIV, HCV mutates frequently, establishing a genetically diverse population of viral quasi-species within each infected host. This genetic diversity is at least partly responsible for the ability of HCV to evade the body’s immune defenses and establish chronic infection. Unlike HIV, HCV RNA replicates in the cytoplasm of its host cell, the hepatocyte. This mode of genetic replication prevents incorporation of the HCV genome into the hepatocyte, enabling possible clearance of HCV from plasma and eradication of infection.
Acute HCV Infection
Acute HCV disease is often asymptomatic, with 25% to 35% of HCV mono-infected patients developing only mild constitutional symptoms or jaundice. Symptoms may be even milder or occur less frequently in HIV-infected patients. This lower incidence of symptomatic presentation in HIV-infected patients has been attributed in part to a weaker immune response compared with HCV mono-infected patients. Patients who experience symptoms, which are suggestive of a stronger immune response, have demonstrated better clinical outcomes in comparison with patients who are asymptomatic during acute HCV infection.[9]
The acute phase is defined as the first 6 months of HCV infection. During this time, serum alanine aminotransferase (ALT) levels frequently rise, fluctuate, and fall again, which indicates recovery from the acute phase. Estimates of spontaneous HCV clearance without treatment are 15% to 45% in non-HIV-infected adults and 11.5% in HIV-infected adults.[10] Likelihood of HCV clearance among HIV-infected individuals is diminished in patients with lower CD4 cell counts, especially CD4 <200 cells/mm3.[11] Treatment of acute HCV infection in HIV-infected adults is supported by a 60% to 70% SVR rate.[12]
Chronic HCV Infection
Chronic infection arises in individuals who do not clear the virus during acute infection. Two thirds of patients with chronic infection develop persistent or fluctuating serum ALT elevations, which are indicative of active liver inflammation. Because serum ALT levels may normalize intermittently, a single normal serum ALT level does not indicate that liver damage is absent. In contrast to many other liver diseases, the degree of ALT elevation in HCV-infected individuals frequently fails to correlate with the degree of liver inflammation observed on liver biopsy.
Key Point
Up to 30% of patients with either HCV mono-infection or HIV/HCV co-infection may have persistently normal liver chemistries but still have significant liver disease.[13]
Histologic Damage in Chronic HCV Infection. Chronic HCV infection can cause inflammatory infiltration, particularly of the portal tracts, as well as both focal and bridging necrosis and fibrosis. Typically, chronic HCV infection results in a lymphocyte-predominant inflammatory infiltrate in the portal tracts and periportal regions of the liver. Inflammation may activate hepatic stellate cells to produce collagen. This, in turn, leads to the deposition of fibrous tissue first in the portal tracts and then in periportal regions. In more advanced stages of fibrosis, bridging fibrosis between portal tracts is present, and, in more advanced cirrhosis, fibrotic nodules are also present.
Cirrhosis and Hepatocellular Carcinoma in HCV Infection. Approximately 10% to 15% of patients with HCV infection will progress to cirrhosis after 20 years of infection.[13] After development of cirrhosis from HCV, hepatocellular carcinoma (HCC) occurs at an estimated rate of 0% to 3% per year. The incidence of HCC from any cause of cirrhosis in the United States increased from 1.6 per 100,000 in 1975 to 4.9 per 100,000 in 2005; among black men, the incidence was 7.0 per 100,000 in 2005.[14]
Key Point
Progression to cirrhosis occurs more quickly in men, in patients who use alcohol, in those who acquire HCV after 40 years of age, and in HIV/HCV co-infected patients.[13]
HCV Genotypes. HCV exists in 6 known genotypes and over 50 genotypic subtypes. Approximately 70% of patients with HCV in the United States are infected with genotypes 1 and 4, with genotypic subtype 1a being more common than subtype 1b. Ninety-one percent of HCV-infected non-Hispanic blacks were infected with genotype 1 in the third National Health and Nutrition Examination Survey (NHANES III).[15] Although there are no known differences in clinical course among the various genotypes and subtypes, genotypes 1 and 4 are known to have a poorer response to interferon-based therapy than genotypes 2 and 3.
Routes of Transmission of Hepatitis C Virus
Parenteral Transmission. Parenteral transmission is the primary route for HCV infection. Injection drug use accounts for at least 60% of all new infections in the United States. In some populations of injecting drug users, >80% have been infected with HCV; however, lower prevalence has been found in other populations, particularly among young users.[16] Patients should be advised to avoid sharing any injection or drug preparation equipment. Although HCV transmission may be reduced through cleansing shared syringes with bleach and water between uses,[17] HCV can also be transmitted through the use of other equipment, including cookers (metal bottle caps), water for dissolving drugs and rinsing syringes, cotton for filtering the solution, and tourniquets.
The risk for HCV infection from injury with an HCV-contaminated needle is 1.8%.[13] For information regarding management of occupational exposure to HCV, refer to HIV Prophylaxis Following Occupational Exposure .
Sexual Transmission. The efficiency of sexual transmission of HCV is much lower than HIV or other sexually transmitted viruses. However, isolated outbreaks of permucosal HCV transmission have been reported among HIV-infected MSM.[18-23] In the setting of the following risk factors, HCV transmission was increased among HIV-infected MSM compared with non-HIV-infected MSM: sharing drugs via anal or intranasal routes; unprotected anal intercourse and anal/oral (“rimming”) or anal/hand contact (“fisting”); and the presence of other sexually transmitted infections (STIs).
Among non-HIV-infected, monogamous, heterosexual couples who are discordant for HCV, the risk for sexual HCV transmission is estimated to be 0% to 0.6% annually.[13] Limited data suggest that the presence of HIV does not increase the risk for sexual HCV transmission amount heterosexual couples.[24] Some studies have shown that long-term, monogamous partners of HCV-infected individuals (>10 years) have slightly higher rates of HCV infection than the general population; however, the rate remains low (1.5%).[25,26]
Key Point
Guidelines indicating that barrier protection may not be necessary between HCV-discordant sexual partners apply only in the setting of HCV mono-infection and do not apply in the setting of HIV/HCV co-infection.
Perinatal Transmission. Maternal-fetal transmission of HCV in mono-infected women with detectable HCV RNA at delivery is approximately 4% to 7%. However, HIV co-infection increases the risk for perinatal transmission to 20%.[13]
Nonsexual Household Transmission. Nonsexual household transmission is rare in the United States, although it has been known to occur, probably through inadvertent exposure to blood or infectious body fluids.
Continue Reading.....
Posted: 01/05/2011
HIV and Hepatitis C: Expert Commentary
Approximately 15% to 30% of people with HIV are estimated to be co-infected with hepatitis C virus (HCV) in the United States, and up to 90% of those with HIV secondary to injection drug use are co-infected.1,2 Chronic liver disease from co-infection, including cirrhosis and hepatocellular carcinoma, leads to significant morbidity and mortality.
Most patients who are co-infected with hepatitis C are diagnosed with chronic disease. This is diagnosed when the hepatitis C antibody is reactive and subsequent viral load (RNA) testing is positive. Acute hepatitis C is less common and can be associated with spontaneous clearance. Estimates of spontaneous clearance rates are lower, however, among persons with HIV than in those who are mono-infected.3 Rates of perinatal transmission of hepatitis C are approximately 20% for HIV-infected mothers co-infected with hepatitis C, considerably more than for HCV mono-infected mothers.4
Substantial progress has been made in the treatment of hepatitis C, and more patients are having sustained virologic responses (SVRs) with combination weekly pegylated interferon and twice-daily oral ribavirin therapy. Most of these patients with SVR are thought to be cured of their hepatitis C. Clinical trials involving co-infected patients have informed treatment guidelines, including those of the New York State Department of Health AIDS Institute.5
Pegylated interferon and ribavirin have greatly improved treatment responses, especially for persons with HCV genotypes 2 and 3. Updated recommendations in these guidelines (see the following sections of this document) include annual HCV antibody testing for persons with continued high-risk behaviors, such as injection drug use and multiple sexual partners; quantitative viral load testing to confirm a reactive HCV antibody result on enzyme-linked immunosorbent assay (ELISA) or enzyme immunoassay (EIA); and consultation with a mental health professional when prescribing anti-HCV therapy for persons with mental health disorders. A section on baseline assessment has been added (Section 8: Hepatitis C Treatment and Treatment Monitoring), along with a table on treatment recommendations based on liver biopsy results (Table 4) and updates on algorithms for the diagnosis of hepatitis C (Figure 1) and for guiding therapeutic decisions on the basis of HCV RNA responses to treatment (Figure 2).
In summary, we should now be looking for reasons to treat our HIV/HCV co-infected patients, as opposed to looking for reasons not to treat. The therapeutic pipeline for newer anti-HCV therapies -- such as telaprevir, an oral protease inhibitor -- is rich, and these therapies will have to be studied in co-infected populations for safety, tolerability, efficacy, and pharmacokinetic interactions with available antiretroviral medications.
Related Resources
• Hepatitis A Virus
• Hepatitis B Virus
• Hepatitis C Virus
References
1.Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients co-infected with human immunodeficiency virus: A cross-sectional analysis of the U.S. Adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34:831-837.
2.Centers for Disease Control and Prevention. Recommendations for the prevention and control of hepatitis C virus (HCV) infection and HCV related disease. MMWR Recomm Rep. 1998;47(RR-19):1-39.
3.Piasecki BA, Lewis JD, Reddy KR, et al. Influence of alcohol use, race, and viral co-infections on spontaneous HCV clearance in a U.S. veteran population. Hepatology. 2004;40:892-899.
4.National Institutes of Health. NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements. 2002;19:1-46.
5.Medical Care Criteria Committee. Hepatitis C. New York State Department of Health AIDS Institute. Available at: http://www.hivguidelines.org/clinical-guidelines/ Accessed October 27, 2010.
Hepatitis C Virus: Guideline for Care
Editor's Note: This guideline was prepared and published by the New York State Department of Health AIDS Institute HIV Clinical Guidelines Program. It has been republished here. Please note that recommendations are assigned an evidence-based rating and use the rating scheme developed by the Department of Health and Human Services.
What's New in the Latest Update (May 2010)
Significant revisions [to this guideline] include the following:
• An annual HCV antibody test is now recommended for HIV-infected patients who have continued high-risk behaviors but are seronegative for HCV; such individuals include:
◦ Injection drug users
◦ Men who have sex with men (MSM) and don't use barrier protection
◦ Anyone with multiple sexual partners
• Quantitative HCV RNA viral load testing is now recommended for HIV-infected patients:
◦ To confirm a reactive HCV ELISA antibody screen
◦ To exclude HCV infection in those who are seronegative for HCV but have risk factors for HCV exposure and unexplained liver disease, including increased serum liver enzymes
• A table has been added that lists the tests for measuring HCV RNA (see Table 1)
• Figure 1. HCV Testing Algorithm for HIV-Infected Patients has been updated
• Assessment for anti-HCV therapy is now recommended for HIV-infected patients with acute HCV infection (see Section 6: Deciding Whether to Treat HCV in HIV-Infected Patients)
• Sections on assessment of mental health disorders and alcohol and substance use have been added (see Section 5: Evaluation and Initial Management of Confirmed Hepatitis C Infection)
• A new section has been added on ongoing evaluation of patients when anti-HCV therapy is deferred (see Section 7: Ongoing Evaluation of Patients in Whom Anti-HCV Treatment Is Deferred)
• A new section has been added that outlines baseline assessments and counseling at initiation of therapy (see Section 8: Hepatitis C Treatment and Treatment Monitoring)
• Consultation with a psychiatrist is now recommended when prescribing anti-HCV therapy for HIV-infected patients with mental health disorders
• Figure 2. Initial Anti-HCV Therapy for HIV/HCV Co-infected Patients has been updated and now recommends determining whether or not to continue anti-HCV treatment after week 12 by assessing for virologic response according to quantitative HCV RNA
• A table has been added that outlines strategies for managing side effects of anti-HCV therapy (see Table 7)
Introduction
Hepatitis C virus (HCV) is a common cause of death from liver disease among the HIV-infected population.[1] Approximately 15% to 30% of people with HIV are estimated to be co-infected with HCV in the United States.[2] The rate is much higher among patients infected with HIV through injection drug use (approximately 70% to 90%) or individuals with hemophilia who received factor concentrates before 1987.[3] Data collected from the ACTG A5001 cohort demonstrate that HIV/HCV co-infected patients visit the emergency department more frequently, are hospitalized more often, and have longer hospital stays than HIV mono-infected patients.[4] Other studies have established HCV-related end-stage liver disease as a leading cause of in-hospital mortality among HIV-infected patients.[5-7]
Therapy for HCV has become increasingly successful. However, anti-HCV therapy is complex, particularly in the presence of HIV, and requires many treatment considerations, as well as careful monitoring.
Key Point
The similar routes of exposure for HIV and HCV place patients with either infection at risk for HIV/HCV co-infection.
Natural History of Hepatitis C Virus
HCV and HIV are both RNA viruses but belong to different viral families (Flaviviridae and Retroviridae, respectively) and have very different life cycles.[8] Like HIV, HCV mutates frequently, establishing a genetically diverse population of viral quasi-species within each infected host. This genetic diversity is at least partly responsible for the ability of HCV to evade the body’s immune defenses and establish chronic infection. Unlike HIV, HCV RNA replicates in the cytoplasm of its host cell, the hepatocyte. This mode of genetic replication prevents incorporation of the HCV genome into the hepatocyte, enabling possible clearance of HCV from plasma and eradication of infection.
Acute HCV Infection
Acute HCV disease is often asymptomatic, with 25% to 35% of HCV mono-infected patients developing only mild constitutional symptoms or jaundice. Symptoms may be even milder or occur less frequently in HIV-infected patients. This lower incidence of symptomatic presentation in HIV-infected patients has been attributed in part to a weaker immune response compared with HCV mono-infected patients. Patients who experience symptoms, which are suggestive of a stronger immune response, have demonstrated better clinical outcomes in comparison with patients who are asymptomatic during acute HCV infection.[9]
The acute phase is defined as the first 6 months of HCV infection. During this time, serum alanine aminotransferase (ALT) levels frequently rise, fluctuate, and fall again, which indicates recovery from the acute phase. Estimates of spontaneous HCV clearance without treatment are 15% to 45% in non-HIV-infected adults and 11.5% in HIV-infected adults.[10] Likelihood of HCV clearance among HIV-infected individuals is diminished in patients with lower CD4 cell counts, especially CD4 <200 cells/mm3.[11] Treatment of acute HCV infection in HIV-infected adults is supported by a 60% to 70% SVR rate.[12]
Chronic HCV Infection
Chronic infection arises in individuals who do not clear the virus during acute infection. Two thirds of patients with chronic infection develop persistent or fluctuating serum ALT elevations, which are indicative of active liver inflammation. Because serum ALT levels may normalize intermittently, a single normal serum ALT level does not indicate that liver damage is absent. In contrast to many other liver diseases, the degree of ALT elevation in HCV-infected individuals frequently fails to correlate with the degree of liver inflammation observed on liver biopsy.
Key Point
Up to 30% of patients with either HCV mono-infection or HIV/HCV co-infection may have persistently normal liver chemistries but still have significant liver disease.[13]
Histologic Damage in Chronic HCV Infection. Chronic HCV infection can cause inflammatory infiltration, particularly of the portal tracts, as well as both focal and bridging necrosis and fibrosis. Typically, chronic HCV infection results in a lymphocyte-predominant inflammatory infiltrate in the portal tracts and periportal regions of the liver. Inflammation may activate hepatic stellate cells to produce collagen. This, in turn, leads to the deposition of fibrous tissue first in the portal tracts and then in periportal regions. In more advanced stages of fibrosis, bridging fibrosis between portal tracts is present, and, in more advanced cirrhosis, fibrotic nodules are also present.
Cirrhosis and Hepatocellular Carcinoma in HCV Infection. Approximately 10% to 15% of patients with HCV infection will progress to cirrhosis after 20 years of infection.[13] After development of cirrhosis from HCV, hepatocellular carcinoma (HCC) occurs at an estimated rate of 0% to 3% per year. The incidence of HCC from any cause of cirrhosis in the United States increased from 1.6 per 100,000 in 1975 to 4.9 per 100,000 in 2005; among black men, the incidence was 7.0 per 100,000 in 2005.[14]
Key Point
Progression to cirrhosis occurs more quickly in men, in patients who use alcohol, in those who acquire HCV after 40 years of age, and in HIV/HCV co-infected patients.[13]
HCV Genotypes. HCV exists in 6 known genotypes and over 50 genotypic subtypes. Approximately 70% of patients with HCV in the United States are infected with genotypes 1 and 4, with genotypic subtype 1a being more common than subtype 1b. Ninety-one percent of HCV-infected non-Hispanic blacks were infected with genotype 1 in the third National Health and Nutrition Examination Survey (NHANES III).[15] Although there are no known differences in clinical course among the various genotypes and subtypes, genotypes 1 and 4 are known to have a poorer response to interferon-based therapy than genotypes 2 and 3.
Routes of Transmission of Hepatitis C Virus
Parenteral Transmission. Parenteral transmission is the primary route for HCV infection. Injection drug use accounts for at least 60% of all new infections in the United States. In some populations of injecting drug users, >80% have been infected with HCV; however, lower prevalence has been found in other populations, particularly among young users.[16] Patients should be advised to avoid sharing any injection or drug preparation equipment. Although HCV transmission may be reduced through cleansing shared syringes with bleach and water between uses,[17] HCV can also be transmitted through the use of other equipment, including cookers (metal bottle caps), water for dissolving drugs and rinsing syringes, cotton for filtering the solution, and tourniquets.
The risk for HCV infection from injury with an HCV-contaminated needle is 1.8%.[13] For information regarding management of occupational exposure to HCV, refer to HIV Prophylaxis Following Occupational Exposure .
Sexual Transmission. The efficiency of sexual transmission of HCV is much lower than HIV or other sexually transmitted viruses. However, isolated outbreaks of permucosal HCV transmission have been reported among HIV-infected MSM.[18-23] In the setting of the following risk factors, HCV transmission was increased among HIV-infected MSM compared with non-HIV-infected MSM: sharing drugs via anal or intranasal routes; unprotected anal intercourse and anal/oral (“rimming”) or anal/hand contact (“fisting”); and the presence of other sexually transmitted infections (STIs).
Among non-HIV-infected, monogamous, heterosexual couples who are discordant for HCV, the risk for sexual HCV transmission is estimated to be 0% to 0.6% annually.[13] Limited data suggest that the presence of HIV does not increase the risk for sexual HCV transmission amount heterosexual couples.[24] Some studies have shown that long-term, monogamous partners of HCV-infected individuals (>10 years) have slightly higher rates of HCV infection than the general population; however, the rate remains low (1.5%).[25,26]
Key Point
Guidelines indicating that barrier protection may not be necessary between HCV-discordant sexual partners apply only in the setting of HCV mono-infection and do not apply in the setting of HIV/HCV co-infection.
Perinatal Transmission. Maternal-fetal transmission of HCV in mono-infected women with detectable HCV RNA at delivery is approximately 4% to 7%. However, HIV co-infection increases the risk for perinatal transmission to 20%.[13]
Nonsexual Household Transmission. Nonsexual household transmission is rare in the United States, although it has been known to occur, probably through inadvertent exposure to blood or infectious body fluids.
Continue Reading.....
Hepatitis C virus infection during pregnancy and the newborn period – are they opportunities for treatment?
Journal of Viral Hepatitis
Early View (Articles online in advance of print)
M. Arshad 1, S. S. El-Kamary 2,3,4, R. Jhaveri 1,5
Article first published online: 7 JAN 2011
DOI: 10.1111/j.1365-2893.2010.01413.x
© 2011 Blackwell Publishing Ltd
Author Information
1 Division of Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC
2 Department of Epidemiology and Public Health
3 Department of Pediatrics
4 Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD
5 Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
* Correspondence: Ravi Jhaveri MD, Division of Pediatric Infectious Diseases, Duke University Medical Center, DUMC 3499, Durham, NC 27710, USA. E-mail: ravi.jhaveri@duke.edu
Abstract
Keywords: hepatitis C virus; infants;pregnancy; treatment; vertical transmission
Summary. The worldwide prevalence of hepatitis C virus (HCV) infection in pregnant women is estimated to be between 1 and 8% and in children between 0.05% and 5%. While parenteral transmission is still common in children living in developing countries, perinatal transmission is now the leading cause of HCV transmission in developed countries. The absence of an HCV vaccine or approved therapy during pregnancy means that prevention of vertical transmission is still not possible. However, a low vertical transmission rate of 3–5%, a high rate of spontaneous clearance (25–50%) and delayed morbidity have resulted in HCV being overlooked in pregnant women and their infants. Yet a study of the natural history in mothers and children demonstrates that the prognosis of HCV can vary greatly and should be taken seriously. Factors known to increase the risk of perinatal transmission include HIV coinfection and higher maternal viral loads, while elective C-section and withholding breastfeeding have not been demonstrated to reduce vertical transmission. Current guidelines for the diagnosis of persistent perinatal infection require a positive anti-HCV test in infants born to infected mothers after 12 months or two positive HCV RNA tests at least 6 months apart. Current HCV treatment options using pegylated interferon and ribavirin are both unsuitable for use in pregnancy and infancy. However, new agents currently in preclinical phases of development, along with the recently identified association between single-nucleotide polymorphisms within the IL28 gene and treatment response, may serve to create a therapeutic window for these patients
Source
Early View (Articles online in advance of print)
M. Arshad 1, S. S. El-Kamary 2,3,4, R. Jhaveri 1,5
Article first published online: 7 JAN 2011
DOI: 10.1111/j.1365-2893.2010.01413.x
© 2011 Blackwell Publishing Ltd
Author Information
1 Division of Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC
2 Department of Epidemiology and Public Health
3 Department of Pediatrics
4 Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD
5 Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
* Correspondence: Ravi Jhaveri MD, Division of Pediatric Infectious Diseases, Duke University Medical Center, DUMC 3499, Durham, NC 27710, USA. E-mail: ravi.jhaveri@duke.edu
Abstract
Keywords: hepatitis C virus; infants;pregnancy; treatment; vertical transmission
Summary. The worldwide prevalence of hepatitis C virus (HCV) infection in pregnant women is estimated to be between 1 and 8% and in children between 0.05% and 5%. While parenteral transmission is still common in children living in developing countries, perinatal transmission is now the leading cause of HCV transmission in developed countries. The absence of an HCV vaccine or approved therapy during pregnancy means that prevention of vertical transmission is still not possible. However, a low vertical transmission rate of 3–5%, a high rate of spontaneous clearance (25–50%) and delayed morbidity have resulted in HCV being overlooked in pregnant women and their infants. Yet a study of the natural history in mothers and children demonstrates that the prognosis of HCV can vary greatly and should be taken seriously. Factors known to increase the risk of perinatal transmission include HIV coinfection and higher maternal viral loads, while elective C-section and withholding breastfeeding have not been demonstrated to reduce vertical transmission. Current guidelines for the diagnosis of persistent perinatal infection require a positive anti-HCV test in infants born to infected mothers after 12 months or two positive HCV RNA tests at least 6 months apart. Current HCV treatment options using pegylated interferon and ribavirin are both unsuitable for use in pregnancy and infancy. However, new agents currently in preclinical phases of development, along with the recently identified association between single-nucleotide polymorphisms within the IL28 gene and treatment response, may serve to create a therapeutic window for these patients
Source
January 7, 2011
Liver Disease a Possible Predictor of Stroke
ScienceDaily (Jan. 7, 2011) — People suffering from fatty liver disease may be three times more likely to suffer a stroke than individuals without fatty liver, according to a study by researchers at St. Michael's Hospital and the London Health Sciences Centre. The study is the first to find a link between nonalcoholic fatty liver disease -- a disease characterized by the accumulation of fat in the liver in non drinkers -- and stroke.
In a research letter to the editor in the journal Epidemiology released January 6, Drs. Joel Ray, Ivan Ying and colleagues explain they found high levels of enzymes known to be markers of liver disease in adults who had an acute stroke. Between 2005 and 2009, they reviewed 103 consecutive adults who had an MRI-proven acute stroke between 2005 and 2009 and compared them to 200 adults with suspected acute stroke, but whose MRI was normal, thereby ruling out acute stroke.
"The risk of stroke in relation to fatty liver disease has never been tested," Dr. Ray says. "Our study shows a strong link between the two and the possibility in future that currently available blood liver enzyme tests, or novel markers of fatty liver, may be used to predict the risk of stroke and help us better care for and treat at risk patients."
Nonalcoholic fatty liver disease is a common condition that often has no symptoms or complications. Risk factors include obesity, high cholesterol, diabetes and, especially, insulin resistance.
While the findings are promising, additional research is needed to validate the study's findings, Dr. Ray said.
Source
In a research letter to the editor in the journal Epidemiology released January 6, Drs. Joel Ray, Ivan Ying and colleagues explain they found high levels of enzymes known to be markers of liver disease in adults who had an acute stroke. Between 2005 and 2009, they reviewed 103 consecutive adults who had an MRI-proven acute stroke between 2005 and 2009 and compared them to 200 adults with suspected acute stroke, but whose MRI was normal, thereby ruling out acute stroke.
"The risk of stroke in relation to fatty liver disease has never been tested," Dr. Ray says. "Our study shows a strong link between the two and the possibility in future that currently available blood liver enzyme tests, or novel markers of fatty liver, may be used to predict the risk of stroke and help us better care for and treat at risk patients."
Nonalcoholic fatty liver disease is a common condition that often has no symptoms or complications. Risk factors include obesity, high cholesterol, diabetes and, especially, insulin resistance.
While the findings are promising, additional research is needed to validate the study's findings, Dr. Ray said.
Source
Liver Disease in the HIV-Infected Individual REVIEW
Download the PDF here
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Dec 2010;8:1002-1012
JENNIFER C. PRICE* and CHLOE L. THIO
*Division of Gastroenterology and Hepatology and Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
"Liver disease among HIV-infected individuals is a common and important cause of non-AIDS-related morbidity and mortality. In the ART era, the spectrum of liver disease among patients with HIV infection has changed dramatically, shifting from opportunistic infections to sequelae of chronic infections, medication toxicities, alcohol use, and fatty liver. Management of HIV-infected patients requires recognition of these conditions and targeted diagnosis and treatment."
Since the advent of effective antiretroviral therapy (ART) for human immunodeficiency virus-1 (HIV), there has been a substantial decrease in deaths related to acquired immunodeficiency syndrome (AIDS). However, in the ART era, liver disease is now the most common non-AIDS-related cause of death among HIV-infected patients, accounting for 14%-18% of all deaths in this population and almost half of deaths among hospitalized HIV-infected patients. Just as the burden of non-AIDS morbidity and mortality has changed in the ART era, the types of liver disease the clinician is likely to encounter among these patients have changed as well. This review will discuss the causes of liver disease in the HIV-infected population in the ART era, including chronic hepatitis C virus, chronic hepatitis B virus, medication-related hepatotoxicity, alcohol abuse, nonalcoholic fatty liver disease, and AIDS-related liver diseases.
Managing liver disease is an increasingly important component to the care of individuals infected with human immunodeficiency virus-1 (HIV). Since the advent of effective antiretroviral therapy (ART) for HIV, there has been a substantial decrease in deaths related to acquired immunodeficiency syndrome (AIDS).1, 2, 3 However, liver disease has emerged as the most common non-AIDS-related cause of death among HIV-infected patients, accounting for 14%-18% of all deaths.3, 4 In some series, nearly half of deaths among hospitalized HIV-infected patients in the ART era have been attributed to liver disease.5, 6
Just as the burden of non-AIDS morbidity and mortality has changed in the ART era, the types of liver disease the clinician is likely to encounter among these patients have also changed.7 Before ART, the most common causes of liver dysfunction in HIV-infected patients were opportunistic infections, including cytomegalovirus (CMV) and mycobacterium infections, and AIDS-related neoplasms such as lymphoma and Kaposi's sarcoma (KS).8, 9 Since the ART era, however, the spectrum of liver disease among HIV-infected individuals has shifted to concomitant infection with chronic HCV, chronic HBV, medication-related hepatotoxicity, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD) (Table 1).7, 10, 11 This review will focus on the major causes of liver disease in the HIV-infected population in the ART era and will briefly review liver disease in persons with AIDS.
Viral Hepatitis
Hepatitis C Virus
Most liver disease among HIV-infected individuals is secondary to coinfection with HCV and/or HBV.12 Because of shared risk factors, coinfection with HCV and HIV is common. Reported prevalence rates of HIV-HCV coinfection vary depending on the route of HIV transmission, from 10% among those with high-risk sexual behavior to 90% with injection drug use.13 Overall, approximately 30% of HIV-infected individuals in the United States and Europe are coinfected with HCV.14
HIV infection alters the natural history of HCV in several ways. HIV-infected patients who are acutely infected with HCV are half as likely as HIV-uninfected individuals to clear HCV viremia.15 Coinfected individuals also have higher HCV RNA levels, accelerated progression to hepatic fibrosis, an increased risk of developing cirrhosis, and a higher risk of decompensated liver disease once cirrhotic.16, 17, 18 In a meta-analysis of 8 studies, HIV-HCV coinfected subjects had a 2-fold increased risk of histologic cirrhosis and 5-fold increased risk of decompensated liver disease compared with HCV-monoinfected individuals.19 Studies of the role of HCV on the natural history of HIV have been conflicting. However, in a recent analysis of 1428 HIV-HCV coinfected individuals treated for HCV, patients who achieved sustained virologic response had lower rates of HIV progression and nonliver mortality after adjusting for fibrosis, Centers for Disease Control and Prevention clinical category, and nadir CD4 count.20
Given both the high prevalence of HCV among the HIV-infected population and the impact of HIV on HCV-related liver disease progression, all HIV-infected patients should be tested for chronic HCV infection by using third-generation enzyme immunoassays, followed by quantitative HCV RNA testing if positive. Although third-generation immunoassays are highly sensitive, even in the setting of HIV infection (>99%), HCV RNA should be checked in patients with significant risk factors for HCV and advanced immunosuppression or in whom acute infection is suspected.21 During the past decade, outbreaks of sexually transmitted HCV among noninjection-drug-using men who have sex with men have been reported in Europe, the United States, and Australia; men who have sex with men should therefore be considered at risk for acquiring HCV.22 Because there is no available vaccine to prevent HCV infection, HIV-infected individuals who test negative for HCV should be counseled to avoid risk factors for HCV infection. For individuals who test positive for HCV, the extent of liver disease should be determined. Aminotransferase levels are not sensitive for fibrosis in the setting of HIV infection; therefore, liver biopsy remains the preferred modality for staging disease among coinfected patients.
Because of the limitations and invasiveness of liver biopsy, noninvasive methods to determine liver disease are being actively investigated and are becoming a viable alternative to liver biopsy. A variety of laboratory markers have been studied as potential surrogates for hepatic fibrosis; most were derived from studies in individuals without HIV infection. A meta-analysis of studies of the markers in the HIV-HCV coinfected population suggested that they might be useful in excluding cirrhosis if used at their most sensitive thresholds; however, their diagnostic odds ratios were suboptimal.23 Transient elastography (TE) uses ultrasound technology to estimate liver stiffness by measuring elastic shear wave velocity through the liver. In a study of 169 HIV-HCV coinfected patients, TE accurately detected significant fibrosis and cirrhosis but was less accurate in discriminating mild from significant fibrosis.24
The decision to treat HCV in the HIV-infected patient should be made on an individual basis, because the benefits must be weighed against safety and efficacy concerns. HCV treatment should be prioritized in coinfected patients without decompensated cirrhosis who have a liver biopsy revealing portal fibrosis or more advanced disease.25 Women of child-bearing age might desire treatment before becoming pregnant, because pregnancy must be avoided during and 6 months after anti-HCV therapy because of ribavirin teratogenicity. Because they usually have favorable treatment responses, patients with HCV genotype 2 or 3 who are motivated and can tolerate treatment should be offered it regardless of liver disease stage. Certain IL28B genotypes respond well to treatment and so might also become an indication to treat without liver disease staging.26 Early treatment of acute HCV infection has also been associated with improved response rates in HIV-infected individuals.27 Patients with decompensated cirrhosis should be referred to a liver transplant center with experience in transplantation with HIV infection.
The current Food and Drug Administration-approved treatment for HCV in the setting of HIV infection is pegylated interferon alfa and ribavirin, which is the standard of care based on 4 large randomized trials.28, 29, 30, 31 This regimen is less effective in HIV-infected patients, with sustained virologic response rates ranging from 14%-38% among those with HCV genotype 1 infection and 44%-73% among genotype 2 and 3 infections. Similar to HCV-monoinfected individuals, genotype, baseline HCV RNA, and early response to therapy are predictors of treatment response.28 In patients receiving HCV treatment, didanosine (ddI) is contraindicated and zidovudine is not recommended, because ribavirin potentiates the risk of mitochondrial toxicity and anemia, respectively.32 Stavudine should also be avoided in patients receiving HCV treatment because of the risk of steatosis.33 Abacavir has been associated with decreased SVR, possibly as a result of competition with ribavirin because both are guanosine analogues.34, 35, 36 However, this competitive interaction appears to be insignificant when weight-based ribavirin dosing is used.37, 38
Although HCV-infected patients have a higher incidence of ART-related liver toxicity, this infrequently leads to ART discontinuation, and the benefits of ART for HIV treatment are profound; therefore, ART should not be withheld in the coinfected population. In addition, ART might have beneficial effects on the progression of liver disease in HIV-HCV coinfection, because improvement in CD4 count might decrease fibrosis progression, although studies investigating this have been inconsistent. A recent systematic review of 11 studies examined the impact of ART on liver disease in HIV-HCV coinfection; 3 associated ART with less severe fibrosis, 6 failed to show a link, 1 associated protease inhibitors (PIs) with decompensated liver disease, and 1 showed varied effects depending on drug class.39 In other studies, HIV viral suppression has been linked to slower fibrosis progression, and ART has been associated with decreased liver-related mortality.40, 41
Individuals with HCV infection and cirrhosis have an increased risk of developing hepatocellular carcinoma (HCC). The American Association for the Study of Liver Disease recommends screening these patients every 6-12 months with alpha-fetoprotein measurement and imaging.42 Although separate recommendations for HIV-HCV coinfection do not exist, screening remains important in this population because HCC incidence has been increasing among HIV-infected individuals.43 Finally, HIV-HCV coinfected patients without immunity to HAV should receive vaccination, because HAV can cause fulminant hepatitis in patients with underlying liver disease.
Hepatitis B Virus
Although the prevalence of HIV-HBV coinfection varies by geographic location, approximately 10% of HIV-infected individuals worldwide are also chronically infected with HBV.44 Like HIV-HCV coinfection, HIV alters the natural history of HBV. Individuals with HIV infection are 3-6 times more likely to develop chronic HBV after an acute exposure than individuals without HIV infection, and hepatitis B surface antibody (anti-HBs) development is improved with higher CD4 cell counts.45, 46 In addition, HIV-infected patients have a lower rate of spontaneous clearance of HBeAg, increased HBV replication, and a higher rate of loss of anti-HBs and reactivation of HBV.47 Coinfected individuals also experience an increased progression to cirrhosis and higher liver-related mortality compared with HBV monoinfected individuals.48, 49 The impact of HBV infection on the natural history of HIV is less clear.
All HIV-infected patients should be screened for HBV with HBsAg, anti-HBs, and hepatitis B core antibody (anti-HBc). Individuals without immunity to HBV should be vaccinated; however, response to vaccination is poor, especially in patients whose CD4 cell count is <200 cells/mm.3,50 Patients should therefore also be counseled to avoid risk factors for HBV transmission. Individuals with persistent HBsAg for a period of 6 months have chronic HBV and should be evaluated for treatment. Isolated anti-HBc is more common in HIV infection than in the general population; in one study, 42% of HIV-infected patients were only positive for anti-HBc.51 Occult HBV, defined as positive HBV DNA in the setting of negative HBsAg, has also been described in HIV-infected subjects, although prevalence estimates range widely.52 The clinical implications of isolated anti-HBc positivity and occult HBV are still unclear, but reactivation of inactive or occult HBV and reverse seroconversion (reappearance of HBsAg and HBV DNA in a patient with evidence of previously resolved infection) have been reported in HIV-infected individuals.53
Once HIV-HBV coinfection is diagnosed, staging of liver disease is important but challenging. Although serum alanine aminotransferase levels are lower in coinfected patients, this correlates poorly with liver disease.48 Noninvasive measures of hepatic fibrosis have not been well-studied in HIV-HBV coinfection; therefore, liver biopsy remains the gold standard for disease staging.
The decision to initiate HBV treatment depends on whether the patient meets indications to treat either the HIV or HBV. Treatment regimens for either virus must consider both infections, because many antiviral agents have dual activity, including tenofovir, lamivudine, emtricitabine, entecavir, and adefovir at doses >10 mg.54 Treatment for HBV is indicated in any patient with cirrhosis and detectable HBV DNA. Although a specific HBV DNA threshold for treatment in the absence of cirrhosis has not been determined, treatment should be considered in patients with HBV DNA ≥2000 IU/mL and more than mild liver disease on biopsy.54
If there is no indication to treat either infection, the patient should be monitored closely. If treatment is indicated for either HIV or HBV, ART should be initiated and should include the combination of tenofovir and emtricitabine (Truvada) or tenofovir and lamivudine.55 If tenofovir is contraindicated, entecavir can be used with the ART regimen, but then lamivudine or emtricitabine should be avoided because of overlapping resistance patterns.47 For patients requiring treatment for HBV but in whom ART is not feasible, options are limited by the need to avoid agents with anti-HIV activity to prevent development of drug-resistant HIV. In these patients, pegylated interferon alfa and adefovir 10 mg can be considered. Telbivudine is also a consideration, but some in vivo studies show declines in HIV RNA without emergence of drug-resistant HIV.56 Elevated ALT and AST during the course of ART might be due to a variety of potential causes including medications, drug-resistant HBV, HBV reactivation in the setting of medication withdrawal (especially with lamivudine withdrawal due to HIV resistance via the M184V mutation), loss of HBeAg, or the immune reconstitution inflammatory syndrome (IRIS).
Screening for HCC among individuals with HIV-HBV coinfection should follow American Association for the Study of Liver Disease guidelines recommending screening for all cirrhotic HBV carriers and for certain groups of noncirrhotic carriers.42 The hepatitis A vaccine should also be provided to individuals without hepatitis A immunity.
Medication Toxicity
Antiretroviral Therapy-Related Medication Toxicity
Liver toxicity is one of the most common serious adverse events associated with ART.57 The clinical presentation can range from mild asymptomatic increases in serum transaminases to overt liver failure.58 In retrospective studies, the incidence of ART-related severe hepatotoxicity is approximately 10%, and life-threatening events occur at a rate of 2.6 per 100 person-years.59, 60
There are 4 primary mechanisms by which ART can lead to liver damage: direct drug toxicity and/or drug metabolism, hypersensitivity reactions, mitochondrial toxicity, and IRIS.60, 61 IRIS is characterized by the paradoxical worsening of preexisting infectious diseases as a result of rapid immune restoration in the setting of successful HIV RNA suppression. The syndrome generally manifests within the first 2 months of ART initiation and is accompanied by a precipitous decline in HIV RNA and rise in CD4 count. In patients with viral hepatitis, immune restoration can lead to clinical hepatitis as a result of the immune response to the virus. There have been case reports of clinical flares of HBV in the setting of ART initiation, even with regimens including anti-HBV activity, and of rapidly progressive HCV-related cirrhosis associated with ART-related immune restoration.62, 63
Coinfection with HBV or HCV has consistently been associated with increased risk of ART-related hepatotoxicity.57, 60 Other risk factors associated with ART-related liver injury include preexisting advanced fibrosis, pretreatment elevated ALT or AST, alcohol abuse, older age, female gender, first exposure to ART, significant increase in CD4 cell count after ART initiation, concomitant tuberculosis medications, and cocaine use.60, 61, 64
Although all antiretroviral drugs have some risk of hepatotoxicity, some are implicated more than others, and classes of drugs have characteristic patterns of injury (Table 2). The non-nucleoside reverse transcriptase inhibitors (NNRTIs) typically cause either hypersensitivity reactions or direct drug toxicity and therefore have 2 peaks of onset, within days to weeks or several months after initiation.60 Nevirapine (NVP) is the NNRTI most associated with hepatotoxicity, although hypersensitivity reactions resulting in liver failure have been reported with the newer NNRTI etravirine.55 Efavirenz can also cause hepatotoxicity but does so less frequently than NVP or etravirine.
Hepatotoxicity associated with PIs generally occurs weeks to months after drug initiation. Full-dose ritonavir (RTV) was strongly associated with hepatotoxicity but is no longer used. The low-dose RTV used to boost levels of other PIs does not appear to increase the risk of hepatotoxicity.65 However, clinical hepatitis and liver failure have been reported with the newer PI tipranavir in combination with RTV boosting.55, 60 Atazanavir and indinavir both commonly cause an indirect hyperbilirubinemia, which is not associated with liver injury and does not require treatment discontinuation.66
The nucleoside reverse transcriptase inhibitors (NRTIs) are associated with mitochondrial toxicity as a result of their ability to inhibit mitochondrial polymerase y. Clinically this presents with hepatic steatosis and lactic acidosis from weeks to months after initiation. Stavudine, ddI, and zidovudine are the most frequently implicated. Prolonged ddI use has also been associated with cryptogenic liver disease and recently has been linked to noncirrhotic portal hypertension and esophageal varices.67, 68 Although less associated with mitochondrial toxicity, abacavir might cause hypersensitivity reactions especially in HLA-B*5701 positive patients. Finally, lamivudine, emtricitabine, and tenofovir can lead to HBV reactivation and severe acute hepatitis if withdrawn in an HBV-infected patient or if resistance develops.
The fusion inhibitor enfuvirtide has been rarely associated with hypersensitivity reactions, and the newer drug maraviroc, a CCR5 inhibitor, carries a black box warning for hepatotoxicity as a result of hypersensitivity.
Given the relatively high incidence of ART-related hepatotoxicity, all patients should have baseline ALT and AST checked, followed by regular monitoring every 3 months. Patients should be educated regarding symptoms of hepatitis and hypersensitivity reactions. If an adverse liver event occurs, ART should be discontinued in patients with symptoms, jaundice and elevated direct hyperbilirubinemia, grade 4 hepatotoxicity (ALT/AST >10 times upper limit of normal), or severe lactic acidosis.55 Mild asymptomatic ALT or AST elevations usually spontaneously resolve without drug discontinuation (Table 3).
Non-Antiretroviral Therapy-Related Medication Toxicity
HIV-infected patients are often prescribed a number of non-ART medications that can have adverse liver effects either alone or in combination (Table 4).
Alcoholic Liver Disease
Although alcoholic liver disease is responsible for nearly half of all deaths due to chronic liver disease in the United States, the role of alcohol abuse on liver disease in HIV-infected populations has not been well-defined. In one study of 2864 HIV-infected adults in the United States, 8% of the entire cohort and 15% of current alcohol drinkers were classified as heavy drinkers, which is almost twice as prevalent as in the general population.69
Active alcohol intake is known to be associated with faster liver disease progression in HCV monoinfection.70 In one study of HIV-HCV coinfected patients, excessive alcohol use was associated with elevated HCV RNA levels.71 In another study of 1358 HIV-infected individuals at an urban center, 10% reported hazardous drinking, which was independently associated with an elevated surrogate for hepatic fibrosis.72 These results suggest that alcohol abuse is prevalent among HIV-infected individuals and can independently contribute to liver disease progression. As a modifiable risk factor for liver disease, it is important that physicians provide counseling regarding alcohol consumption in this population.
Nonalcoholic Fatty Liver Disease
NAFLD refers to fat deposition in hepatocytes, or steatosis, in individuals with little or no alcohol use. When accompanied by inflammation and fibrosis, it is referred to as nonalcoholic steatohepatitis (NASH). The prevalence of NAFLD in the U.S. population ranges from 17%-33%, and risk factors include obesity, hyperglycemia, diabetes mellitus, and hypertriglyceridemia.73 Recently, mounting evidence suggests that the prevalence of hepatic steatosis in HIV-infected patients is high, especially in patients with chronic HCV or on NRTIs.61 Most of the prevalence data come from studies in HIV-HCV coinfected individuals, with rates of steatosis in this population ranging from 40%-69%.33, 74 However, in a recent study of 216 HIV-infected patients without viral hepatitis coinfection, 31% had NAFLD diagnosed, although most were diagnosed with ultrasound rather than the gold standard of liver biopsy.75
Metabolic abnormalities are extremely common in HIV-infected persons on ART, especially NRTI-PI combinations. These include insulin resistance, dyslipidemia, hypertriglyceridemia, and lipodystrophy, a disorder of peripheral fat distribution resulting in lipotrophy and visceral adiposity.76 NRTIs can also lead to hepatic steatosis via inhibition of mitochondrial DNA replication, resulting in triglyceride accumulation in the liver.77 Hypertriglyceridemia, low high-density lipoprotein, and low total cholesterol have also been independently associated with HIV infection and might be mediated by cytokines like interferon alfa.78 These metabolic abnormalities have been associated with the development of NASH in HIV-infected patients.79
The natural history of NAFLD in HIV infection is unknown. In the general population, approximately 10%-15% of patients with simple steatosis progress to NASH, and 15%-20% of these patients progress to cirrhosis.80 In general, steatosis alone is not concerning for liver damage, but it might exacerbate underlying chronic liver disease. In HCV-monoinfected patients, steatosis is associated with faster progression of fibrosis and decreased response to treatment.81 Similarly, in cohorts of HIV-HCV coinfection, hepatic steatosis has been associated with more advanced liver fibrosis.33, 74 With continued investigation and research into NAFLD, its impact on liver disease progression in HIV-infected individuals will likely be further elucidated.
Nodular Regenerative Hyperplasia
Nodular regenerative hyperplasia (NRH) is a rare condition characterized by multiple small regenerative nodules in the liver parenchyma. NRH has recently become increasingly recognized in HIV-infected patients with cryptogenic liver disease.82 Although the etiology is unclear, both ddI use and thrombophilia have been associated with the disease.82, 83 NRH should be considered in HIV-infected patients with portal hypertension of unclear etiology, especially those on ddI.
Acquired Immunodeficiency Syndrome-Related Liver Disease
Acquired Immunodeficiency Syndrome Cholangiopathy
AIDS cholangiopathy occurs when infection-related strictures in the biliary tract lead to biliary obstruction. It typically presents with right upper quadrant (RUQ) pain and a markedly increased alkaline phosphatase level, with less elevated bilirubin and normal or slightly increased transaminase levels. Patients might also have fever, nausea, vomiting, and diarrhea; jaundice is uncommon.84 It is usually seen in low CD4 counts (<100/mm3). Consequently, although previously relatively common among HIV-infected patients, it is much less common in the ART era. Indeed, in a recent retrospective study of 94 patients diagnosed with AIDS cholangiopathy at an urban hospital between 1983 and 2001, only 13 were diagnosed after 1996.85
The most common infection associated with AIDS cholangiopathy is Cryptosporidium parvum, followed by CMV. Microsporidia, Cyclospora cayetanensis, Mycobacterium avium-intracellulare, and Histoplasma capsulatum have all been reported with AIDS cholangiopathy as well.84 Ultrasound or magnetic resonance cholangiopancreatography might reveal intrahepatic and common bile duct dilation with terminal stenosis. However, endoscopic retrograde cholangiopancreatography remains the gold standard for diagnosis. Biopsies of the papilla and bile duct as well as bile duct brushings might help identify the infectious cause. Sphincterotomy improves the abdominal pain but does not extend survival, and the alkaline phosphatase level often remains elevated.85, 86 The most important aspect to treatment of AIDS cholangiopathy is ART administration, because survival after diagnosis is poor without ART.85
Acalculous Cholecystitis
Acalculous cholecystitis has been well-documented in HIV infection and is usually associated with CMV or Cryptospordium, although other infections, including Isospora and microsporidia have been implicated.87, 88 Patients typically present with RUQ abdominal pain and fever with cholestasis; leukocytosis is often not present. Imaging reveals a thickened, distended, acalculous gallbladder, and HIDA scan often shows a nonfunctioning gallbladder.88 Cholecystectomy is the treatment of choice.
Acquired Immunodeficiency Syndrome-Related Neoplasms
The AIDS-defining malignancies non-Hodgkin lymphoma (NHL) and KS involve the liver in 33% and 9% of cases, respectively.89, 90 Hepatic involvement of NHL might present with asymptomatic liver function test abnormalities, although patients might develop abdominal pain or jaundice. Hepatic involvement of KS rarely causes symptoms or death.90
Opportunistic Infections
Several opportunistic infections have been associated with hepatic involvement in advanced AIDS (Table 5). Of these, Mycobacterium avium complex is the most common. It is usually characterized histologically by acid-fast bacilli-containing poorly formed granulomas, although mass lesions have been described.90, 91 Patients often present with nausea, diarrhea, and abdominal pain. Alkaline phosphatase is usually disproportionately increased.92 Hepatic involvement of Mycobacterium tuberculosis, including liver abscesses, has been reported in approximately 8% of patients with extrapulmonary tuberculosis and HIV infection.91, 93 CMV is one of the most common opportunistic infections involving the liver detected on autopsy of patients with advanced AIDS but rarely results in clinical hepatitis.90, 92 When CMV presents as hepatitis, patients usually have mild transaminitis, fever, malaise, weight loss, and hepatomegaly.
Hepatic involvement of fungal infections, including Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis, can be seen in patients with AIDS and is usually detected on liver biopsy or autopsy. Although liver function test results are often abnormal, the liver involvement is usually asymptomatic.94, 95 Extrapulmonary Pneumocystis jiroveci involving the liver has been described and might be seen in the setting of inhaled pentamidine for prophylaxis of Pneumocystis jiroveci pneumonia.96 Bacillary peliosis hepatis is a rare disease characterized by multiple blood-filled cavities in the liver parenchyma; it has been reported in patients with AIDS and Bartonella henselae infection.97 Other reported opportunistic infections involving the liver of patients with AIDS include disseminated herpes simplex virus, human herpesvirus 6, varicella-zoster virus, Epstein-Barr virus, adenovirus, Candida albicans, Aspergillus fumigatus, Toxoplasma gondii, and Strongyloides stercoralis.90, 91, 92
Vanishing Bile Duct Syndrome
The vanishing bile duct syndrome (VBDS) is an acquired disease resulting in loss of small and medium-sized intrahepatic bile ducts. Multiple causes have been identified, and there have been case reports of VBDS associated with advanced AIDS, with cases attributed to CMV viremia and medication toxicity.98, 99 The presentation is variable and often related to cholestasis. Diagnosis is based on histology, although the work-up should include imaging to rule out extrahepatic biliary obstruction. The outcome of reported AIDS-associated VBDS cases is very poor, with progression to liver failure and death.98, 99
Conclusions
Liver disease among HIV-infected individuals is a common and important cause of non-AIDS-related morbidity and mortality. In the ART era, the spectrum of liver disease among patients with HIV infection has changed dramatically, shifting from opportunistic infections to sequelae of chronic infections, medication toxicities, alcohol use, and fatty liver. Management of HIV-infected patients requires recognition of these conditions and targeted diagnosis and treatment.
Source
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Dec 2010;8:1002-1012
JENNIFER C. PRICE* and CHLOE L. THIO
*Division of Gastroenterology and Hepatology and Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
"Liver disease among HIV-infected individuals is a common and important cause of non-AIDS-related morbidity and mortality. In the ART era, the spectrum of liver disease among patients with HIV infection has changed dramatically, shifting from opportunistic infections to sequelae of chronic infections, medication toxicities, alcohol use, and fatty liver. Management of HIV-infected patients requires recognition of these conditions and targeted diagnosis and treatment."
Since the advent of effective antiretroviral therapy (ART) for human immunodeficiency virus-1 (HIV), there has been a substantial decrease in deaths related to acquired immunodeficiency syndrome (AIDS). However, in the ART era, liver disease is now the most common non-AIDS-related cause of death among HIV-infected patients, accounting for 14%-18% of all deaths in this population and almost half of deaths among hospitalized HIV-infected patients. Just as the burden of non-AIDS morbidity and mortality has changed in the ART era, the types of liver disease the clinician is likely to encounter among these patients have changed as well. This review will discuss the causes of liver disease in the HIV-infected population in the ART era, including chronic hepatitis C virus, chronic hepatitis B virus, medication-related hepatotoxicity, alcohol abuse, nonalcoholic fatty liver disease, and AIDS-related liver diseases.
Managing liver disease is an increasingly important component to the care of individuals infected with human immunodeficiency virus-1 (HIV). Since the advent of effective antiretroviral therapy (ART) for HIV, there has been a substantial decrease in deaths related to acquired immunodeficiency syndrome (AIDS).1, 2, 3 However, liver disease has emerged as the most common non-AIDS-related cause of death among HIV-infected patients, accounting for 14%-18% of all deaths.3, 4 In some series, nearly half of deaths among hospitalized HIV-infected patients in the ART era have been attributed to liver disease.5, 6
Just as the burden of non-AIDS morbidity and mortality has changed in the ART era, the types of liver disease the clinician is likely to encounter among these patients have also changed.7 Before ART, the most common causes of liver dysfunction in HIV-infected patients were opportunistic infections, including cytomegalovirus (CMV) and mycobacterium infections, and AIDS-related neoplasms such as lymphoma and Kaposi's sarcoma (KS).8, 9 Since the ART era, however, the spectrum of liver disease among HIV-infected individuals has shifted to concomitant infection with chronic HCV, chronic HBV, medication-related hepatotoxicity, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD) (Table 1).7, 10, 11 This review will focus on the major causes of liver disease in the HIV-infected population in the ART era and will briefly review liver disease in persons with AIDS.
Viral Hepatitis
Hepatitis C Virus
Most liver disease among HIV-infected individuals is secondary to coinfection with HCV and/or HBV.12 Because of shared risk factors, coinfection with HCV and HIV is common. Reported prevalence rates of HIV-HCV coinfection vary depending on the route of HIV transmission, from 10% among those with high-risk sexual behavior to 90% with injection drug use.13 Overall, approximately 30% of HIV-infected individuals in the United States and Europe are coinfected with HCV.14
HIV infection alters the natural history of HCV in several ways. HIV-infected patients who are acutely infected with HCV are half as likely as HIV-uninfected individuals to clear HCV viremia.15 Coinfected individuals also have higher HCV RNA levels, accelerated progression to hepatic fibrosis, an increased risk of developing cirrhosis, and a higher risk of decompensated liver disease once cirrhotic.16, 17, 18 In a meta-analysis of 8 studies, HIV-HCV coinfected subjects had a 2-fold increased risk of histologic cirrhosis and 5-fold increased risk of decompensated liver disease compared with HCV-monoinfected individuals.19 Studies of the role of HCV on the natural history of HIV have been conflicting. However, in a recent analysis of 1428 HIV-HCV coinfected individuals treated for HCV, patients who achieved sustained virologic response had lower rates of HIV progression and nonliver mortality after adjusting for fibrosis, Centers for Disease Control and Prevention clinical category, and nadir CD4 count.20
Given both the high prevalence of HCV among the HIV-infected population and the impact of HIV on HCV-related liver disease progression, all HIV-infected patients should be tested for chronic HCV infection by using third-generation enzyme immunoassays, followed by quantitative HCV RNA testing if positive. Although third-generation immunoassays are highly sensitive, even in the setting of HIV infection (>99%), HCV RNA should be checked in patients with significant risk factors for HCV and advanced immunosuppression or in whom acute infection is suspected.21 During the past decade, outbreaks of sexually transmitted HCV among noninjection-drug-using men who have sex with men have been reported in Europe, the United States, and Australia; men who have sex with men should therefore be considered at risk for acquiring HCV.22 Because there is no available vaccine to prevent HCV infection, HIV-infected individuals who test negative for HCV should be counseled to avoid risk factors for HCV infection. For individuals who test positive for HCV, the extent of liver disease should be determined. Aminotransferase levels are not sensitive for fibrosis in the setting of HIV infection; therefore, liver biopsy remains the preferred modality for staging disease among coinfected patients.
Because of the limitations and invasiveness of liver biopsy, noninvasive methods to determine liver disease are being actively investigated and are becoming a viable alternative to liver biopsy. A variety of laboratory markers have been studied as potential surrogates for hepatic fibrosis; most were derived from studies in individuals without HIV infection. A meta-analysis of studies of the markers in the HIV-HCV coinfected population suggested that they might be useful in excluding cirrhosis if used at their most sensitive thresholds; however, their diagnostic odds ratios were suboptimal.23 Transient elastography (TE) uses ultrasound technology to estimate liver stiffness by measuring elastic shear wave velocity through the liver. In a study of 169 HIV-HCV coinfected patients, TE accurately detected significant fibrosis and cirrhosis but was less accurate in discriminating mild from significant fibrosis.24
The decision to treat HCV in the HIV-infected patient should be made on an individual basis, because the benefits must be weighed against safety and efficacy concerns. HCV treatment should be prioritized in coinfected patients without decompensated cirrhosis who have a liver biopsy revealing portal fibrosis or more advanced disease.25 Women of child-bearing age might desire treatment before becoming pregnant, because pregnancy must be avoided during and 6 months after anti-HCV therapy because of ribavirin teratogenicity. Because they usually have favorable treatment responses, patients with HCV genotype 2 or 3 who are motivated and can tolerate treatment should be offered it regardless of liver disease stage. Certain IL28B genotypes respond well to treatment and so might also become an indication to treat without liver disease staging.26 Early treatment of acute HCV infection has also been associated with improved response rates in HIV-infected individuals.27 Patients with decompensated cirrhosis should be referred to a liver transplant center with experience in transplantation with HIV infection.
The current Food and Drug Administration-approved treatment for HCV in the setting of HIV infection is pegylated interferon alfa and ribavirin, which is the standard of care based on 4 large randomized trials.28, 29, 30, 31 This regimen is less effective in HIV-infected patients, with sustained virologic response rates ranging from 14%-38% among those with HCV genotype 1 infection and 44%-73% among genotype 2 and 3 infections. Similar to HCV-monoinfected individuals, genotype, baseline HCV RNA, and early response to therapy are predictors of treatment response.28 In patients receiving HCV treatment, didanosine (ddI) is contraindicated and zidovudine is not recommended, because ribavirin potentiates the risk of mitochondrial toxicity and anemia, respectively.32 Stavudine should also be avoided in patients receiving HCV treatment because of the risk of steatosis.33 Abacavir has been associated with decreased SVR, possibly as a result of competition with ribavirin because both are guanosine analogues.34, 35, 36 However, this competitive interaction appears to be insignificant when weight-based ribavirin dosing is used.37, 38
Although HCV-infected patients have a higher incidence of ART-related liver toxicity, this infrequently leads to ART discontinuation, and the benefits of ART for HIV treatment are profound; therefore, ART should not be withheld in the coinfected population. In addition, ART might have beneficial effects on the progression of liver disease in HIV-HCV coinfection, because improvement in CD4 count might decrease fibrosis progression, although studies investigating this have been inconsistent. A recent systematic review of 11 studies examined the impact of ART on liver disease in HIV-HCV coinfection; 3 associated ART with less severe fibrosis, 6 failed to show a link, 1 associated protease inhibitors (PIs) with decompensated liver disease, and 1 showed varied effects depending on drug class.39 In other studies, HIV viral suppression has been linked to slower fibrosis progression, and ART has been associated with decreased liver-related mortality.40, 41
Individuals with HCV infection and cirrhosis have an increased risk of developing hepatocellular carcinoma (HCC). The American Association for the Study of Liver Disease recommends screening these patients every 6-12 months with alpha-fetoprotein measurement and imaging.42 Although separate recommendations for HIV-HCV coinfection do not exist, screening remains important in this population because HCC incidence has been increasing among HIV-infected individuals.43 Finally, HIV-HCV coinfected patients without immunity to HAV should receive vaccination, because HAV can cause fulminant hepatitis in patients with underlying liver disease.
Hepatitis B Virus
Although the prevalence of HIV-HBV coinfection varies by geographic location, approximately 10% of HIV-infected individuals worldwide are also chronically infected with HBV.44 Like HIV-HCV coinfection, HIV alters the natural history of HBV. Individuals with HIV infection are 3-6 times more likely to develop chronic HBV after an acute exposure than individuals without HIV infection, and hepatitis B surface antibody (anti-HBs) development is improved with higher CD4 cell counts.45, 46 In addition, HIV-infected patients have a lower rate of spontaneous clearance of HBeAg, increased HBV replication, and a higher rate of loss of anti-HBs and reactivation of HBV.47 Coinfected individuals also experience an increased progression to cirrhosis and higher liver-related mortality compared with HBV monoinfected individuals.48, 49 The impact of HBV infection on the natural history of HIV is less clear.
All HIV-infected patients should be screened for HBV with HBsAg, anti-HBs, and hepatitis B core antibody (anti-HBc). Individuals without immunity to HBV should be vaccinated; however, response to vaccination is poor, especially in patients whose CD4 cell count is <200 cells/mm.3,50 Patients should therefore also be counseled to avoid risk factors for HBV transmission. Individuals with persistent HBsAg for a period of 6 months have chronic HBV and should be evaluated for treatment. Isolated anti-HBc is more common in HIV infection than in the general population; in one study, 42% of HIV-infected patients were only positive for anti-HBc.51 Occult HBV, defined as positive HBV DNA in the setting of negative HBsAg, has also been described in HIV-infected subjects, although prevalence estimates range widely.52 The clinical implications of isolated anti-HBc positivity and occult HBV are still unclear, but reactivation of inactive or occult HBV and reverse seroconversion (reappearance of HBsAg and HBV DNA in a patient with evidence of previously resolved infection) have been reported in HIV-infected individuals.53
Once HIV-HBV coinfection is diagnosed, staging of liver disease is important but challenging. Although serum alanine aminotransferase levels are lower in coinfected patients, this correlates poorly with liver disease.48 Noninvasive measures of hepatic fibrosis have not been well-studied in HIV-HBV coinfection; therefore, liver biopsy remains the gold standard for disease staging.
The decision to initiate HBV treatment depends on whether the patient meets indications to treat either the HIV or HBV. Treatment regimens for either virus must consider both infections, because many antiviral agents have dual activity, including tenofovir, lamivudine, emtricitabine, entecavir, and adefovir at doses >10 mg.54 Treatment for HBV is indicated in any patient with cirrhosis and detectable HBV DNA. Although a specific HBV DNA threshold for treatment in the absence of cirrhosis has not been determined, treatment should be considered in patients with HBV DNA ≥2000 IU/mL and more than mild liver disease on biopsy.54
If there is no indication to treat either infection, the patient should be monitored closely. If treatment is indicated for either HIV or HBV, ART should be initiated and should include the combination of tenofovir and emtricitabine (Truvada) or tenofovir and lamivudine.55 If tenofovir is contraindicated, entecavir can be used with the ART regimen, but then lamivudine or emtricitabine should be avoided because of overlapping resistance patterns.47 For patients requiring treatment for HBV but in whom ART is not feasible, options are limited by the need to avoid agents with anti-HIV activity to prevent development of drug-resistant HIV. In these patients, pegylated interferon alfa and adefovir 10 mg can be considered. Telbivudine is also a consideration, but some in vivo studies show declines in HIV RNA without emergence of drug-resistant HIV.56 Elevated ALT and AST during the course of ART might be due to a variety of potential causes including medications, drug-resistant HBV, HBV reactivation in the setting of medication withdrawal (especially with lamivudine withdrawal due to HIV resistance via the M184V mutation), loss of HBeAg, or the immune reconstitution inflammatory syndrome (IRIS).
Screening for HCC among individuals with HIV-HBV coinfection should follow American Association for the Study of Liver Disease guidelines recommending screening for all cirrhotic HBV carriers and for certain groups of noncirrhotic carriers.42 The hepatitis A vaccine should also be provided to individuals without hepatitis A immunity.
Medication Toxicity
Antiretroviral Therapy-Related Medication Toxicity
Liver toxicity is one of the most common serious adverse events associated with ART.57 The clinical presentation can range from mild asymptomatic increases in serum transaminases to overt liver failure.58 In retrospective studies, the incidence of ART-related severe hepatotoxicity is approximately 10%, and life-threatening events occur at a rate of 2.6 per 100 person-years.59, 60
There are 4 primary mechanisms by which ART can lead to liver damage: direct drug toxicity and/or drug metabolism, hypersensitivity reactions, mitochondrial toxicity, and IRIS.60, 61 IRIS is characterized by the paradoxical worsening of preexisting infectious diseases as a result of rapid immune restoration in the setting of successful HIV RNA suppression. The syndrome generally manifests within the first 2 months of ART initiation and is accompanied by a precipitous decline in HIV RNA and rise in CD4 count. In patients with viral hepatitis, immune restoration can lead to clinical hepatitis as a result of the immune response to the virus. There have been case reports of clinical flares of HBV in the setting of ART initiation, even with regimens including anti-HBV activity, and of rapidly progressive HCV-related cirrhosis associated with ART-related immune restoration.62, 63
Coinfection with HBV or HCV has consistently been associated with increased risk of ART-related hepatotoxicity.57, 60 Other risk factors associated with ART-related liver injury include preexisting advanced fibrosis, pretreatment elevated ALT or AST, alcohol abuse, older age, female gender, first exposure to ART, significant increase in CD4 cell count after ART initiation, concomitant tuberculosis medications, and cocaine use.60, 61, 64
Although all antiretroviral drugs have some risk of hepatotoxicity, some are implicated more than others, and classes of drugs have characteristic patterns of injury (Table 2). The non-nucleoside reverse transcriptase inhibitors (NNRTIs) typically cause either hypersensitivity reactions or direct drug toxicity and therefore have 2 peaks of onset, within days to weeks or several months after initiation.60 Nevirapine (NVP) is the NNRTI most associated with hepatotoxicity, although hypersensitivity reactions resulting in liver failure have been reported with the newer NNRTI etravirine.55 Efavirenz can also cause hepatotoxicity but does so less frequently than NVP or etravirine.
Hepatotoxicity associated with PIs generally occurs weeks to months after drug initiation. Full-dose ritonavir (RTV) was strongly associated with hepatotoxicity but is no longer used. The low-dose RTV used to boost levels of other PIs does not appear to increase the risk of hepatotoxicity.65 However, clinical hepatitis and liver failure have been reported with the newer PI tipranavir in combination with RTV boosting.55, 60 Atazanavir and indinavir both commonly cause an indirect hyperbilirubinemia, which is not associated with liver injury and does not require treatment discontinuation.66
The nucleoside reverse transcriptase inhibitors (NRTIs) are associated with mitochondrial toxicity as a result of their ability to inhibit mitochondrial polymerase y. Clinically this presents with hepatic steatosis and lactic acidosis from weeks to months after initiation. Stavudine, ddI, and zidovudine are the most frequently implicated. Prolonged ddI use has also been associated with cryptogenic liver disease and recently has been linked to noncirrhotic portal hypertension and esophageal varices.67, 68 Although less associated with mitochondrial toxicity, abacavir might cause hypersensitivity reactions especially in HLA-B*5701 positive patients. Finally, lamivudine, emtricitabine, and tenofovir can lead to HBV reactivation and severe acute hepatitis if withdrawn in an HBV-infected patient or if resistance develops.
The fusion inhibitor enfuvirtide has been rarely associated with hypersensitivity reactions, and the newer drug maraviroc, a CCR5 inhibitor, carries a black box warning for hepatotoxicity as a result of hypersensitivity.
Given the relatively high incidence of ART-related hepatotoxicity, all patients should have baseline ALT and AST checked, followed by regular monitoring every 3 months. Patients should be educated regarding symptoms of hepatitis and hypersensitivity reactions. If an adverse liver event occurs, ART should be discontinued in patients with symptoms, jaundice and elevated direct hyperbilirubinemia, grade 4 hepatotoxicity (ALT/AST >10 times upper limit of normal), or severe lactic acidosis.55 Mild asymptomatic ALT or AST elevations usually spontaneously resolve without drug discontinuation (Table 3).
Non-Antiretroviral Therapy-Related Medication Toxicity
HIV-infected patients are often prescribed a number of non-ART medications that can have adverse liver effects either alone or in combination (Table 4).
Alcoholic Liver Disease
Although alcoholic liver disease is responsible for nearly half of all deaths due to chronic liver disease in the United States, the role of alcohol abuse on liver disease in HIV-infected populations has not been well-defined. In one study of 2864 HIV-infected adults in the United States, 8% of the entire cohort and 15% of current alcohol drinkers were classified as heavy drinkers, which is almost twice as prevalent as in the general population.69
Active alcohol intake is known to be associated with faster liver disease progression in HCV monoinfection.70 In one study of HIV-HCV coinfected patients, excessive alcohol use was associated with elevated HCV RNA levels.71 In another study of 1358 HIV-infected individuals at an urban center, 10% reported hazardous drinking, which was independently associated with an elevated surrogate for hepatic fibrosis.72 These results suggest that alcohol abuse is prevalent among HIV-infected individuals and can independently contribute to liver disease progression. As a modifiable risk factor for liver disease, it is important that physicians provide counseling regarding alcohol consumption in this population.
Nonalcoholic Fatty Liver Disease
NAFLD refers to fat deposition in hepatocytes, or steatosis, in individuals with little or no alcohol use. When accompanied by inflammation and fibrosis, it is referred to as nonalcoholic steatohepatitis (NASH). The prevalence of NAFLD in the U.S. population ranges from 17%-33%, and risk factors include obesity, hyperglycemia, diabetes mellitus, and hypertriglyceridemia.73 Recently, mounting evidence suggests that the prevalence of hepatic steatosis in HIV-infected patients is high, especially in patients with chronic HCV or on NRTIs.61 Most of the prevalence data come from studies in HIV-HCV coinfected individuals, with rates of steatosis in this population ranging from 40%-69%.33, 74 However, in a recent study of 216 HIV-infected patients without viral hepatitis coinfection, 31% had NAFLD diagnosed, although most were diagnosed with ultrasound rather than the gold standard of liver biopsy.75
Metabolic abnormalities are extremely common in HIV-infected persons on ART, especially NRTI-PI combinations. These include insulin resistance, dyslipidemia, hypertriglyceridemia, and lipodystrophy, a disorder of peripheral fat distribution resulting in lipotrophy and visceral adiposity.76 NRTIs can also lead to hepatic steatosis via inhibition of mitochondrial DNA replication, resulting in triglyceride accumulation in the liver.77 Hypertriglyceridemia, low high-density lipoprotein, and low total cholesterol have also been independently associated with HIV infection and might be mediated by cytokines like interferon alfa.78 These metabolic abnormalities have been associated with the development of NASH in HIV-infected patients.79
The natural history of NAFLD in HIV infection is unknown. In the general population, approximately 10%-15% of patients with simple steatosis progress to NASH, and 15%-20% of these patients progress to cirrhosis.80 In general, steatosis alone is not concerning for liver damage, but it might exacerbate underlying chronic liver disease. In HCV-monoinfected patients, steatosis is associated with faster progression of fibrosis and decreased response to treatment.81 Similarly, in cohorts of HIV-HCV coinfection, hepatic steatosis has been associated with more advanced liver fibrosis.33, 74 With continued investigation and research into NAFLD, its impact on liver disease progression in HIV-infected individuals will likely be further elucidated.
Nodular Regenerative Hyperplasia
Nodular regenerative hyperplasia (NRH) is a rare condition characterized by multiple small regenerative nodules in the liver parenchyma. NRH has recently become increasingly recognized in HIV-infected patients with cryptogenic liver disease.82 Although the etiology is unclear, both ddI use and thrombophilia have been associated with the disease.82, 83 NRH should be considered in HIV-infected patients with portal hypertension of unclear etiology, especially those on ddI.
Acquired Immunodeficiency Syndrome-Related Liver Disease
Acquired Immunodeficiency Syndrome Cholangiopathy
AIDS cholangiopathy occurs when infection-related strictures in the biliary tract lead to biliary obstruction. It typically presents with right upper quadrant (RUQ) pain and a markedly increased alkaline phosphatase level, with less elevated bilirubin and normal or slightly increased transaminase levels. Patients might also have fever, nausea, vomiting, and diarrhea; jaundice is uncommon.84 It is usually seen in low CD4 counts (<100/mm3). Consequently, although previously relatively common among HIV-infected patients, it is much less common in the ART era. Indeed, in a recent retrospective study of 94 patients diagnosed with AIDS cholangiopathy at an urban hospital between 1983 and 2001, only 13 were diagnosed after 1996.85
The most common infection associated with AIDS cholangiopathy is Cryptosporidium parvum, followed by CMV. Microsporidia, Cyclospora cayetanensis, Mycobacterium avium-intracellulare, and Histoplasma capsulatum have all been reported with AIDS cholangiopathy as well.84 Ultrasound or magnetic resonance cholangiopancreatography might reveal intrahepatic and common bile duct dilation with terminal stenosis. However, endoscopic retrograde cholangiopancreatography remains the gold standard for diagnosis. Biopsies of the papilla and bile duct as well as bile duct brushings might help identify the infectious cause. Sphincterotomy improves the abdominal pain but does not extend survival, and the alkaline phosphatase level often remains elevated.85, 86 The most important aspect to treatment of AIDS cholangiopathy is ART administration, because survival after diagnosis is poor without ART.85
Acalculous Cholecystitis
Acalculous cholecystitis has been well-documented in HIV infection and is usually associated with CMV or Cryptospordium, although other infections, including Isospora and microsporidia have been implicated.87, 88 Patients typically present with RUQ abdominal pain and fever with cholestasis; leukocytosis is often not present. Imaging reveals a thickened, distended, acalculous gallbladder, and HIDA scan often shows a nonfunctioning gallbladder.88 Cholecystectomy is the treatment of choice.
Acquired Immunodeficiency Syndrome-Related Neoplasms
The AIDS-defining malignancies non-Hodgkin lymphoma (NHL) and KS involve the liver in 33% and 9% of cases, respectively.89, 90 Hepatic involvement of NHL might present with asymptomatic liver function test abnormalities, although patients might develop abdominal pain or jaundice. Hepatic involvement of KS rarely causes symptoms or death.90
Opportunistic Infections
Several opportunistic infections have been associated with hepatic involvement in advanced AIDS (Table 5). Of these, Mycobacterium avium complex is the most common. It is usually characterized histologically by acid-fast bacilli-containing poorly formed granulomas, although mass lesions have been described.90, 91 Patients often present with nausea, diarrhea, and abdominal pain. Alkaline phosphatase is usually disproportionately increased.92 Hepatic involvement of Mycobacterium tuberculosis, including liver abscesses, has been reported in approximately 8% of patients with extrapulmonary tuberculosis and HIV infection.91, 93 CMV is one of the most common opportunistic infections involving the liver detected on autopsy of patients with advanced AIDS but rarely results in clinical hepatitis.90, 92 When CMV presents as hepatitis, patients usually have mild transaminitis, fever, malaise, weight loss, and hepatomegaly.
Hepatic involvement of fungal infections, including Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis, can be seen in patients with AIDS and is usually detected on liver biopsy or autopsy. Although liver function test results are often abnormal, the liver involvement is usually asymptomatic.94, 95 Extrapulmonary Pneumocystis jiroveci involving the liver has been described and might be seen in the setting of inhaled pentamidine for prophylaxis of Pneumocystis jiroveci pneumonia.96 Bacillary peliosis hepatis is a rare disease characterized by multiple blood-filled cavities in the liver parenchyma; it has been reported in patients with AIDS and Bartonella henselae infection.97 Other reported opportunistic infections involving the liver of patients with AIDS include disseminated herpes simplex virus, human herpesvirus 6, varicella-zoster virus, Epstein-Barr virus, adenovirus, Candida albicans, Aspergillus fumigatus, Toxoplasma gondii, and Strongyloides stercoralis.90, 91, 92
Vanishing Bile Duct Syndrome
The vanishing bile duct syndrome (VBDS) is an acquired disease resulting in loss of small and medium-sized intrahepatic bile ducts. Multiple causes have been identified, and there have been case reports of VBDS associated with advanced AIDS, with cases attributed to CMV viremia and medication toxicity.98, 99 The presentation is variable and often related to cholestasis. Diagnosis is based on histology, although the work-up should include imaging to rule out extrahepatic biliary obstruction. The outcome of reported AIDS-associated VBDS cases is very poor, with progression to liver failure and death.98, 99
Conclusions
Liver disease among HIV-infected individuals is a common and important cause of non-AIDS-related morbidity and mortality. In the ART era, the spectrum of liver disease among patients with HIV infection has changed dramatically, shifting from opportunistic infections to sequelae of chronic infections, medication toxicities, alcohol use, and fatty liver. Management of HIV-infected patients requires recognition of these conditions and targeted diagnosis and treatment.
Source
Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3
Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3
This study is currently recruiting participants.
First Received: December 13, 2010 Last Updated: December 21, 2010
Purpose
To assess safety and tolerability of PSI-7977 400 mg and ribavirin (RBV) with and without pegylated interferon alfa 2a (PEG-IFN) in treatment naive subjects with hepatitis C (HCV) genotypes 2 or 3
Further study details as provided by Pharmasset:
Primary Outcome Measures:
· Safety and Tolerability [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]To assess the safety and tolerability of PSI-7977 400 mg and ribavirin for 12 weeks, administered with and without pegylated interferon alfa-2a (PEG-IFN) in treatment naïve subjects with HCV genotypes 2 or 3
Secondary Outcome Measures:
· HCV RNA [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]To evaluate the change in circulating HCV RNA in subjects over 12 weeks of dosing with PSI-7977 and ribavirin administered with and without PEG-IFN in treatment-naïve subjects with HCV genotypes 2 or 3
· HCV RNA [ Time Frame: Ongoing ] [ Designated as safety issue: No ]To evaluate the proportion of subjects who have HCV RNA below the limit of quantitation (LOQ) and below the limit of detection (LOD) at various time points in the study
· Sustained Virologic Response (SVR) [ Time Frame: SVR 12 and SVR 24 ] [ Designated as safety issue: No ]To evaluate the sustained virologic response at 12 (SVR12) and 24 (SVR24) weeks following completion of all treatment
· Resistance [ Time Frame: Ongoing ] [ Designated as safety issue: No ]To evaluate the emergence of HCV resistance against PSI-7977
· Duration of PEG-IFN therapy [ Time Frame: SVR 12 and SVR 24 ] [ Designated as safety issue: No ]To explore the effects of the duration of PEG-IFN therapy on safety, tolerability, emergence of resistance, viral kinetics, SVR12, and SVR24
· Pharmacokinetics [ Time Frame: Ongoing ] [ Designated as safety issue: No ]To characterize the steady-state plasma pharmacokinetics of the PSI-6206 metabolite of PSI-7977
Source
This study is currently recruiting participants.
First Received: December 13, 2010 Last Updated: December 21, 2010
Purpose
To assess safety and tolerability of PSI-7977 400 mg and ribavirin (RBV) with and without pegylated interferon alfa 2a (PEG-IFN) in treatment naive subjects with hepatitis C (HCV) genotypes 2 or 3
Further study details as provided by Pharmasset:
Primary Outcome Measures:
· Safety and Tolerability [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]To assess the safety and tolerability of PSI-7977 400 mg and ribavirin for 12 weeks, administered with and without pegylated interferon alfa-2a (PEG-IFN) in treatment naïve subjects with HCV genotypes 2 or 3
Secondary Outcome Measures:
· HCV RNA [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]To evaluate the change in circulating HCV RNA in subjects over 12 weeks of dosing with PSI-7977 and ribavirin administered with and without PEG-IFN in treatment-naïve subjects with HCV genotypes 2 or 3
· HCV RNA [ Time Frame: Ongoing ] [ Designated as safety issue: No ]To evaluate the proportion of subjects who have HCV RNA below the limit of quantitation (LOQ) and below the limit of detection (LOD) at various time points in the study
· Sustained Virologic Response (SVR) [ Time Frame: SVR 12 and SVR 24 ] [ Designated as safety issue: No ]To evaluate the sustained virologic response at 12 (SVR12) and 24 (SVR24) weeks following completion of all treatment
· Resistance [ Time Frame: Ongoing ] [ Designated as safety issue: No ]To evaluate the emergence of HCV resistance against PSI-7977
· Duration of PEG-IFN therapy [ Time Frame: SVR 12 and SVR 24 ] [ Designated as safety issue: No ]To explore the effects of the duration of PEG-IFN therapy on safety, tolerability, emergence of resistance, viral kinetics, SVR12, and SVR24
· Pharmacokinetics [ Time Frame: Ongoing ] [ Designated as safety issue: No ]To characterize the steady-state plasma pharmacokinetics of the PSI-6206 metabolite of PSI-7977
Source
Fatty Liver Disease Soars in U.S.
January 7, 2011
There's a fair amount of guesswork to the estimates, but perhaps as many as 20% of American adults have some degree of fatty liver disease, a condition that used to occur almost exclusively in people who drink excessively. The epidemics of obesity and diabetes are to blame. Fatty liver affects between 70% and 90% of people with those conditions, so as obesity and diabetes have become more common, so has fatty liver disease.
Fatty liver disease isn't confined to any one group, and there don't seem to be pronounced gender differences, but studies suggest that Latinos are disproportionately affected. It's primarily a condition of middle age, although children may get it, too. Fatty liver disease is rapidly becoming more common in Asia, and some research suggests that men in India may be especially susceptible.
Plumped-up liver cells
The prevailing theory is that the condition gets started because of insulin resistance, which is, in turn, frequently a consequence of obesity and excess fat tissue in the abdomen. When people are insulin resistant, their muscle, fat, and liver cells don't respond normally to insulin, so levels of the hormone — and the blood sugar it ushers into cells — build up in the blood. As a result, the risk of developing diabetes and heart disease increases. But insulin resistance is a complicated metabolic state that also includes an increase in the amount of free fatty acids circulating in the blood.
Fatty liver disease occurs when some of those fat molecules accumulate inside liver cells. The presence of those fattened cells can then lead to inflammation in the liver and damage to surrounding liver tissue. Once that happens, if excess alcohol is not involved, the condition is called nonalcoholic steatohepatitis (steato- for fat and –hepatitis because the liver is inflamed). Fortunately, that unwieldy name boils down to a handier acronym, NASH. Estimates vary quite a bit, but it seems that 5% to 10% of people with fatty liver disease go on to develop NASH.
NASH is often a relatively stable, low-grade condition that people live with for years, with few if any symptoms. But it can also start a cascade of serious damage to the liver and attempts by the organ to regenerate itself that culminate in an abundance of scar tissue and impaired liver function — a condition called cirrhosis. Cirrhosis is irreversible and can lead to total failure of the liver. It also is associated with an increased risk for developing liver cancer.
Some studies have shown as few as 3% of people with NASH developing cirrhosis, while others have shown as many as 26% doing so. There's no test or risk factor that predicts who will develop cirrhosis and who won't, although one study did find that people who are older or whose initial liver biopsies showed more inflammation were at greater risk. It's clear, though, that the prognosis for NASH is far better than it is for steatohepatitis that's the result of heavy alcohol consumption. Perhaps as many as half of all those with alcoholic steatohepatitis (which lacks a handy acronym) go on to develop cirrhosis.
It's just a theory at this point, but people with fatty liver disease and NASH may need to be more worried about heart disease and stroke than about serious liver problems. An article published in The New England Journal of Medicine in late 2009 argued that the inflammatory and other factors pumped out by a fat-afflicted liver promote the atherosclerotic process that damages the insides of arteries and makes blood more likely to clot, a combination that can lead to heart attack or stroke. The evidence the authors cited is intriguing, if circumstantial. They pointed to a study showing that people with NASH are twice as likely to die from heart attack or stroke as people without it. And NASH seems to add to the risks that come with excess weight. Overweight men with NASH have higher levels of C-reactive protein, an inflammatory factor, and fibrinogen, a clotting factor, than overweight men without NASH. Moreover, the levels of those and other factors go up as NASH gets more severe.
Diagnosis requires a biopsy
Most people with fatty liver disease don't have symptoms, and that's true even if it has developed into NASH. Only occasionally do people feel run-down, or they have an achy feeling in the upper right side of the abdomen, where the liver is located. So, more often than not, fatty liver disease and NASH are discovered incidentally, starting with higher than normal levels of liver enzymes on a routine blood test. Ultrasound imaging, the same technology used to get pictures of developing fetuses, can be informative: the liver looks bright because the fat shows up as white on the image. But neither an ultrasound nor a CT or MRI scan is completely reliable for making a diagnosis. The fat in the liver is visible, but not the NASH-related inflammation. Some researchers have developed formulas that use a simple blood test and measurements of various hormones, inflammatory factors, and liver enzymes to arrive at a diagnosis, but this work is at a preliminary stage.
Currently, a liver biopsy is the only way to make a definitive diagnosis of fatty liver or NASH. Liver biopsies involve inserting a long needle into the right side of the abdomen and extracting a small piece of liver tissue that can be examined under a microscope. Liver biopsies are an invasive procedure, so they aren't entirely free of risk and complications, but they're also fairly routine these days and can be done on an outpatient basis.
Whether a doctor will order a biopsy to nail down a diagnosis depends on many factors, including whether the person is obese or has diabetes or shows other signs of liver trouble.
Weight loss is the treatment
There's been a fair amount of research into using diabetes drugs to treat NASH, even in people who don't have diabetes. Rosiglitazone (sold as Avandia) and pioglitazone (sold as Actos) have been the leading candidates because they reduce insulin resistance, the root cause of fatty livers. They're not looking so promising these days. The FDA has moved to sharply curtail the use of Avandia because it seems to cause heart problems. The results of an important trial published in 2010 in The New England Journal of Medicine showed Actos to be no better than a placebo in improving NASH in people without diabetes.
Another diabetes drug, metformin (Glucophage), might prove to be an effective treatment, but there isn't enough evidence yet. Vitamin E is a possibility: the same trial that showed Actos wasn't effective showed some improvement in the livers of people who took large doses (800 IU daily) of the vitamin. But many doctors are wary about prescribing large doses of vitamin E because they've been associated with an increased risk of bleeding. Besides, the improvements in the liver were limited. Fish oil has produced some favorable results, and clinical trials are under way, but it can't be endorsed yet.
These setbacks and uncertainties have left weight loss (ideally from changes in diet and an increase in physical activity) as the only recommended treatment for most cases of fatty liver disease and NASH. In many cases, weight loss seems to have a very direct effect: as people lose weight, the fatty liver becomes less fatty. Crash dieting is a bad idea, though, because rapid weight loss (losing 4 pounds a week or more) can wind up damaging the liver. Of course, if sustained weight loss were easy, a lot of today's health problems would be solved, not just fatty liver disease and NASH.
In addition to encouraging people to lose weight, doctors will often advise people with diabetes who have fatty liver disease or NASH to be vigilant about controlling their blood sugar.
The bottom line Many parts of the body come to grief once people become obese or develop diabetes. It's not surprising that our livers do too, given how central they are to a whole suite of metabolic processes. There's some evidence that a fatty liver may add to the already high risk of heart disease among people who are obese or have diabetes. Fatty livers can also develop into cirrhotic ones if the inflammatory processes take off.
But there are two bright spots in the take-home message about fatty livers. First, most cases stay relatively stable and don't result in serious liver disease. Second, the treatment is not an expensive drug with side effects, but losing weight — and that will benefit many other parts of the body besides the liver.
Source: Harvard Univ.
Source
There's a fair amount of guesswork to the estimates, but perhaps as many as 20% of American adults have some degree of fatty liver disease, a condition that used to occur almost exclusively in people who drink excessively. The epidemics of obesity and diabetes are to blame. Fatty liver affects between 70% and 90% of people with those conditions, so as obesity and diabetes have become more common, so has fatty liver disease.
Fatty liver disease isn't confined to any one group, and there don't seem to be pronounced gender differences, but studies suggest that Latinos are disproportionately affected. It's primarily a condition of middle age, although children may get it, too. Fatty liver disease is rapidly becoming more common in Asia, and some research suggests that men in India may be especially susceptible.
Plumped-up liver cells
The prevailing theory is that the condition gets started because of insulin resistance, which is, in turn, frequently a consequence of obesity and excess fat tissue in the abdomen. When people are insulin resistant, their muscle, fat, and liver cells don't respond normally to insulin, so levels of the hormone — and the blood sugar it ushers into cells — build up in the blood. As a result, the risk of developing diabetes and heart disease increases. But insulin resistance is a complicated metabolic state that also includes an increase in the amount of free fatty acids circulating in the blood.
Fatty liver disease occurs when some of those fat molecules accumulate inside liver cells. The presence of those fattened cells can then lead to inflammation in the liver and damage to surrounding liver tissue. Once that happens, if excess alcohol is not involved, the condition is called nonalcoholic steatohepatitis (steato- for fat and –hepatitis because the liver is inflamed). Fortunately, that unwieldy name boils down to a handier acronym, NASH. Estimates vary quite a bit, but it seems that 5% to 10% of people with fatty liver disease go on to develop NASH.
NASH is often a relatively stable, low-grade condition that people live with for years, with few if any symptoms. But it can also start a cascade of serious damage to the liver and attempts by the organ to regenerate itself that culminate in an abundance of scar tissue and impaired liver function — a condition called cirrhosis. Cirrhosis is irreversible and can lead to total failure of the liver. It also is associated with an increased risk for developing liver cancer.
Some studies have shown as few as 3% of people with NASH developing cirrhosis, while others have shown as many as 26% doing so. There's no test or risk factor that predicts who will develop cirrhosis and who won't, although one study did find that people who are older or whose initial liver biopsies showed more inflammation were at greater risk. It's clear, though, that the prognosis for NASH is far better than it is for steatohepatitis that's the result of heavy alcohol consumption. Perhaps as many as half of all those with alcoholic steatohepatitis (which lacks a handy acronym) go on to develop cirrhosis.
It's just a theory at this point, but people with fatty liver disease and NASH may need to be more worried about heart disease and stroke than about serious liver problems. An article published in The New England Journal of Medicine in late 2009 argued that the inflammatory and other factors pumped out by a fat-afflicted liver promote the atherosclerotic process that damages the insides of arteries and makes blood more likely to clot, a combination that can lead to heart attack or stroke. The evidence the authors cited is intriguing, if circumstantial. They pointed to a study showing that people with NASH are twice as likely to die from heart attack or stroke as people without it. And NASH seems to add to the risks that come with excess weight. Overweight men with NASH have higher levels of C-reactive protein, an inflammatory factor, and fibrinogen, a clotting factor, than overweight men without NASH. Moreover, the levels of those and other factors go up as NASH gets more severe.
Diagnosis requires a biopsy
Most people with fatty liver disease don't have symptoms, and that's true even if it has developed into NASH. Only occasionally do people feel run-down, or they have an achy feeling in the upper right side of the abdomen, where the liver is located. So, more often than not, fatty liver disease and NASH are discovered incidentally, starting with higher than normal levels of liver enzymes on a routine blood test. Ultrasound imaging, the same technology used to get pictures of developing fetuses, can be informative: the liver looks bright because the fat shows up as white on the image. But neither an ultrasound nor a CT or MRI scan is completely reliable for making a diagnosis. The fat in the liver is visible, but not the NASH-related inflammation. Some researchers have developed formulas that use a simple blood test and measurements of various hormones, inflammatory factors, and liver enzymes to arrive at a diagnosis, but this work is at a preliminary stage.
Currently, a liver biopsy is the only way to make a definitive diagnosis of fatty liver or NASH. Liver biopsies involve inserting a long needle into the right side of the abdomen and extracting a small piece of liver tissue that can be examined under a microscope. Liver biopsies are an invasive procedure, so they aren't entirely free of risk and complications, but they're also fairly routine these days and can be done on an outpatient basis.
Whether a doctor will order a biopsy to nail down a diagnosis depends on many factors, including whether the person is obese or has diabetes or shows other signs of liver trouble.
Weight loss is the treatment
There's been a fair amount of research into using diabetes drugs to treat NASH, even in people who don't have diabetes. Rosiglitazone (sold as Avandia) and pioglitazone (sold as Actos) have been the leading candidates because they reduce insulin resistance, the root cause of fatty livers. They're not looking so promising these days. The FDA has moved to sharply curtail the use of Avandia because it seems to cause heart problems. The results of an important trial published in 2010 in The New England Journal of Medicine showed Actos to be no better than a placebo in improving NASH in people without diabetes.
Another diabetes drug, metformin (Glucophage), might prove to be an effective treatment, but there isn't enough evidence yet. Vitamin E is a possibility: the same trial that showed Actos wasn't effective showed some improvement in the livers of people who took large doses (800 IU daily) of the vitamin. But many doctors are wary about prescribing large doses of vitamin E because they've been associated with an increased risk of bleeding. Besides, the improvements in the liver were limited. Fish oil has produced some favorable results, and clinical trials are under way, but it can't be endorsed yet.
These setbacks and uncertainties have left weight loss (ideally from changes in diet and an increase in physical activity) as the only recommended treatment for most cases of fatty liver disease and NASH. In many cases, weight loss seems to have a very direct effect: as people lose weight, the fatty liver becomes less fatty. Crash dieting is a bad idea, though, because rapid weight loss (losing 4 pounds a week or more) can wind up damaging the liver. Of course, if sustained weight loss were easy, a lot of today's health problems would be solved, not just fatty liver disease and NASH.
In addition to encouraging people to lose weight, doctors will often advise people with diabetes who have fatty liver disease or NASH to be vigilant about controlling their blood sugar.
The bottom line Many parts of the body come to grief once people become obese or develop diabetes. It's not surprising that our livers do too, given how central they are to a whole suite of metabolic processes. There's some evidence that a fatty liver may add to the already high risk of heart disease among people who are obese or have diabetes. Fatty livers can also develop into cirrhotic ones if the inflammatory processes take off.
But there are two bright spots in the take-home message about fatty livers. First, most cases stay relatively stable and don't result in serious liver disease. Second, the treatment is not an expensive drug with side effects, but losing weight — and that will benefit many other parts of the body besides the liver.
Source: Harvard Univ.
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