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Idenix Pharmaceuticals Reports Second Quarter 2010 Financial Results and Provides Research and Development Update on HCV Programs
CAMBRIDGE, Mass., July 26 /PRNewswire-FirstCall/ -- Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today reported unaudited financial results for the second quarter and six months ended June 30, 2010. At June 30, 2010, Idenix's cash and cash equivalents totaled $51.0 million.
Research and Development Highlights
Phase IIa: IDX184, a liver-targeted hepatitis C virus (HCV) nucleotide prodrug
* All patients have recently completed dosing in the 14-day Phase IIa clinical trial evaluating 50 to 200 mg doses of IDX184 in combination with pegylated interferon and ribavirin in treatment-naive HCV genotype 1-infected patients. Data from this study have been submitted to the annual meeting of the American Association for the Study of Liver Diseases (AASLD), which will be held at the end of October in Boston.
Phase I/II: IDX320, an HCV protease inhibitor
* In the second quarter of 2010, Idenix initiated a three-day proof-of-concept study in 38 treatment-naive HCV genotype 1-infected patients. This trial is a Phase I/II randomized, parallel-arm, double-blind, placebo-controlled study evaluating the safety and antiviral activity of IDX320. The study is evaluating four doses of IDX320, ranging from 50 to 400 mg once-per-day, and one 200 mg twice-daily dose. Data from this study will be submitted as a late-breaker to the upcoming AASLD meeting.
Phase I: IDX184/IDX320 Combination
* In July 2010, Idenix conducted a two-week Phase I, randomized, double-blind, placebo-controlled study to evaluate the pharmacokinetic drug-drug interaction between IDX320 and IDX184 in healthy volunteers. Two cohorts were evaluated in the study with 10 subjects in each cohort randomized eight to active drug and two to placebo. Subjects in the first cohort received 400 mg once-daily of IDX320 plus placebo for the first week, subsequently adding 100 mg once-daily of IDX184 for the second week. Subjects in the second cohort received 100 mg once-daily of IDX184 plus placebo for the first week, subsequently adding 400 mg once-daily of IDX320 for the second week. Data analysis is ongoing.
Phase I: IDX375, an HCV non-nucleoside polymerase inhibitor
* In the second quarter of 2010, Idenix continued the Phase I clinical trial in healthy volunteers evaluating single and multiple doses, ranging from 200 to 1200 mg per day, of the free acid form of IDX375. Assuming favorable data in this study, the company expects that a three-day proof-of-concept study in treatment-naive genotype 1-infected patients will be initiated in the second half of 2010. An abstract from this program has been submitted to the upcoming AASLD meeting.
"I am pleased to report that our three hepatitis C clinical programs continue to advance and we are also on track to select a clinical candidate with pan-genotypic properties from our preclinical NS5A program later this year," said Jean-Pierre Sommadossi, Ph.D., chairman and chief executive officer of Idenix. "Assuming favorable clinical results, we will submit data to regulatory agencies from the IDX184 Phase IIa study, the IDX320 proof-of-concept study and the IDX184/IDX320 drug-drug interaction study to support discussions related to the potential initiation of a combination study of IDX184 and IDX320 in HCV-infected patients in the second half of the year."
Second Quarter 2010 Financial Results
For the second quarter ended June 30, 2010, Idenix reported total revenues of $1.3 million, compared to total revenues of $2.4 million in the second quarter of 2009. The company reported a net loss of $16.3 million, or a loss of $0.23 per basic and diluted share, for the second quarter ended June 30, 2010, compared to a net loss of $16.3 million, or a loss of $0.28 per basic and diluted share for the second quarter ended June 30, 2009.
For the six months ended June 30, 2010, Idenix reported total revenues of $4.0 million, compared to total revenues of $6.5 million for the six months ended June 30, 2009. The company reported a net loss of $32.5 million, or a loss of $0.47 per basic and diluted share, for the six months ended June 30, 2010, compared to a net loss of $29.2 million, or a loss of $0.50 per basic and diluted share, for the six months ended June 30, 2009.
2010 Financial Guidance
The company expects that its current cash and cash equivalents, together with the anticipated royalty payments associated with product sales of Tyzeka®/Sebivo® (telbivudine), can fund operations into mid-2011. This guidance assumes no additional milestone payments, license fees, reimbursement for development programs and no financing activities.
Conference Call and Webcast Information
Idenix will hold a conference call today at 4:30 p.m. ET. To access the call please dial (800) 471-3635 U.S./Canada or (706) 758-9475 International and enter passcode 87241600. To listen to a live webcast of the call, go to "Calendar of Events" in the Idenix Investor Center at www.idenix.com. Please log in approximately 10 minutes before the call to ensure a timely connection. A replay of the conference call and webcast will be available until August 9, 2010. To access the replay, please dial (800) 642-1687 U.S./Canada or (706) 645-9291 International and enter the passcode 87241600.
Recent Scientific Presentations
Scientists from Idenix presented data at the following two clinical workshops in Boston: The 5th International Workshop on Clinical Pharmacology of Hepatitis Therapy on June 23rd-24th and the 5th International Workshop on Hepatitis C - Resistance and New Compounds on June 24th-25th. The presentations are available on the company's website athttp://www.idenix.com/hepc/publications/.
About Idenix
Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of patients with chronic hepatitis C infection. For further information about Idenix, please refer to www.idenix.com.
Forward-looking Statements
This press release contains "forward-looking statements" for purposes of the safe harbor provisions of The Private Securities Litigation Reform Act of 1995, including, but not limited to, the statements regarding the company's future business and financial performance. For this purpose, any statements contained herein that are not statements of historical fact may be deemed forward-looking statements. Without limiting the foregoing, the words "plans," "anticipates," "will," "expects," "goal," "estimates," "projects," "would," "could," "targets," and similar expressions are also intended to identify forward-looking statements, as are expressed or implied statements with respect to the company's clinical development programs or commercialization activities in HIV or hepatitis C including any expressed or implied statements regarding the efficacy and safety of our drug candidates, the likelihood and success of any future clinical trials involving our drug candidates or successful development of novel combinations of direct-acting antivirals for the treatment of hepatitis C, or any potential pipeline candidates and expectations with respect to additional milestone payments, future royalty payments and cash balances at the end of 2010. Actual results may differ materially from those indicated by such forward-looking statements as a result of risks and uncertainties, including but not limited to the following: there can be no guarantees that historical sales of Tyzeka®/Sebivo® (telbivudine) will in any way suggest future royalty payments or royalty rates owed to the company, or that the company will advance any clinical product candidate or other component of its potential pipeline to the clinic, to the regulatory process or to commercialization; management's expectations could be affected by unexpected regulatory actions or delays; uncertainties relating to, or unsuccessful results of, clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; the company's ability to obtain additional funding required to conduct its research, development and commercialization activities; the company's dependence on its collaborations with Novartis Pharma AG and GlaxoSmithKline; changes in the company's business plan or objectives; the ability of the company to attract and retain qualified personnel; competition in general; and the company's ability to obtain, maintain and enforce patent and other intellectual property protection for its product candidates and its discoveries. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. These and other risks which may impact management's expectations are described in greater detail under the heading "Risk Factors" in each of the company's annual report on Form 10-K for the year ended December 31, 2009 and quarterly report on Form 10-Q for the quarter ended March 31, 2010 as filed with the Securities and Exchange Commission (SEC), and in any subsequent periodic or current report that the company files with the SEC.
All forward-looking statements reflect the company's estimates only as of the date of this release (unless another date is indicated) and should not be relied upon as reflecting the company's views, expectations or beliefs at any date subsequent to the date of this release. While Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, even if the company's estimates change.
IDENIX PHARMACEUTICALS, INC.
CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS
(IN THOUSANDS, EXCEPT PER SHARE DATA)
(UNAUDITED)
Three Months Ended
June 30,
Six Months Ended
June 30,
2010
2009
2010
2009
Revenues:
Collaboration revenue – related party
$ 527
$2,182
$2,943
$6,098
Other revenue
789
267
1,056
362
Total revenues
1,316
2,449
3,999
6,460
Operating expenses (1):
Cost of revenues
675
492
1,234
954
Research and development
12,149
11,400
23,911
22,250
General and administrative
5,091
5,357
9,868
11,373
Restructuring charges
-
1,506
2,238
1,506
Total operating expenses
17,915
18,755
37,251
36,083
Loss from operations
(16,599)
(16,306)
(33,252)
(29,623)
Other income, net
347
59
788
469
Loss before income taxes
(16,252)
(16,247)
(32,464)
(29,154)
Income tax expense
(4)
(67)
(5)
(87)
Net loss
$(16,256)
$(16,314)
$(32,469)
$(29,241)
Basic and diluted net loss per share:
($0.23)
($0.28)
($0.47)
($0.50)
Shares used in calculation of basic and diluted net loss per share:
70,446
59,077
68,419
58,014
(1) Share-based compensation expenses included in operating expenses amounted to approximately:
Research and development
$ 314
$ 408
$ 634
$ 847
General and administrative
643
783
1,304
1,599
IDENIX PHARMACEUTICALS, INC.
CONDENSED CONSOLIDATED BALANCE SHEETS
(IN THOUSANDS)
(UNAUDITED)
June 30,
2010
December 31,
2009
ASSETS
Cash and cash equivalents
$ 51,007
$ 46,519
Receivables from related party
910
1,049
Other current assets
3,849
4,012
Total current assets
55,766
51,580
Intangible asset, net
10,438
11,069
Property and equipment, net
7,963
10,091
Marketable securities
-
1,584
Other assets
3,005
2,326
Total assets
$ 77,172
$ 76,650
LIABILITIES AND STOCKHOLDERS' DEFICIT
Accounts payable and accrued expenses
$ 12,867
$ 10,720
Deferred revenue, related party
3,042
6,155
Other current liabilities
1,732
1,469
Total current liabilities
17,641
18,344
Long-term obligations
36,674
32,983
Deferred revenue, related party, net of current portion
30,170
30,776
Total liabilities
84,485
82,103
Stockholders' deficit
(7,313)
(5,453)
Total liabilities and stockholders' deficit
$ 77,172
$ 76,650
Idenix Pharmaceuticals Contacts:
Teri Dahlman (617) 995-9905 (media)
Jonae Barnes (617) 224-4485 (investors)
SOURCE Idenix Pharmaceuticals, Inc.
Tuesday, July 27, 2010
Hope Against Hepatitis C - ' this will be revolutionary'
Hope Against Hepatitis C - '
this will be revolutionary'
NY Times
Andrew Pollack July 21 2010
New medicines are being developed that are expected to transform the care of patients with hepatitis C, making treatment far more effective and far less grueling.
Betty Stevenson, a hepatitis C patient and former heroin addict, speaking about how the Oasis program helped save her life.
The new drugs, which could start reaching the market as early as next year, could help subdue a virus that infects roughly four million Americans, most of them baby boomers, and 170 million people worldwide.
Screen shot 2010-07-22 at 1.05.13 AM.png
“I almost think this will be revolutionary, to be honest,” said Dr. Fred Poordad, chief of hepatology at Cedars-Sinai Medical Center in Los Angeles. “We are chomping at the bit to try to treat as many patients as we can.”
About two dozen pharmaceutical companies are now pursuing drugs for hepatitis C, which an executive at Vertex Pharmaceuticals recently called “one of the largest pharmaceutical opportunities this decade.”
That is because the toll of the disease, which now kills about 12,000 Americans a year, is expected to rise in the coming decade. Although new cases have dropped sharply, hundreds of thousands of people who were infected decades ago are expected to start experiencing the effects of liver damage.
New cases of liver cancer are already rising year by year. And hepatitis C is the leading cause of liver transplants, like the one recently received by the rock musician Gregg Allman.
Hopes for new treatments were buoyed in May by the first results from a late-stage clinical trial of one of the new drugs, telaprevir from Vertex. When added to the existing treatment — a combination of alpha interferon and ribavirin — telaprevir effectively cured 75 percent of patients, compared with 44 percent of those treated with the existing drugs alone. And for many patients, the course of treatment could be halved to 24 weeks.
Dr. Poordad, who is a consultant to some of the pharmaceutical companies, said that one-fifth of his patients were being “warehoused,” meaning they were forgoing treatment now to wait for the new drugs.
But even if the drugs do work, some experts and doctors warn that this virus may be particularly tough to vanquish. Three-quarters of the people who are infected do not know it because they are not tested for the virus and because the infection can be asymptomatic for years while it stealthily attacks the liver.
And because this disease is transmitted by blood, those infected largely are former or current IV-drug users — a population that characteristically has little or no health insurance — who may not be the most able to stick to a lengthy treatment regimen that can cause brutal side effects.
Pharmaceutical companies “completely ignore the real face of hepatitis C,” said Dr. Diana L. Sylvestre, who runs a clinic in Oakland, Calif., that treats drug addicts and former addicts with hepatitis C. “A minority of patients who have hepatitis C will benefit from these drugs.”
When she gave a recent talk at Vertex, Dr. Sylvestre’s first slide showed a man in a suit, meant to be a Vertex executive, with his head in the sand.
Dr. Camilla Graham, a senior director of medical affairs at Vertex, said that addicts accounted for less than 10 percent of people with hepatitis C. While many people got infected by trying drugs in the 1960s and 1970s, they have long since kicked the habit, she said.
Hepatitis C can also be transmitted sexually, particularly when men have sex with other men. And many people got the virus from blood transfusions before 1992, when donated blood began being tested for the virus.
Nevertheless, pharmaceutical companies realize that difficulties getting patients screened and treated could limit the use of their drugs. So they are contributing to a groundswell of activism to raise awareness of what has long been known as a silent epidemic. Also contributing to the new advocacy is the highly organized H.I.V. community, since 15 to 30 percent of those with H.I.V. also have hepatitis C.
A report issued by the Institute of Medicine in January urged a new national strategy to improve prevention, detection and treatment of hepatitis C and hepatitis B, which also causes liver disease. A hepatitis task force created by the Department of Health and Human Services is preparing an action plan by October. The House Oversight and Government Reform Committee held a hearing on hepatitis last month.
Drug makers contribute to the National Viral Hepatitis Roundtable, which helped pay for the Institute of Medicine report, and several companies have banded together into the Corporate Hepatitis Alliance to lobby for more government funding. In January, several companies started the Viral Hepatitis Action Coalition, to help finance research at the Centers for Disease Control and Prevention.
Vertex has commissioned studies projecting a rising toll from hepatitis C. One such study, done by Milliman, a health insurance consulting firm, projected that the number of people with advanced liver disease from hepatitis C would quadruple in 20 years if treatment did not improve.
Screening people for hepatitis C should become easier. In June, the Food and Drug Administration approved a rapid blood test developed by OraSure Technologies that gives an answer in 20 minutes rather than several hours needed if the sample is sent to a lab. Future versions might use a mouth swab, allowing screening to be done at churches, street fairs and other gatherings.
There is a risk that increased screening could result in treatment for people who will never need it. Only 5 to 20 percent of people with chronic infection develop cirrhosis in about 20 to 30 years, and doctors cannot predict which patients those will be.
“I think the companies have done a superb job of marketing this disease,” said Dr. Ronald L. Koretz, emeritus professor of clinical medicine at the University of California, Los Angeles. Dr. Koretz said there was no good evidence that treatment made a difference since many patients cured by the drugs might never have developed serious problems anyway.
The current treatment for hepatitis C consists of weekly injections of alpha interferon — the leading brands are Roche’s Pegasys and Merck’s PegIntron — combined with ribavirin, a generic oral drug. It is not quite clear how these drugs work.
The regimen usually lasts either 24 or 48 weeks and costs more than $30,000. It can be rough, causing flulike symptoms, depression, anemia and other problems. And the treatment fails to cure the patient about half the time, either because it cannot clear the virus from the body or because the patient cannot tolerate the drugs.
The new drugs generally inhibit enzymes needed by the virus, a strategy that has worked well against H.I.V. The two drugs that could conceivably make it to the market by next year, Vertex’s telaprevir and Merck’s boceprevir, are both pills that inhibit the protease enzyme.
For a few years at least, the new drugs would have to be used along with interferon. But doctors are hopeful that starting perhaps in five years, combinations of the new pills will do away with the need for interferon.
The drugs could offer new hope to an estimated 300,000 people for whom the existing treatment has not worked. Some early data suggests that telaprevir, when combined with the existing drugs, could cure half of them.
“I was willing to try yesterday,” said Kenny C. Charles, 58, of Woodbourne, N.Y., who said he got hepatitis C from blood transfusions and had undergone four unsuccessful treatment attempts with the existing drugs. Now, he said, his liver was starting to show signs of cirrhosis, or scarring.
Some people with hemophilia, who were infected more than 25 years ago by blood-clotting drugs derived from human plasma, are pressing the Food and Drug Administration to allow them to be treated with combinations of the new drugs, without interferon, even before the new drugs are approved. The F.D.A. held a public hearing on the request in April and is now formulating a policy.
Mark Antell of Rosslyn, Va., one of the organizers of the petition, said he had to stop taking interferon because of flulike symptoms, loss of hair and creaking joints. “It was as though I was aging very rapidly,” he said.
Mr. Antell, 63, a retired Environmental Protection Agency employee, said hemophiliacs were typically not allowed into clinical trials to test the new drugs, so they needed another way to obtain them.
“I think there’s a lot of guys in my situation, and we don’t have a lot of time,” he said.
this will be revolutionary'
NY Times
Andrew Pollack July 21 2010
New medicines are being developed that are expected to transform the care of patients with hepatitis C, making treatment far more effective and far less grueling.
Betty Stevenson, a hepatitis C patient and former heroin addict, speaking about how the Oasis program helped save her life.
The new drugs, which could start reaching the market as early as next year, could help subdue a virus that infects roughly four million Americans, most of them baby boomers, and 170 million people worldwide.
Screen shot 2010-07-22 at 1.05.13 AM.png
“I almost think this will be revolutionary, to be honest,” said Dr. Fred Poordad, chief of hepatology at Cedars-Sinai Medical Center in Los Angeles. “We are chomping at the bit to try to treat as many patients as we can.”
About two dozen pharmaceutical companies are now pursuing drugs for hepatitis C, which an executive at Vertex Pharmaceuticals recently called “one of the largest pharmaceutical opportunities this decade.”
That is because the toll of the disease, which now kills about 12,000 Americans a year, is expected to rise in the coming decade. Although new cases have dropped sharply, hundreds of thousands of people who were infected decades ago are expected to start experiencing the effects of liver damage.
New cases of liver cancer are already rising year by year. And hepatitis C is the leading cause of liver transplants, like the one recently received by the rock musician Gregg Allman.
Hopes for new treatments were buoyed in May by the first results from a late-stage clinical trial of one of the new drugs, telaprevir from Vertex. When added to the existing treatment — a combination of alpha interferon and ribavirin — telaprevir effectively cured 75 percent of patients, compared with 44 percent of those treated with the existing drugs alone. And for many patients, the course of treatment could be halved to 24 weeks.
Dr. Poordad, who is a consultant to some of the pharmaceutical companies, said that one-fifth of his patients were being “warehoused,” meaning they were forgoing treatment now to wait for the new drugs.
But even if the drugs do work, some experts and doctors warn that this virus may be particularly tough to vanquish. Three-quarters of the people who are infected do not know it because they are not tested for the virus and because the infection can be asymptomatic for years while it stealthily attacks the liver.
And because this disease is transmitted by blood, those infected largely are former or current IV-drug users — a population that characteristically has little or no health insurance — who may not be the most able to stick to a lengthy treatment regimen that can cause brutal side effects.
Pharmaceutical companies “completely ignore the real face of hepatitis C,” said Dr. Diana L. Sylvestre, who runs a clinic in Oakland, Calif., that treats drug addicts and former addicts with hepatitis C. “A minority of patients who have hepatitis C will benefit from these drugs.”
When she gave a recent talk at Vertex, Dr. Sylvestre’s first slide showed a man in a suit, meant to be a Vertex executive, with his head in the sand.
Dr. Camilla Graham, a senior director of medical affairs at Vertex, said that addicts accounted for less than 10 percent of people with hepatitis C. While many people got infected by trying drugs in the 1960s and 1970s, they have long since kicked the habit, she said.
Hepatitis C can also be transmitted sexually, particularly when men have sex with other men. And many people got the virus from blood transfusions before 1992, when donated blood began being tested for the virus.
Nevertheless, pharmaceutical companies realize that difficulties getting patients screened and treated could limit the use of their drugs. So they are contributing to a groundswell of activism to raise awareness of what has long been known as a silent epidemic. Also contributing to the new advocacy is the highly organized H.I.V. community, since 15 to 30 percent of those with H.I.V. also have hepatitis C.
A report issued by the Institute of Medicine in January urged a new national strategy to improve prevention, detection and treatment of hepatitis C and hepatitis B, which also causes liver disease. A hepatitis task force created by the Department of Health and Human Services is preparing an action plan by October. The House Oversight and Government Reform Committee held a hearing on hepatitis last month.
Drug makers contribute to the National Viral Hepatitis Roundtable, which helped pay for the Institute of Medicine report, and several companies have banded together into the Corporate Hepatitis Alliance to lobby for more government funding. In January, several companies started the Viral Hepatitis Action Coalition, to help finance research at the Centers for Disease Control and Prevention.
Vertex has commissioned studies projecting a rising toll from hepatitis C. One such study, done by Milliman, a health insurance consulting firm, projected that the number of people with advanced liver disease from hepatitis C would quadruple in 20 years if treatment did not improve.
Screening people for hepatitis C should become easier. In June, the Food and Drug Administration approved a rapid blood test developed by OraSure Technologies that gives an answer in 20 minutes rather than several hours needed if the sample is sent to a lab. Future versions might use a mouth swab, allowing screening to be done at churches, street fairs and other gatherings.
There is a risk that increased screening could result in treatment for people who will never need it. Only 5 to 20 percent of people with chronic infection develop cirrhosis in about 20 to 30 years, and doctors cannot predict which patients those will be.
“I think the companies have done a superb job of marketing this disease,” said Dr. Ronald L. Koretz, emeritus professor of clinical medicine at the University of California, Los Angeles. Dr. Koretz said there was no good evidence that treatment made a difference since many patients cured by the drugs might never have developed serious problems anyway.
The current treatment for hepatitis C consists of weekly injections of alpha interferon — the leading brands are Roche’s Pegasys and Merck’s PegIntron — combined with ribavirin, a generic oral drug. It is not quite clear how these drugs work.
The regimen usually lasts either 24 or 48 weeks and costs more than $30,000. It can be rough, causing flulike symptoms, depression, anemia and other problems. And the treatment fails to cure the patient about half the time, either because it cannot clear the virus from the body or because the patient cannot tolerate the drugs.
The new drugs generally inhibit enzymes needed by the virus, a strategy that has worked well against H.I.V. The two drugs that could conceivably make it to the market by next year, Vertex’s telaprevir and Merck’s boceprevir, are both pills that inhibit the protease enzyme.
For a few years at least, the new drugs would have to be used along with interferon. But doctors are hopeful that starting perhaps in five years, combinations of the new pills will do away with the need for interferon.
The drugs could offer new hope to an estimated 300,000 people for whom the existing treatment has not worked. Some early data suggests that telaprevir, when combined with the existing drugs, could cure half of them.
“I was willing to try yesterday,” said Kenny C. Charles, 58, of Woodbourne, N.Y., who said he got hepatitis C from blood transfusions and had undergone four unsuccessful treatment attempts with the existing drugs. Now, he said, his liver was starting to show signs of cirrhosis, or scarring.
Some people with hemophilia, who were infected more than 25 years ago by blood-clotting drugs derived from human plasma, are pressing the Food and Drug Administration to allow them to be treated with combinations of the new drugs, without interferon, even before the new drugs are approved. The F.D.A. held a public hearing on the request in April and is now formulating a policy.
Mark Antell of Rosslyn, Va., one of the organizers of the petition, said he had to stop taking interferon because of flulike symptoms, loss of hair and creaking joints. “It was as though I was aging very rapidly,” he said.
Mr. Antell, 63, a retired Environmental Protection Agency employee, said hemophiliacs were typically not allowed into clinical trials to test the new drugs, so they needed another way to obtain them.
“I think there’s a lot of guys in my situation, and we don’t have a lot of time,” he said.
July 28th Harlem Hepatitis C Task Force (3-5 PM)- Harlem Public Library - Community Room - 9 West 124th Tuesday, July 20, 2010 6:21 PM
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July 28th Harlem Hepatitis C Task Force (3-5 PM)- Harlem Public Library - Community Room - 9 West 124th
Tuesday, July 20, 2010 6:21 PM
From:
"Nirah Johnson"
View contact details
To:
undisclosed-recipients
Message contains attachments
1 File (4KB)
* image001.jpgimage001.jpg
Harlem Hepatitis C Task Force Meeting
Wednesday July 28th (3-5 PM)
Location Change! Harlem Public Library - Community Room - 9 West 124th Street , Harlem, 10027 (north side of Marcus Garvey Park )
* RSVP would be appreciated. Refreshments will be provided.
Agenda
* “A Comparison of HIV and HCV Health Beliefs in an Inner-City Community” Presentation - Katie Krauskopf, MD, Mount Sinai
* HCV Treatment Readiness Tool (HCV–PRT) - HCV Task Force Project Update – Caroline Licht, PhD , Harlem Hospital
* Hepatitis B & C Advocacy Committee Update – Meets the 2nd Thursday of every month from 10 -12. Please join!
o NYC Hepatitis B & C Advocacy Web Page: http://sites.google.com/site/nychepadvo/home
o Advocacy Alert Planning
+ Engaging the community to take action through disseminating newsletters, email alerts, or subscription to advocacy alert posts to the webpage
o “Adopt-A-Representative” Initiative
+ Making contact and developing a relationship with legislators
+ Tracking contact & progress with shared database
+ Developing “HCV Advocacy Team Leaders” for each legislative district
+ Developing “HCV Advocacy Teams” in key districts who will act upon action alerts
+ Providing advocacy training to the Teams
o Open legislation Update
+ Viral Hepatitis and Liver Cancer Control & Prevention Act (H.R. 3974) - Update
· Sign the Online Petition: Tell Congress: Support the Viral Hepatitis and Liver Cancer Control & Prevention Act (H.R. 3974). When you sign up an email is automatically sent to your U.S. Representative asking him/her to join as a co-sponsor of the bill. You can sign the petition in less than 30 seconds.
* HCV Services Referral Pathway Map – Update
o Getting patients from testing into medical care: Overcoming insurance obstacles & HCV Coaching Program Project
* NYC Hepatitis C Task Force Website Update
o Job, Volunteer & Clinical Trial boards
* Community Announcements
o If you would like to add an announcement to the agenda, reply to this email.
Nirah Johnson , LMSW, Community Projects Specialist
Office of Viral Hepatitis Coordination - NYC Department of Health & Mental Hygiene
125 Worth Street, Room 326. New York , NY 10013
(212) 341-0432 - njohnso2@health.nyc.gov
Office of Viral Hepatitis Coordination Website
NYC Hepatitis B Coalition Website
NYC Hepatitis C Task Force Website
**********************************************************************
The New York City Department of Health & Mental Hygiene is now offering information important for the health of all New Yorkers. To sign up for these new and valuable updates, log-on to our website at http://www.nyc.gov/health/email and select the NYC DOHMH updates you'd like to receive.
IMPORTANT NOTICE: This email is meant only for the use of the intended recipient. It may contain confidential information that is legally privileged or otherwise protected by law. If you have received this communication in error, please notify me immediately by replying to this message and please delete it from your computer. Thank you for your cooperation.
July 28th Harlem Hepatitis C Task Force (3-5 PM)- Harlem Public Library - Community Room - 9 West 124th
Tuesday, July 20, 2010 6:21 PM
From:
"Nirah Johnson"
View contact details
To:
undisclosed-recipients
Message contains attachments
1 File (4KB)
* image001.jpgimage001.jpg
Harlem Hepatitis C Task Force Meeting
Wednesday July 28th (3-5 PM)
Location Change! Harlem Public Library - Community Room - 9 West 124th Street , Harlem, 10027 (north side of Marcus Garvey Park )
* RSVP would be appreciated. Refreshments will be provided.
Agenda
* “A Comparison of HIV and HCV Health Beliefs in an Inner-City Community” Presentation - Katie Krauskopf, MD, Mount Sinai
* HCV Treatment Readiness Tool (HCV–PRT) - HCV Task Force Project Update – Caroline Licht, PhD , Harlem Hospital
* Hepatitis B & C Advocacy Committee Update – Meets the 2nd Thursday of every month from 10 -12. Please join!
o NYC Hepatitis B & C Advocacy Web Page: http://sites.google.com/site/nychepadvo/home
o Advocacy Alert Planning
+ Engaging the community to take action through disseminating newsletters, email alerts, or subscription to advocacy alert posts to the webpage
o “Adopt-A-Representative” Initiative
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Cutting Edge HCV Drug Development with 2 Oral HCV Drugs in Combination
Cutting Edge HCV Drug Development with 2 Oral HCV Drugs in Combination
In 2009 at EASL liver meeting Roche reported for the 1st time data on giving patients 2 HCV oral drugs (R7227, protease + R7128, nuke) in combination alone for 14 days without peg/rbv and achieved potent reductions in viral load in treatment-naives, see link immediately below. This was the proof of concept that 2 HCV oral drugs without peg/rbv is potent, but can we cure HCV without peg/rbv. Subsequently Roche, now Genentech in the USA, decided to boost with ritonavir their HCV protease inhibitor R227 (aka ITMN191), so studies of 2 orals by Roche/Genentech would now be with the nuke R7128 (from Pharmasset) plus the boosted protease R7227. See data below from boosting R7227 with ritonavir and from early INFORM Study. In late 2009 BMS announced they were starting a study giving null responder patients 2 of their oral HCV drugs, the NS5A inhibitor BMS-790052 plus their protease BMS-650032, see below. So can we cure HCV at least for some patients with only 2 oral HCV drugs without peg/rbv??? We may have an early view of data at the end of 2011.
In 2009 at EASL liver meeting Roche reported for the 1st time data on giving patients 2 HCV oral drugs (R7227, protease + R7128, nuke) in combination alone for 14 days without peg/rbv and achieved potent reductions in viral load in treatment-naives, see link immediately below. This was the proof of concept that 2 HCV oral drugs without peg/rbv is potent, but can we cure HCV without peg/rbv. Subsequently Roche, now Genentech in the USA, decided to boost with ritonavir their HCV protease inhibitor R227 (aka ITMN191), so studies of 2 orals by Roche/Genentech would now be with the nuke R7128 (from Pharmasset) plus the boosted protease R7227. See data below from boosting R7227 with ritonavir and from early INFORM Study. In late 2009 BMS announced they were starting a study giving null responder patients 2 of their oral HCV drugs, the NS5A inhibitor BMS-790052 plus their protease BMS-650032, see below. So can we cure HCV at least for some patients with only 2 oral HCV drugs without peg/rbv??? We may have an early view of data at the end of 2011.
Presidio Pharmaceuticals, Inc. Successfully Completes Phase 1a Clinical Trial of PPI-461, a Potent, New Hepatitis C Virus (HCV) Inhibito
Presidio Pharmaceuticals, Inc. Successfully Completes Phase 1a Clinical Trial of PPI-461, a Potent, New Hepatitis C Virus (HCV) Inhibitor
SAN FRANCISCO--(BUSINESS WIRE)--Presidio Pharmaceuticals, Inc. announced today the successful completion of a Phase 1a clinical trial of PPI-461, its lead HCV NS5A inhibitor, in healthy subjects. This first-in-human trial evaluated four single doses of PPI-461, followed by a five-day, once-a-day treatment regimen with PPI-461 at the highest tested dose.
“These first clinical data of PPI-461 indicate excellent tolerance in healthy subjects with all tested dosing regimens. The PK profile is very encouraging, suggesting that plasma concentrations of PPI-461 can be obtained with a relatively low dose, once-daily (QD) regimen that may provide a continuous antiviral effect”
The randomized, double-blind, placebo-controlled trial was completed with 40 healthy subjects in the United Kingdom. The trial results indicated that PPI-461 was well-tolerated in all dose regimens. There were no serious adverse events, and all subjects completed the trial successfully. Among PPI-461 recipients there were only transient adverse events, none of which were attributed to study drug by the investigator, and there were no significant changes in safety-related clinical laboratory assessments.
Pharmacokinetic (PK) analyses showed substantial blood levels of PPI-461 were rapidly and consistently achieved and were dose proportional. PPI-461 plasma concentrations were orders of magnitude above those shown to suppress viral replication in vitro and were maintained at predicted effective concentrations for more than 24 hours. In the five-day, multi-dose regimen, steady-state PK was readily achieved, supportive of once-daily dosing.
“These first clinical data of PPI-461 indicate excellent tolerance in healthy subjects with all tested dosing regimens. The PK profile is very encouraging, suggesting that plasma concentrations of PPI-461 can be obtained with a relatively low dose, once-daily (QD) regimen that may provide a continuous antiviral effect,” said Nathaniel Brown, M.D., Chief Medical Officer.
Presidio Pharmaceuticals, Inc. plans to initiate a Phase 1b proof-of-concept trial in patients with HCV in Q4 2010 and expects to have early results regarding the clinical efficacy of PPI-461 near year-end.
ABOUT PPI-461
PPI-461 is a novel, proprietary NS5A inhibitor against hepatitis C virus (HCV), exhibiting highly potent and selective activity against all genotypes in HCV replicon assays.
Inhibitors of the HCV NS5A protein represent an exciting, highly potent class that is distinct from other classes of HCV antivirals that target the viral protease or replicase. With poor response and tolerance issues associated with the current standard of care treatment—pegylated-IFN and ribavirin—there is clear need for more potent and better tolerated inhibitors that can be orally administered in future combination therapies.
ABOUT PRESIDIO
Presidio Pharmaceuticals, Inc. is a San Francisco-based specialty pharmaceutical company dedicated to the discovery and development of small-molecule antiviral therapeutics for novel and validated targets. For more information, please visit our website at: www.presidiopharma.com.
Contacts
Presidio Pharmaceuticals, Inc.
Omar K. Haffar, PhD, 415-655-7561
omar@presidiopharma.com
SAN FRANCISCO--(BUSINESS WIRE)--Presidio Pharmaceuticals, Inc. announced today the successful completion of a Phase 1a clinical trial of PPI-461, its lead HCV NS5A inhibitor, in healthy subjects. This first-in-human trial evaluated four single doses of PPI-461, followed by a five-day, once-a-day treatment regimen with PPI-461 at the highest tested dose.
“These first clinical data of PPI-461 indicate excellent tolerance in healthy subjects with all tested dosing regimens. The PK profile is very encouraging, suggesting that plasma concentrations of PPI-461 can be obtained with a relatively low dose, once-daily (QD) regimen that may provide a continuous antiviral effect”
The randomized, double-blind, placebo-controlled trial was completed with 40 healthy subjects in the United Kingdom. The trial results indicated that PPI-461 was well-tolerated in all dose regimens. There were no serious adverse events, and all subjects completed the trial successfully. Among PPI-461 recipients there were only transient adverse events, none of which were attributed to study drug by the investigator, and there were no significant changes in safety-related clinical laboratory assessments.
Pharmacokinetic (PK) analyses showed substantial blood levels of PPI-461 were rapidly and consistently achieved and were dose proportional. PPI-461 plasma concentrations were orders of magnitude above those shown to suppress viral replication in vitro and were maintained at predicted effective concentrations for more than 24 hours. In the five-day, multi-dose regimen, steady-state PK was readily achieved, supportive of once-daily dosing.
“These first clinical data of PPI-461 indicate excellent tolerance in healthy subjects with all tested dosing regimens. The PK profile is very encouraging, suggesting that plasma concentrations of PPI-461 can be obtained with a relatively low dose, once-daily (QD) regimen that may provide a continuous antiviral effect,” said Nathaniel Brown, M.D., Chief Medical Officer.
Presidio Pharmaceuticals, Inc. plans to initiate a Phase 1b proof-of-concept trial in patients with HCV in Q4 2010 and expects to have early results regarding the clinical efficacy of PPI-461 near year-end.
ABOUT PPI-461
PPI-461 is a novel, proprietary NS5A inhibitor against hepatitis C virus (HCV), exhibiting highly potent and selective activity against all genotypes in HCV replicon assays.
Inhibitors of the HCV NS5A protein represent an exciting, highly potent class that is distinct from other classes of HCV antivirals that target the viral protease or replicase. With poor response and tolerance issues associated with the current standard of care treatment—pegylated-IFN and ribavirin—there is clear need for more potent and better tolerated inhibitors that can be orally administered in future combination therapies.
ABOUT PRESIDIO
Presidio Pharmaceuticals, Inc. is a San Francisco-based specialty pharmaceutical company dedicated to the discovery and development of small-molecule antiviral therapeutics for novel and validated targets. For more information, please visit our website at: www.presidiopharma.com.
Contacts
Presidio Pharmaceuticals, Inc.
Omar K. Haffar, PhD, 415-655-7561
omar@presidiopharma.com
HIV & Hepatitis C: Coping with Coinfection (Part 1)
HIV & Hepatitis C: Coping with Coinfection (Part 1)
Bova, Ogawa, and Sullivan-Bolyai (2010) report that "an estimated 25% to 40% of HIV-infected patients are also infected with HCV [hepatitis C virus], and in some practices the prevalence is as high as 75% to 90%. . . . Recent estimates suggest that approximately 250,000 persons are coinfected with HIV and HCV in the United States" (p. 63), "and with HIV antiretroviral therapy (ART) extending the life of people living with HIV, end-stage liver disease is now a leading cause of death in this population. . . . Studies show that a majority of coinfected patients have at least moderate liver inflammation or other signs of disease progression, . . . however, several studies published over the past 5 years have shown that less than one third of HIV coinfected patients in the United States are deemed eligible for HCV treatment, and under 10% actually receive treatment" (Wagner et al., 2009, p. 715).
Increasing attention has been directed to individuals coinfected with HIV and HCV because
in patients infected only with HCV, the time between infection and development of fibrosis [scar tissue resulting from inflammation of the liver] averages 20 years, whereas in patients coinfected with HIV/HCV, liver disease may develop in 5 to 10 years. . . . [Additionally,] HCV infection . . . influences the course and management of HIV disease, particularly by increasing the risk of ART-induced hepatotoxicity [liver damage]. . . . The goal of HCV treatment is to achieve a sustained virologic response (SVR), which is defined as the absence of serum hepatitis C RNA for 24 weeks after treatment completion. . . . Without HCV treatment, increasing numbers of HIV-infected patients will die either from end-stage liver disease or from HIV-related complications resulting from the inability to use antiretroviral agents because of their hepatotoxicity. (Bova et al., 2010, p. 64)
This is the first of a two-part series. Part 1 provides a medical, psychiatric, psychosocial, and neuropsychological overview of HIV/HCV coinfection, the process of determining eligibility for HCV treatment, and the important role mental health clinicians play in assessing eligibility and intervening with clients who elect to receive treatment for HCV.
Part 2 (to be presented in the Summer 2010 issue of mental health AIDS) will expand on how providers make the decision to offer HCV treatment to individuals living with HIV and chronic HCV infection, how coinfected individuals make decisions to accept or defer treatment for HCV, and the latest thinking on HCV-treatment interventions.
The Chance of a Cure
"A patient's willingness to undergo HCV treatment is likely influenced by how the patient views the efficacy and burden or risk of treatment" (Osilla et al., 2009, p. 993).
On the question of efficacy, it's important to know that "at least six distinct genotypes (numbered 1-6) and more than 30 subtypes of HCV are known," but "the most common genotype present in the United States, genotype 1, is also the most resistant to treatment" (Bova et al., 2010, pp. 63-64). According to Osilla et al. (2009), "standard HCV treatment, which consists of 48 weeks of weekly pegylated interferon (PEG-IFN) injections in combination with daily ribavirin (RBV), . . . has demonstrated a success rate of 30%-45% among HIV coinfected patients across all genotypes, . . . but only 17%-29% among HIV patients with . . . HCV . . . genotype 1" (p. 993). Although "new treatment agents (e.g., protease and polymerase inhibitors) that may improve treatment efficacy are at various stages of development and testing, . . . [they] are not expected to be available for routine practice for at least a few years and [IFN] will remain a component of treatment" (Wagner et al., 2009, p. 715).
As for the risks involved, treatment for HCV has been characterized as "lengthy, rigorous, and associated with side effects that are difficult to manage" (Silberbogen, Ulloa, Janke, & Mori, 2009, p. 114). "Flu-like symptoms (nausea, diarrhea, weight loss)" and "fatigue associated with hematologic abnormalities (anemia, neutropenia) . . . [are] highly prevalent" (Wagner et al., 2009, pp. 715-716). "In addition to physiological side effects, there are also significant neuropsychiatric side effects, including depression, anxiety, irritability, psychosis, suicidality, apathy/malaise, fatigue, impaired concentration, anhedonia, and recurrence of posttraumatic stress disorder symptoms" (Silberbogen et al., 2009, p. 114).
"Not surprisingly, a general fear and apprehension regarding side effects and their impact on quality of life and functioning are common among patients considering treatment" (Osilla et al., 2009, p. 993), and Wagner and colleagues report "dropout rates as high as 40%-50% in community samples of coinfected patients" (p. 716). Yet, "despite these side effects and related patient concerns," proponents of HCV treatment "recommend early treatment for coinfected patients to prevent more serious disease development" (Osilla et al., 2009, pp. 993-994) and "can argue that PEG-IFN/RBV, unlike ART, has a limited duration and at least a chance of a cure" (Wagner et al., 2009, p. 716; see also neuropsychology sidebar).
The Offer of Treatment
"Upon detection of HCV infection, for treatment to be provided, providers must first consider a patient an appropriate treatment candidate, and multiple medical and psychosocial factors can contribute to a provider's reluctance to recommend or offer treatment to a patient" (Osilla et al., 2009, p. 993). In a Seattle HIV-specialty clinic, for example, among 248 predominantly white and male, HCV/HIV-coinfected patients, fewer than half . . . were evaluated for possible [IFN]-based HCV treatment. Only 16% received treatment, and only 2.4% of the entire cohort achieved an SVR. The median time to evaluation for treatment was almost 3 years, a significant period of delay in patients who may have a much more rapid progression to cirrhosis [the final stage of fibrosis], compared to patients without HIV. . . . Similarly, the median time elapsing between evaluation and treatment initiation was 1.4 years. Substance abuse and advanced HIV infection were the primary reasons for nonevaluation. (Scott et al., 2009, p. 928)
According to Wagner and colleagues (2009), substance abuse and mental illness each account for 20%-30% of coinfected patients being deemed ineligible for treatment, as clinicians are concerned that the side effects of HCV treatment may lead to psychiatric deterioration, relapse into substance abuse, poor adherence, and treatment discontinuation. . . . Psychiatric and substance abuse patients have been excluded from most clinical trials, but the little data available show mixed results; some studies find that such patients do equally as well in terms of ability to complete and respond to treatment, . . . while others suggest that patients with active substance abuse and psychiatric problems are less likely to respond and more likely to drop out of treatment. (p. 716)
For this reason, mental health clinicians are often called upon to conduct a psychological evaluation to determine appropriateness for this course of treatment. . . . A pre-treatment psychological evaluation should assess for those factors that will maximize the likelihood of a successful treatment course. Therefore, clinicians should assess for: psychiatric stability and safety (e.g., suicidal ideation, uncontrolled depression), current and past substance use and abuse, knowledge and expectations about treatment for HCV, motivation and ability to adhere to treatment, and psychosocial support.1 . . . After an assessment, clinicians can help prepare patients for treatment by providing education, establishing realistic expectations of treatment success, developing stress-management skills, and identifying areas of concern that patients and/or providers can monitor throughout the course of treatment. Also, a clinician can discuss the potential benefits of a referral for psychiatry consultation to consider psychotropic medication. However, it is important to note that there have been few large-sample, controlled studies evaluating the benefits of prophylactic psychotropic medications in HCV patients on IFN treatment, and that studies with small sample sizes have found inconsistent results. (Silberbogen et al., 2009, p. 117; see alsopsychiatry sidebar)
The Role of the Mental Health Clinician
Silberbogen and colleagues (2009) "have identified areas in which clinicians can intervene [with patients diagnosed with HCV]; these include adjustment to having a chronic medical illness, coping with stigma and relationship changes, management of side effects, and implementing healthy lifestyle changes" (p. 114). Some of the recommendations from these authors in each of these areas follow:
Adjustment to having a chronic medical illness - At the time of diagnosis with HCV, "a mental health clinician can help a patient to process this new diagnosis, generate effective coping strategies, facilitate communication between the patient and hepatologists, and serve as a resource for patients' questions and concerns while providing stability and support" (p. 115). In fact, a key role for the mental health clinician is to ensure that HCV-positive patients have a thorough understanding of their diagnosis and to help translate this knowledge into behavioral change. A well-informed clinician can assess patients' current level of understanding, correct inaccurate beliefs, increase their base of knowledge, and help patients set behaviorally-based goals consistent with treatment recommendations.
Although education may be sufficient to assist some during this adjustment process, other patients may benefit from counseling that helps them to make sense of this diagnosis. Cognitive-behavioral stress-management interventions have proven effective in reducing depressive symptoms and enhancing benefit-finding, positive reframing, and perceived social support in chronic medical populations, including those with HIV. . . . Stress- and anger-management interventions are likely to benefit patients struggling with the unpredictability that often accompanies the diagnosis of a chronic illness. Mental health clinicians can also help patients to identify areas of their life in which they can exert some control (i.e., response to stressors) that may counterbalance these negative psychological sequelae. (pp. 115-116) Coping with stigma and relationship changes - Clinician can help individuals living with HCV to "identity ways to buffer themselves from the impact of stigmatization, such as building a supportive network of friends, family, and medical providers, advocating assertively for . . . [their] needs, and learning how to disclose information while being self-protective. Therapy can also focus on enhancing patients' self-esteem by identifying and building on their positive attributes. Some patients may find value in activities that give them a sense of purpose (e.g., public-awareness programs, political advocacy)" (p. 116). In addition, "mental health clinicians can assist individuals with HCV to navigate . . . changes within their social support network. Communication and problem-solving skills training specifically focused on managing role-changes may prove beneficial, as well as acceptance-based work. Also, participation in couples or family therapy can allow patients to practice these skills in a supportive environment" (p. 116).
Finally, clinicians can help patients build their social support networks by treating mood disorders that interfere with social efforts and by setting small goals toward increased socialization. Clinicians can also assist HCV patients to identify and enhance existing relationships that they may initially overlook or discount. Patients may find it beneficial to engage in "safer" outlets for social interaction, such as online support communities, volunteer positions, or psycho-educational/support groups for patients with HCV, liver disease, or chronic medical conditions. Support groups can be a useful source of information and connection for patients with chronic illness. Mental health providers can make an important contribution to the care of patients with HCV by organizing and/or facilitating support groups focused on issues relevant to this patient population. In addition to providing much-needed social support, these groups can provide education, promote positive health behaviors, and moderate experiences of stigma or discrimination. (p. 117)2
Management of side effects - Once treatment has been initiated, mental health clinicians can use brief standardized measures (e.g., the Beck Depression Inventory) . . . to monitor the presence and severity of psychiatric symptoms . . . and can address specific symptoms in the context of therapy. Stress-management (e.g., relaxation exercises, problem-solving practice), behavioral activation, cognitive restructuring, and enhancement of self-care behaviors (e.g., exercise, proper diet, sleep hygiene) are useful strategies for minimizing potential side effects. Clinicians are also in an excellent position to provide feedback to medical staff, such as psychiatrists, should greater intervention be necessary (i.e., psychotropic medications). (pp. 117-118) In the area of medication adherence, "clinicians can help patients to identify and problem-solve barriers to treatment-adherence, assist in the organization and scheduling of medications, manage side effects, and facilitate access to medical providers" (p. 118).
Implementing healthy lifestyle changes - Because alcohol has a detrimental effect on liver functioning, "reduction in alcohol use is one of the most important behavioral changes patients can make to slow the rate of HCV progression" (p. 118), and "patients with an understanding of the relationship between HCV and alcohol use may be increasingly motivated to make and sustain healthy lifestyle changes" (p. 119). In support of this effort, mental health clinicians can work with patients to develop a concrete change plan based on their stated goals for treatment and anticipate challenges that may interfere with the execution of these goals. Also, patients on IFN treatment who have a history of alcohol abuse or dependence may benefit from ongoing monitoring and support from a clinician with experience in substance-abuse counseling, because the side effects of treatment may result in increased urges and cravings. . . .
Several standardized instruments, such as the Alcohol Use Disorders Identification Test (AUDIT) . . . or the Alcohol Abstinence Self-Efficacy Scale, . . . may prove useful to the clinician assessing and monitoring alcohol intake for patients with HCV. These brief measures are easy to administer and can be used to identify patients in need of additional intervention. All patients should be educated regarding the effects of alcohol on the course of HCV, and, when appropriate, should be evaluated by a chemical-dependency specialist. (p. 118)
Because cigarette-smoking can affect "liver health, treatment efficacy, and quality of life," clinicians are encouraged to review "evidence-based recommendations from research in general populations that can be used as guides for . . . assisting . . . HCV-positive patient[s] to quit smoking or reduce the amount that they smoke. . . . Goals of these recommendations are to increase screening, enhance motivation, and assist patients to reduce tobacco use through problem-solving techniques" (p. 119).
Since "it is likely that improved nutritional status will have a positive effect on disease-progression and long-term outcome for HCV-positive patients," mental health clinicians can take several steps to assist the HCV-positive patient to achieve his or her individual dietary goals. First, clinicians should encourage all HCV-positive patients to pursue a healthy diet and educate patients about how diet can affect their disease progression and quality of life. Unhealthy diet patterns should be identified (e.g., high-sugar and high-fat diets, high daily caloric intake, frequent fast-food consumption, limited fruit and vegetable intake) and addressed. Finally, referrals to nutrition services may be appropriate for some patients, particularly for cases in which the nutritional needs may require a unique or intensive intervention, such as with HCV-positive patients who are overweight/obese, those for whom there are concerns about iron overload, and those who have comorbid metabolic concerns, such as diabetes. (p. 119)
Additionally, with medical-provider approval, HCV-positive patients should be encouraged to participate in regular physical activity to address weight-management, quality of life, and symptom-management. Clinicians can assist HCV patients with setting exercise goals, enhancing motivation to exercise, addressing barriers to activities, and challenging any unhelpful thoughts that interfere with exercise. Devices such as pedometers may motivate patients who are ready to make changes in activity levels. When appropriate, a referral to rehabilitation or physical therapy services for exercise recommendations can be extremely useful. (p. 119) ----Compiled by Abraham Feingold, Psy.D.
References
Bova, C., Ogawa, L.F., & Sullivan-Bolyai, S. (2010). Hepatitis C treatment experiences and decision making among patients living with HIV infection. Journal of the Association of Nurses in AIDS Care, 21(1), 63-74.
Osilla, K.C., Ryan, G., Bhatti, L., Goetz, M., Witt, M., & Wagner, G. (2009). Factors that influence an HIV coinfected patient's decision to start hepatitis C treatment. AIDS Patient Care & STDs, 23(12), 993-999.
Scott, J.D., Wald, A., Kitahata, M., Krantz, E., Drolette, L., Corey, L., & Wang, C.C. (2009). Hepatitis C virus is infrequently evaluated and treated in an urban HIV clinic population. AIDS Patient Care & STDs, 23(11), 925-929. Silberbogen, A.K., Mori, D.L., & Sogg, S. (2005). The Structured Interview for the Treatment of the Hepatitis C Virus (SIT-HCV). Journal of Clinical Psychology in Medical Settings, 12(1), 57-69.
Silberbogen, A.K., Ulloa, E.W., Janke, E.A., & Mori, D.L. (2009). Psychosocial issues and mental health treatment recommendations for patients with hepatitis C. Psychosomatics 50(2), 114-122.
Wagner, G., Ryan, G., Osilla, K.C., Bhatti, L., Goetz, M., & Witt, M. (2009). Treat early or wait and monitor? A qualitative analysis of provider hepatitis C virus treatment decision-making in the context of HIV coinfection. AIDS Patient Care & STDs, 23(9), 715-725. -------------------- 1 One version of the pre-treatment psychological evaluation, "the Structured Interview for the Treatment of the Hepatitis C Virus (SIT-HCV), developed by the Medical Psychology Service at the VA Boston Healthcare System in collaboration with the VA Liver Clinic[,] . . . expands upon a standard psychiatric interview by addressing those psychological and behavioral factors that are unique to this population and essential to consider prior to recommending a patient for IFN therapy. . . . On the basis of the information gathered during the administration of the SIT-HCV, clinicians can make behavioral recommendations that will enhance a patient's likelihood of attaining an optimal treatment outcome while minimizing the impact of incapacitating side effects" (Silberbogen, Mori, & Sogg, 2005, p. 58). The complete protocol can be found in the appendix of Silberbogen and colleagues' article.
2 "As the nation's largest care-provider of patients with HCV, the [Department of Veterans Affairs] has developed a comprehensive website designed to meet both patients' and providers' needs (www.hepatitis.va.gov). . . . Available resources for mental health providers include a 'how-to' program guide that outlines the basic steps for initiating and maintaining a hepatitis C support group. This valuable resource includes a discussion of issues to consider when developing a group, suggestions for group topics, descriptions of therapeutic and facilitation techniques, and sample forms and handouts" (Silberbogen, Ulloa, Janke, & Mori, 2009, p. 117).
Neuropsychology of HIV/HCV Coinfection
"HCV mono-infection is associated with significant impairment in neuropsychological domains typically characterized as 'subcortical' in nature, with predominant impact on attention, information processing speed, and verbal memory. Further, evidence of neuropsychological impairment among HCV mono-infected individuals exists independent of comorbid substance abuse and severe liver disease, raising the possibility of direct brain involvement from HCV" (Martin-Thormeyer & Paul, 2009, p. 223). Moreover, individuals infected with both HCV and HIV express more severe neuropsychological impairment than individuals with HIV alone but the mechanisms underlying these effects remain unclear. To date a handful of studies have examined neuropsychological function among individuals co-infected with HCV and HIV. Among these studies there is notable variability in the methods to examine neuropsychological function, the use of various comparison groups (e.g., HCV alone, HIV alone, both mono-infected groups compared to co-infected patients), and the focus on various laboratory indices of disease burden. These methodological differences require some caution when drawing conclusions regarding the impact of co-infection on cognitive outcome. For example, a number of studies did not involve a comprehensive neuropsychological assessment, and therefore, conclusions regarding the neuropsychological pattern associated with co-infection remains premature. With that caveat noted, there is some suggestion in the literature that several domains of cognitive function are more likely impacted by co-infection than others.
Decreased processing speed and psychomotor speed among co-infected individuals is a commonly reported outcome of the studies . . . [although e]vidence of selective impairment in psychomotor speed/information processing is not universal. . . . [In fact, n]ot all studies have reported greater cognitive impairment among co-infected patients. . . . When taken collectively the majority of studies have reported more severe neuropsychological impairment among co-infected patients than mono-infected patients. (Martin-Thormeyer & Paul, 2009, pp. 224-225) Importantly, "recent studies of dually infected subjects indicate that neurocognitive function may improve with successful therapy for either disorder" (Gonzalez, Quartana, & Martin, 2009, p. 223).
References
Gonzalez, R., Quartana, P.J., & Martin, E.M. (2009). Co-occurrence of HIV, hepatitis C, and substance use disorders: Effects on brain functioning. In R.H. Paul, N.C. Sacktor, V. Valcour, & K.T. Tashima (Eds.), HIV and the brain: New challenges in the modern era (pp. 213-233). Totowa, NJ: Humana Press. Martin-Thormeyer, E.M., & Paul, R.H. (2009). Drug abuse and hepatitis C infection as comorbid features of HIV associated neurocognitive disorder: Neurocognitive and neuroimaging features [Review]. Neuropsychology Review, 19(2), 215-231.
Psychiatry & HIV/HCV Coinfection
According to Silberbogen and colleagues (2009), "numerous studies . . . document high prevalence rates of preexisting psychiatric disorders among patients with HCV. . . . Within the HCV-positive population, approximately 27%-78% of patients are diagnosed with past or current substance abuse, 15%-62% with mood disorders, and 30%-40% with anxiety disorders such as PTSD [posttraumatic stress disorder]" (p. 115).
With regard to the population of co-infected individuals, however, and "in the absence of established guidelines for the management of [the] psychiatric status of HIV/HCV-coinfected patients initiating PEG-IFN/RBV therapy," Weiss and Morgello (2009) "sought to determine what the state of practice is for providers actively engaged in the care of these patients" (p. 532). The investigators developed and reported on "a provider survey designed to determine whether consensus exists in the management of these patients and what factors might impact differing treatment approaches taken by health care providers" (p. 532). They focused in particular on "the use of prophylactic treatment with antidepressants [to] prevent . . . the development of depressive side effects during HCV treatment" (p. 532).
From a pool of 236 "expert" providers invited to participate, the sample consisted of 92 providers who completed the anonymous online survey, 26% of whom were psychiatrists. With regard to practice setting and provider discipline, Weiss and Morgello found that "the psychiatric management of HIV-coinfected patients being treated for HCV occurs in multiple contexts (varying from comprehensive integrated clinics to individual practices) and is done by providers from a wide range of disciplines (infectious disease, psychiatry, internal medicine, nurse practitioner). The survey was able to establish the practice patterns of expert providers who are predominantly physicians working in varied practice settings internationally" (p. 535).1 Notably, most of the nonpsychiatrist survey respondents have "very limited access to psychiatric consultation" (p. 535).
With regard to these practice patterns, more than one third of providers indicate[d] that they use or offer the option of antidepressant use prophylactically in HIV-positive patients with no past or current depression beginning HCV treatment, and more than three quarters do so in patients with a history of depression but no current symptoms of depression. The most experienced nonpsychiatrist providers were more likely to use antidepressants prior to the start of treatment in HIV-coinfected patients as compared to in HCV mono[-]infected patients. There . . . [wa]s consensus among providers to leave psychiatric medication unchanged in patients currently treated for unipolar depression. (p. 531)
Weiss and Morgello conclude that "many expert providers prescribe antidepressants to HIV/HCV-coinfected patients initiating [HCV] treatment in the absence of symptoms of depression, despite the lack of data supporting this approach in this population" (p. 531). The investigators surmise that "this pattern of prescribing . . . may be related to . . . limited access to psychiatric consultation, with providers viewing the prophylactic use of antidepressants as the safest and most cautious treatment approach" (p. 536). Weiss and Morgello advocate for "increasing [nonpsychiatrist] provider skills and competence through advanced training in psychiatric assessment and management[, because this] would likely reduce the extent to which these providers use antidepressants prophylactically and could potentially lead to better HCV treatment outcomes" (p. 536). Additionally (and importantly), "research is needed to provide an evidence base to guide the optimal psychiatric management of HIV/HCV-coinfected patients beginning [HCV] treatment" (p. 531).
References
Silberbogen, A.K., Ulloa, E.W., Janke, E.A., & Mori, D.L. (2009). Psychosocial issues and mental health treatment recommendations for patients with hepatitis C. Psychosomatics 50(2), 114-122.
Wagner, G., Ryan, G., Osilla, K.C., Bhatti, L., Goetz, M., & Witt, M. (2009). Treat early or wait and monitor? A qualitative analysis of provider hepatitis C virus treatment decision-making in the context of HIV coinfection. AIDS Patient Care & STDs, 23(9), 715-725.
Weiss, J.J., & Morgello, S. (2009). Psychiatric management of HIV/HCV-coinfected patients beginning treatment for hepatitis C virus infection: Survey of provider practices. General Hospital Psychiatry, 31(6), 531-537.
1 Wagner et al. (2009) point out that "unlike HCV mono-infected patients, who are typically treated by liver specialists (e.g., hepatologist or gastroenterologist) with extensive experience with HCV treatment, HIV coinfected patients are most often treated by HIV primary care providers (with relatively limited experience with PEG-IFN/RBV) because liver specialists are unavailable" (p. 716).
Bova, Ogawa, and Sullivan-Bolyai (2010) report that "an estimated 25% to 40% of HIV-infected patients are also infected with HCV [hepatitis C virus], and in some practices the prevalence is as high as 75% to 90%. . . . Recent estimates suggest that approximately 250,000 persons are coinfected with HIV and HCV in the United States" (p. 63), "and with HIV antiretroviral therapy (ART) extending the life of people living with HIV, end-stage liver disease is now a leading cause of death in this population. . . . Studies show that a majority of coinfected patients have at least moderate liver inflammation or other signs of disease progression, . . . however, several studies published over the past 5 years have shown that less than one third of HIV coinfected patients in the United States are deemed eligible for HCV treatment, and under 10% actually receive treatment" (Wagner et al., 2009, p. 715).
Increasing attention has been directed to individuals coinfected with HIV and HCV because
in patients infected only with HCV, the time between infection and development of fibrosis [scar tissue resulting from inflammation of the liver] averages 20 years, whereas in patients coinfected with HIV/HCV, liver disease may develop in 5 to 10 years. . . . [Additionally,] HCV infection . . . influences the course and management of HIV disease, particularly by increasing the risk of ART-induced hepatotoxicity [liver damage]. . . . The goal of HCV treatment is to achieve a sustained virologic response (SVR), which is defined as the absence of serum hepatitis C RNA for 24 weeks after treatment completion. . . . Without HCV treatment, increasing numbers of HIV-infected patients will die either from end-stage liver disease or from HIV-related complications resulting from the inability to use antiretroviral agents because of their hepatotoxicity. (Bova et al., 2010, p. 64)
This is the first of a two-part series. Part 1 provides a medical, psychiatric, psychosocial, and neuropsychological overview of HIV/HCV coinfection, the process of determining eligibility for HCV treatment, and the important role mental health clinicians play in assessing eligibility and intervening with clients who elect to receive treatment for HCV.
Part 2 (to be presented in the Summer 2010 issue of mental health AIDS) will expand on how providers make the decision to offer HCV treatment to individuals living with HIV and chronic HCV infection, how coinfected individuals make decisions to accept or defer treatment for HCV, and the latest thinking on HCV-treatment interventions.
The Chance of a Cure
"A patient's willingness to undergo HCV treatment is likely influenced by how the patient views the efficacy and burden or risk of treatment" (Osilla et al., 2009, p. 993).
On the question of efficacy, it's important to know that "at least six distinct genotypes (numbered 1-6) and more than 30 subtypes of HCV are known," but "the most common genotype present in the United States, genotype 1, is also the most resistant to treatment" (Bova et al., 2010, pp. 63-64). According to Osilla et al. (2009), "standard HCV treatment, which consists of 48 weeks of weekly pegylated interferon (PEG-IFN) injections in combination with daily ribavirin (RBV), . . . has demonstrated a success rate of 30%-45% among HIV coinfected patients across all genotypes, . . . but only 17%-29% among HIV patients with . . . HCV . . . genotype 1" (p. 993). Although "new treatment agents (e.g., protease and polymerase inhibitors) that may improve treatment efficacy are at various stages of development and testing, . . . [they] are not expected to be available for routine practice for at least a few years and [IFN] will remain a component of treatment" (Wagner et al., 2009, p. 715).
As for the risks involved, treatment for HCV has been characterized as "lengthy, rigorous, and associated with side effects that are difficult to manage" (Silberbogen, Ulloa, Janke, & Mori, 2009, p. 114). "Flu-like symptoms (nausea, diarrhea, weight loss)" and "fatigue associated with hematologic abnormalities (anemia, neutropenia) . . . [are] highly prevalent" (Wagner et al., 2009, pp. 715-716). "In addition to physiological side effects, there are also significant neuropsychiatric side effects, including depression, anxiety, irritability, psychosis, suicidality, apathy/malaise, fatigue, impaired concentration, anhedonia, and recurrence of posttraumatic stress disorder symptoms" (Silberbogen et al., 2009, p. 114).
"Not surprisingly, a general fear and apprehension regarding side effects and their impact on quality of life and functioning are common among patients considering treatment" (Osilla et al., 2009, p. 993), and Wagner and colleagues report "dropout rates as high as 40%-50% in community samples of coinfected patients" (p. 716). Yet, "despite these side effects and related patient concerns," proponents of HCV treatment "recommend early treatment for coinfected patients to prevent more serious disease development" (Osilla et al., 2009, pp. 993-994) and "can argue that PEG-IFN/RBV, unlike ART, has a limited duration and at least a chance of a cure" (Wagner et al., 2009, p. 716; see also neuropsychology sidebar).
The Offer of Treatment
"Upon detection of HCV infection, for treatment to be provided, providers must first consider a patient an appropriate treatment candidate, and multiple medical and psychosocial factors can contribute to a provider's reluctance to recommend or offer treatment to a patient" (Osilla et al., 2009, p. 993). In a Seattle HIV-specialty clinic, for example, among 248 predominantly white and male, HCV/HIV-coinfected patients, fewer than half . . . were evaluated for possible [IFN]-based HCV treatment. Only 16% received treatment, and only 2.4% of the entire cohort achieved an SVR. The median time to evaluation for treatment was almost 3 years, a significant period of delay in patients who may have a much more rapid progression to cirrhosis [the final stage of fibrosis], compared to patients without HIV. . . . Similarly, the median time elapsing between evaluation and treatment initiation was 1.4 years. Substance abuse and advanced HIV infection were the primary reasons for nonevaluation. (Scott et al., 2009, p. 928)
According to Wagner and colleagues (2009), substance abuse and mental illness each account for 20%-30% of coinfected patients being deemed ineligible for treatment, as clinicians are concerned that the side effects of HCV treatment may lead to psychiatric deterioration, relapse into substance abuse, poor adherence, and treatment discontinuation. . . . Psychiatric and substance abuse patients have been excluded from most clinical trials, but the little data available show mixed results; some studies find that such patients do equally as well in terms of ability to complete and respond to treatment, . . . while others suggest that patients with active substance abuse and psychiatric problems are less likely to respond and more likely to drop out of treatment. (p. 716)
For this reason, mental health clinicians are often called upon to conduct a psychological evaluation to determine appropriateness for this course of treatment. . . . A pre-treatment psychological evaluation should assess for those factors that will maximize the likelihood of a successful treatment course. Therefore, clinicians should assess for: psychiatric stability and safety (e.g., suicidal ideation, uncontrolled depression), current and past substance use and abuse, knowledge and expectations about treatment for HCV, motivation and ability to adhere to treatment, and psychosocial support.1 . . . After an assessment, clinicians can help prepare patients for treatment by providing education, establishing realistic expectations of treatment success, developing stress-management skills, and identifying areas of concern that patients and/or providers can monitor throughout the course of treatment. Also, a clinician can discuss the potential benefits of a referral for psychiatry consultation to consider psychotropic medication. However, it is important to note that there have been few large-sample, controlled studies evaluating the benefits of prophylactic psychotropic medications in HCV patients on IFN treatment, and that studies with small sample sizes have found inconsistent results. (Silberbogen et al., 2009, p. 117; see alsopsychiatry sidebar)
The Role of the Mental Health Clinician
Silberbogen and colleagues (2009) "have identified areas in which clinicians can intervene [with patients diagnosed with HCV]; these include adjustment to having a chronic medical illness, coping with stigma and relationship changes, management of side effects, and implementing healthy lifestyle changes" (p. 114). Some of the recommendations from these authors in each of these areas follow:
Adjustment to having a chronic medical illness - At the time of diagnosis with HCV, "a mental health clinician can help a patient to process this new diagnosis, generate effective coping strategies, facilitate communication between the patient and hepatologists, and serve as a resource for patients' questions and concerns while providing stability and support" (p. 115). In fact, a key role for the mental health clinician is to ensure that HCV-positive patients have a thorough understanding of their diagnosis and to help translate this knowledge into behavioral change. A well-informed clinician can assess patients' current level of understanding, correct inaccurate beliefs, increase their base of knowledge, and help patients set behaviorally-based goals consistent with treatment recommendations.
Although education may be sufficient to assist some during this adjustment process, other patients may benefit from counseling that helps them to make sense of this diagnosis. Cognitive-behavioral stress-management interventions have proven effective in reducing depressive symptoms and enhancing benefit-finding, positive reframing, and perceived social support in chronic medical populations, including those with HIV. . . . Stress- and anger-management interventions are likely to benefit patients struggling with the unpredictability that often accompanies the diagnosis of a chronic illness. Mental health clinicians can also help patients to identify areas of their life in which they can exert some control (i.e., response to stressors) that may counterbalance these negative psychological sequelae. (pp. 115-116) Coping with stigma and relationship changes - Clinician can help individuals living with HCV to "identity ways to buffer themselves from the impact of stigmatization, such as building a supportive network of friends, family, and medical providers, advocating assertively for . . . [their] needs, and learning how to disclose information while being self-protective. Therapy can also focus on enhancing patients' self-esteem by identifying and building on their positive attributes. Some patients may find value in activities that give them a sense of purpose (e.g., public-awareness programs, political advocacy)" (p. 116). In addition, "mental health clinicians can assist individuals with HCV to navigate . . . changes within their social support network. Communication and problem-solving skills training specifically focused on managing role-changes may prove beneficial, as well as acceptance-based work. Also, participation in couples or family therapy can allow patients to practice these skills in a supportive environment" (p. 116).
Finally, clinicians can help patients build their social support networks by treating mood disorders that interfere with social efforts and by setting small goals toward increased socialization. Clinicians can also assist HCV patients to identify and enhance existing relationships that they may initially overlook or discount. Patients may find it beneficial to engage in "safer" outlets for social interaction, such as online support communities, volunteer positions, or psycho-educational/support groups for patients with HCV, liver disease, or chronic medical conditions. Support groups can be a useful source of information and connection for patients with chronic illness. Mental health providers can make an important contribution to the care of patients with HCV by organizing and/or facilitating support groups focused on issues relevant to this patient population. In addition to providing much-needed social support, these groups can provide education, promote positive health behaviors, and moderate experiences of stigma or discrimination. (p. 117)2
Management of side effects - Once treatment has been initiated, mental health clinicians can use brief standardized measures (e.g., the Beck Depression Inventory) . . . to monitor the presence and severity of psychiatric symptoms . . . and can address specific symptoms in the context of therapy. Stress-management (e.g., relaxation exercises, problem-solving practice), behavioral activation, cognitive restructuring, and enhancement of self-care behaviors (e.g., exercise, proper diet, sleep hygiene) are useful strategies for minimizing potential side effects. Clinicians are also in an excellent position to provide feedback to medical staff, such as psychiatrists, should greater intervention be necessary (i.e., psychotropic medications). (pp. 117-118) In the area of medication adherence, "clinicians can help patients to identify and problem-solve barriers to treatment-adherence, assist in the organization and scheduling of medications, manage side effects, and facilitate access to medical providers" (p. 118).
Implementing healthy lifestyle changes - Because alcohol has a detrimental effect on liver functioning, "reduction in alcohol use is one of the most important behavioral changes patients can make to slow the rate of HCV progression" (p. 118), and "patients with an understanding of the relationship between HCV and alcohol use may be increasingly motivated to make and sustain healthy lifestyle changes" (p. 119). In support of this effort, mental health clinicians can work with patients to develop a concrete change plan based on their stated goals for treatment and anticipate challenges that may interfere with the execution of these goals. Also, patients on IFN treatment who have a history of alcohol abuse or dependence may benefit from ongoing monitoring and support from a clinician with experience in substance-abuse counseling, because the side effects of treatment may result in increased urges and cravings. . . .
Several standardized instruments, such as the Alcohol Use Disorders Identification Test (AUDIT) . . . or the Alcohol Abstinence Self-Efficacy Scale, . . . may prove useful to the clinician assessing and monitoring alcohol intake for patients with HCV. These brief measures are easy to administer and can be used to identify patients in need of additional intervention. All patients should be educated regarding the effects of alcohol on the course of HCV, and, when appropriate, should be evaluated by a chemical-dependency specialist. (p. 118)
Because cigarette-smoking can affect "liver health, treatment efficacy, and quality of life," clinicians are encouraged to review "evidence-based recommendations from research in general populations that can be used as guides for . . . assisting . . . HCV-positive patient[s] to quit smoking or reduce the amount that they smoke. . . . Goals of these recommendations are to increase screening, enhance motivation, and assist patients to reduce tobacco use through problem-solving techniques" (p. 119).
Since "it is likely that improved nutritional status will have a positive effect on disease-progression and long-term outcome for HCV-positive patients," mental health clinicians can take several steps to assist the HCV-positive patient to achieve his or her individual dietary goals. First, clinicians should encourage all HCV-positive patients to pursue a healthy diet and educate patients about how diet can affect their disease progression and quality of life. Unhealthy diet patterns should be identified (e.g., high-sugar and high-fat diets, high daily caloric intake, frequent fast-food consumption, limited fruit and vegetable intake) and addressed. Finally, referrals to nutrition services may be appropriate for some patients, particularly for cases in which the nutritional needs may require a unique or intensive intervention, such as with HCV-positive patients who are overweight/obese, those for whom there are concerns about iron overload, and those who have comorbid metabolic concerns, such as diabetes. (p. 119)
Additionally, with medical-provider approval, HCV-positive patients should be encouraged to participate in regular physical activity to address weight-management, quality of life, and symptom-management. Clinicians can assist HCV patients with setting exercise goals, enhancing motivation to exercise, addressing barriers to activities, and challenging any unhelpful thoughts that interfere with exercise. Devices such as pedometers may motivate patients who are ready to make changes in activity levels. When appropriate, a referral to rehabilitation or physical therapy services for exercise recommendations can be extremely useful. (p. 119) ----Compiled by Abraham Feingold, Psy.D.
References
Bova, C., Ogawa, L.F., & Sullivan-Bolyai, S. (2010). Hepatitis C treatment experiences and decision making among patients living with HIV infection. Journal of the Association of Nurses in AIDS Care, 21(1), 63-74.
Osilla, K.C., Ryan, G., Bhatti, L., Goetz, M., Witt, M., & Wagner, G. (2009). Factors that influence an HIV coinfected patient's decision to start hepatitis C treatment. AIDS Patient Care & STDs, 23(12), 993-999.
Scott, J.D., Wald, A., Kitahata, M., Krantz, E., Drolette, L., Corey, L., & Wang, C.C. (2009). Hepatitis C virus is infrequently evaluated and treated in an urban HIV clinic population. AIDS Patient Care & STDs, 23(11), 925-929. Silberbogen, A.K., Mori, D.L., & Sogg, S. (2005). The Structured Interview for the Treatment of the Hepatitis C Virus (SIT-HCV). Journal of Clinical Psychology in Medical Settings, 12(1), 57-69.
Silberbogen, A.K., Ulloa, E.W., Janke, E.A., & Mori, D.L. (2009). Psychosocial issues and mental health treatment recommendations for patients with hepatitis C. Psychosomatics 50(2), 114-122.
Wagner, G., Ryan, G., Osilla, K.C., Bhatti, L., Goetz, M., & Witt, M. (2009). Treat early or wait and monitor? A qualitative analysis of provider hepatitis C virus treatment decision-making in the context of HIV coinfection. AIDS Patient Care & STDs, 23(9), 715-725. -------------------- 1 One version of the pre-treatment psychological evaluation, "the Structured Interview for the Treatment of the Hepatitis C Virus (SIT-HCV), developed by the Medical Psychology Service at the VA Boston Healthcare System in collaboration with the VA Liver Clinic[,] . . . expands upon a standard psychiatric interview by addressing those psychological and behavioral factors that are unique to this population and essential to consider prior to recommending a patient for IFN therapy. . . . On the basis of the information gathered during the administration of the SIT-HCV, clinicians can make behavioral recommendations that will enhance a patient's likelihood of attaining an optimal treatment outcome while minimizing the impact of incapacitating side effects" (Silberbogen, Mori, & Sogg, 2005, p. 58). The complete protocol can be found in the appendix of Silberbogen and colleagues' article.
2 "As the nation's largest care-provider of patients with HCV, the [Department of Veterans Affairs] has developed a comprehensive website designed to meet both patients' and providers' needs (www.hepatitis.va.gov). . . . Available resources for mental health providers include a 'how-to' program guide that outlines the basic steps for initiating and maintaining a hepatitis C support group. This valuable resource includes a discussion of issues to consider when developing a group, suggestions for group topics, descriptions of therapeutic and facilitation techniques, and sample forms and handouts" (Silberbogen, Ulloa, Janke, & Mori, 2009, p. 117).
Neuropsychology of HIV/HCV Coinfection
"HCV mono-infection is associated with significant impairment in neuropsychological domains typically characterized as 'subcortical' in nature, with predominant impact on attention, information processing speed, and verbal memory. Further, evidence of neuropsychological impairment among HCV mono-infected individuals exists independent of comorbid substance abuse and severe liver disease, raising the possibility of direct brain involvement from HCV" (Martin-Thormeyer & Paul, 2009, p. 223). Moreover, individuals infected with both HCV and HIV express more severe neuropsychological impairment than individuals with HIV alone but the mechanisms underlying these effects remain unclear. To date a handful of studies have examined neuropsychological function among individuals co-infected with HCV and HIV. Among these studies there is notable variability in the methods to examine neuropsychological function, the use of various comparison groups (e.g., HCV alone, HIV alone, both mono-infected groups compared to co-infected patients), and the focus on various laboratory indices of disease burden. These methodological differences require some caution when drawing conclusions regarding the impact of co-infection on cognitive outcome. For example, a number of studies did not involve a comprehensive neuropsychological assessment, and therefore, conclusions regarding the neuropsychological pattern associated with co-infection remains premature. With that caveat noted, there is some suggestion in the literature that several domains of cognitive function are more likely impacted by co-infection than others.
Decreased processing speed and psychomotor speed among co-infected individuals is a commonly reported outcome of the studies . . . [although e]vidence of selective impairment in psychomotor speed/information processing is not universal. . . . [In fact, n]ot all studies have reported greater cognitive impairment among co-infected patients. . . . When taken collectively the majority of studies have reported more severe neuropsychological impairment among co-infected patients than mono-infected patients. (Martin-Thormeyer & Paul, 2009, pp. 224-225) Importantly, "recent studies of dually infected subjects indicate that neurocognitive function may improve with successful therapy for either disorder" (Gonzalez, Quartana, & Martin, 2009, p. 223).
References
Gonzalez, R., Quartana, P.J., & Martin, E.M. (2009). Co-occurrence of HIV, hepatitis C, and substance use disorders: Effects on brain functioning. In R.H. Paul, N.C. Sacktor, V. Valcour, & K.T. Tashima (Eds.), HIV and the brain: New challenges in the modern era (pp. 213-233). Totowa, NJ: Humana Press. Martin-Thormeyer, E.M., & Paul, R.H. (2009). Drug abuse and hepatitis C infection as comorbid features of HIV associated neurocognitive disorder: Neurocognitive and neuroimaging features [Review]. Neuropsychology Review, 19(2), 215-231.
Psychiatry & HIV/HCV Coinfection
According to Silberbogen and colleagues (2009), "numerous studies . . . document high prevalence rates of preexisting psychiatric disorders among patients with HCV. . . . Within the HCV-positive population, approximately 27%-78% of patients are diagnosed with past or current substance abuse, 15%-62% with mood disorders, and 30%-40% with anxiety disorders such as PTSD [posttraumatic stress disorder]" (p. 115).
With regard to the population of co-infected individuals, however, and "in the absence of established guidelines for the management of [the] psychiatric status of HIV/HCV-coinfected patients initiating PEG-IFN/RBV therapy," Weiss and Morgello (2009) "sought to determine what the state of practice is for providers actively engaged in the care of these patients" (p. 532). The investigators developed and reported on "a provider survey designed to determine whether consensus exists in the management of these patients and what factors might impact differing treatment approaches taken by health care providers" (p. 532). They focused in particular on "the use of prophylactic treatment with antidepressants [to] prevent . . . the development of depressive side effects during HCV treatment" (p. 532).
From a pool of 236 "expert" providers invited to participate, the sample consisted of 92 providers who completed the anonymous online survey, 26% of whom were psychiatrists. With regard to practice setting and provider discipline, Weiss and Morgello found that "the psychiatric management of HIV-coinfected patients being treated for HCV occurs in multiple contexts (varying from comprehensive integrated clinics to individual practices) and is done by providers from a wide range of disciplines (infectious disease, psychiatry, internal medicine, nurse practitioner). The survey was able to establish the practice patterns of expert providers who are predominantly physicians working in varied practice settings internationally" (p. 535).1 Notably, most of the nonpsychiatrist survey respondents have "very limited access to psychiatric consultation" (p. 535).
With regard to these practice patterns, more than one third of providers indicate[d] that they use or offer the option of antidepressant use prophylactically in HIV-positive patients with no past or current depression beginning HCV treatment, and more than three quarters do so in patients with a history of depression but no current symptoms of depression. The most experienced nonpsychiatrist providers were more likely to use antidepressants prior to the start of treatment in HIV-coinfected patients as compared to in HCV mono[-]infected patients. There . . . [wa]s consensus among providers to leave psychiatric medication unchanged in patients currently treated for unipolar depression. (p. 531)
Weiss and Morgello conclude that "many expert providers prescribe antidepressants to HIV/HCV-coinfected patients initiating [HCV] treatment in the absence of symptoms of depression, despite the lack of data supporting this approach in this population" (p. 531). The investigators surmise that "this pattern of prescribing . . . may be related to . . . limited access to psychiatric consultation, with providers viewing the prophylactic use of antidepressants as the safest and most cautious treatment approach" (p. 536). Weiss and Morgello advocate for "increasing [nonpsychiatrist] provider skills and competence through advanced training in psychiatric assessment and management[, because this] would likely reduce the extent to which these providers use antidepressants prophylactically and could potentially lead to better HCV treatment outcomes" (p. 536). Additionally (and importantly), "research is needed to provide an evidence base to guide the optimal psychiatric management of HIV/HCV-coinfected patients beginning [HCV] treatment" (p. 531).
References
Silberbogen, A.K., Ulloa, E.W., Janke, E.A., & Mori, D.L. (2009). Psychosocial issues and mental health treatment recommendations for patients with hepatitis C. Psychosomatics 50(2), 114-122.
Wagner, G., Ryan, G., Osilla, K.C., Bhatti, L., Goetz, M., & Witt, M. (2009). Treat early or wait and monitor? A qualitative analysis of provider hepatitis C virus treatment decision-making in the context of HIV coinfection. AIDS Patient Care & STDs, 23(9), 715-725.
Weiss, J.J., & Morgello, S. (2009). Psychiatric management of HIV/HCV-coinfected patients beginning treatment for hepatitis C virus infection: Survey of provider practices. General Hospital Psychiatry, 31(6), 531-537.
1 Wagner et al. (2009) point out that "unlike HCV mono-infected patients, who are typically treated by liver specialists (e.g., hepatologist or gastroenterologist) with extensive experience with HCV treatment, HIV coinfected patients are most often treated by HIV primary care providers (with relatively limited experience with PEG-IFN/RBV) because liver specialists are unavailable" (p. 716).
Medivir Announces Phase 2b 24-week Interim Results of TMC435 in Treatment-naïve Patients Chronically Infected with Genotype-1 Hepatitis C Virus
Medivir Announces Phase 2b 24-week Interim Results of TMC435 in Treatment-naïve Patients Chronically Infected with Genotype-1 Hepatitis C Virus - News Releases
BusinessWire - Monday, Jul. 12, 2010
Potent and consistent antiviral efficacy was demonstrated at 24-week end-of-treatment and in interim SVR4 and SVR12 results. There were no clinically relevant differences between TMC435 treatment groups and placebo for adverse events.
Medivir (STO:MVIRB) announced today 24-week end-of-treatment interim results from the 5-arm phase 2b response guided PILLAR study in 386 treatment-naïve patients with hepatitis C virus (HCV) genotype-1 (TMC435-C205).
TMC435 is a protease inhibitor jointly developed by Medivir and Tibotec Pharmaceuticals, dosed as one pill once daily (q.d.) to treat hepatitis C virus infections (HCV).
In the PILLAR study, 75mg or 150mg TMC435 was given for either 12 weeks or 24 weeks in combination with 24 weeks of ribavirin and pegIFNalpha-2A, the current standard of care (SOC). Patients stopped all treatment at week 24 when HCV RNA levels at week 4 were < 25 log10 IU/mL detectable or undetectable and HCV RNA levels at week 12, week 16 and week 20 were < 25 log10 IU/mL undetectable. Patients who did not meet the above response-guided criteria continued with SOC until week 48. The results showed that in the TMC435 treatment groups 83% of patients were able to stop all therapy at Week 24.
Potent and consistent antiviral efficacy was demonstrated at 24-week end-of-treatment and in interim SVR4 and SVR12 rates with no major differences between TMC435 doses or length of triple therapy. 92% of patients taking TMC435 and Peg-IFN/RBV (SoC) achieved undetectable HCV RNA levels at week 4 and 92% at week 12 after cessation of treatment, i.e. SVR4 and SVR12. SVR4 and SVR12 data were available for 82% and 42% of the TMC435-treated patients respectively who had stopped all therapy before or at Week 24 and had completed the follow-up visits. Both the viral breakthrough rate (4.9%) and relapse rate (1.6%) were low in the TMC435 treatment groups.
TMC435 was generally safe and well tolerated with no relevant differences in adverse events (AEs) between placebo and TMC435 treatment groups. Most AEs were mild to moderate in severity and the discontinuation rate due to AEs was low and not different from placebo.
When looking at particular adverse events of interest, the incidence of rash, pruritis, GI side effects and anemia were similar in TMC435 groups and placebo and were generally mild to moderate in nature. Use of erythropoetin-stimulating agents (ESAs) was not allowed during the trial.
In laboratory parameters, there were no clinically relevant differences between any TMC435 groups and placebo except for mild bilirubin elevations. Significant decreases in transaminases (ALT and AST) were observed in all treatment groups.
Further safety and efficacy data will be presented at future scientific meetings later in 2010.
"We are extremely encouraged and excited by the efficacy and safety demonstrating that TMC435 is truly a second-generation HCV protease inhibitor," stated Bertil Samuelsson, CSO of Medivir. "We also are looking forward to the top-line data coming up from the phase 2b trial C206 (ASPIRE) in treatment-experienced patients later this year as well as start of phase 3 clinical trials in treatment-naïve patients early next year."
Frequency of Undetectable* HCV RNA Levels During and After Treatment
* < 25 log10 IU/mL undetectable
** End of treatment
***EoT: End of Treatment
**** Patients in the control arm continue SoC till Week 48 and SVR data are not available
q.d.: once daily, PR: pegIFNalpha-2A and ribavirin, SVR4: undetectable HCV RNA at EoT & undetectable HCV RNA 4 weeks after planned EoT, SVR12: undetectable HCV RNA at EoT & undetectable HCV RNA 12 weeks after planned EoT
About TMC435 clinical trial programs
TMC435 is a protease inhibitor jointly developed by Medivir and Tibotec Pharmaceuticals to treat hepatitis C virus infections (HCV).
TMC435 is currently being developed in three phase 2b clinical trials (TMC435-C205, TMC435-C206 and TMC435-C215) in G1 treatment-naïve and in G1 patients that failed previous IFN-based treatment. Safety and efficacy data from the phase 2b trials will be presented at scientific meetings later in 2010.
TMC435-C205 is a global phase 2b study in 386 genotype-1 treatment-naïve patients. It is a once daily treatment of TMC435 with different doses and durations given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.
TMC435-C215 is a Japan phase 2b study in 92 genotype-1 treatment-naïve patients. It is a once daily treatment of TMC435 with different doses and durations given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.
TMC435-C206 is a global phase 2b study in 463 genotype-1 treatment-experienced patients. It is a once daily treatment of TMC435 in with different doses of given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.
About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.
Invitation to a Press Conference
Medivir will host a teleconference today at 15:00 (Central European summer time) focusing on the phase 2b 24-week interim results.
To participate in the teleconference, please call +46 8 619 75 30 using the participant code 195272#.
For more information on Medivir, please see the company website: www.medivir.se (http://www.medivir.se)
Contacts
Medivir
Rein Piir, CFO & VP Investor Relations
Tel: +46 8 54683123
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BusinessWire - Monday, Jul. 12, 2010
Potent and consistent antiviral efficacy was demonstrated at 24-week end-of-treatment and in interim SVR4 and SVR12 results. There were no clinically relevant differences between TMC435 treatment groups and placebo for adverse events.
Medivir (STO:MVIRB) announced today 24-week end-of-treatment interim results from the 5-arm phase 2b response guided PILLAR study in 386 treatment-naïve patients with hepatitis C virus (HCV) genotype-1 (TMC435-C205).
TMC435 is a protease inhibitor jointly developed by Medivir and Tibotec Pharmaceuticals, dosed as one pill once daily (q.d.) to treat hepatitis C virus infections (HCV).
In the PILLAR study, 75mg or 150mg TMC435 was given for either 12 weeks or 24 weeks in combination with 24 weeks of ribavirin and pegIFNalpha-2A, the current standard of care (SOC). Patients stopped all treatment at week 24 when HCV RNA levels at week 4 were < 25 log10 IU/mL detectable or undetectable and HCV RNA levels at week 12, week 16 and week 20 were < 25 log10 IU/mL undetectable. Patients who did not meet the above response-guided criteria continued with SOC until week 48. The results showed that in the TMC435 treatment groups 83% of patients were able to stop all therapy at Week 24.
Potent and consistent antiviral efficacy was demonstrated at 24-week end-of-treatment and in interim SVR4 and SVR12 rates with no major differences between TMC435 doses or length of triple therapy. 92% of patients taking TMC435 and Peg-IFN/RBV (SoC) achieved undetectable HCV RNA levels at week 4 and 92% at week 12 after cessation of treatment, i.e. SVR4 and SVR12. SVR4 and SVR12 data were available for 82% and 42% of the TMC435-treated patients respectively who had stopped all therapy before or at Week 24 and had completed the follow-up visits. Both the viral breakthrough rate (4.9%) and relapse rate (1.6%) were low in the TMC435 treatment groups.
TMC435 was generally safe and well tolerated with no relevant differences in adverse events (AEs) between placebo and TMC435 treatment groups. Most AEs were mild to moderate in severity and the discontinuation rate due to AEs was low and not different from placebo.
When looking at particular adverse events of interest, the incidence of rash, pruritis, GI side effects and anemia were similar in TMC435 groups and placebo and were generally mild to moderate in nature. Use of erythropoetin-stimulating agents (ESAs) was not allowed during the trial.
In laboratory parameters, there were no clinically relevant differences between any TMC435 groups and placebo except for mild bilirubin elevations. Significant decreases in transaminases (ALT and AST) were observed in all treatment groups.
Further safety and efficacy data will be presented at future scientific meetings later in 2010.
"We are extremely encouraged and excited by the efficacy and safety demonstrating that TMC435 is truly a second-generation HCV protease inhibitor," stated Bertil Samuelsson, CSO of Medivir. "We also are looking forward to the top-line data coming up from the phase 2b trial C206 (ASPIRE) in treatment-experienced patients later this year as well as start of phase 3 clinical trials in treatment-naïve patients early next year."
Frequency of Undetectable* HCV RNA Levels During and After Treatment
* < 25 log10 IU/mL undetectable
** End of treatment
***EoT: End of Treatment
**** Patients in the control arm continue SoC till Week 48 and SVR data are not available
q.d.: once daily, PR: pegIFNalpha-2A and ribavirin, SVR4: undetectable HCV RNA at EoT & undetectable HCV RNA 4 weeks after planned EoT, SVR12: undetectable HCV RNA at EoT & undetectable HCV RNA 12 weeks after planned EoT
About TMC435 clinical trial programs
TMC435 is a protease inhibitor jointly developed by Medivir and Tibotec Pharmaceuticals to treat hepatitis C virus infections (HCV).
TMC435 is currently being developed in three phase 2b clinical trials (TMC435-C205, TMC435-C206 and TMC435-C215) in G1 treatment-naïve and in G1 patients that failed previous IFN-based treatment. Safety and efficacy data from the phase 2b trials will be presented at scientific meetings later in 2010.
TMC435-C205 is a global phase 2b study in 386 genotype-1 treatment-naïve patients. It is a once daily treatment of TMC435 with different doses and durations given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.
TMC435-C215 is a Japan phase 2b study in 92 genotype-1 treatment-naïve patients. It is a once daily treatment of TMC435 with different doses and durations given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.
TMC435-C206 is a global phase 2b study in 463 genotype-1 treatment-experienced patients. It is a once daily treatment of TMC435 in with different doses of given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.
About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.
Invitation to a Press Conference
Medivir will host a teleconference today at 15:00 (Central European summer time) focusing on the phase 2b 24-week interim results.
To participate in the teleconference, please call +46 8 619 75 30 using the participant code 195272#.
For more information on Medivir, please see the company website: www.medivir.se (http://www.medivir.se)
Contacts
Medivir
Rein Piir, CFO & VP Investor Relations
Tel: +46 8 54683123
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Hepatic steatosis in patients coinfected with human immunodeficiency virus/hepatitis C virus:
Hepatic steatosis in patients coinfected with human immunodeficiency virus/hepatitis C virus: A meta-analysis of the risk factors
Hepatology July 2010
(from Jules: the key message here is that in certain patients steatosis is more pre prevalent so in coinfected patients diabetes, high BMI are associated with fatty liver). "the overall prevalence of HS was 50.8% (23%-72%).... In coinfected patients, HS does not seem to be more frequent than in HCV monoinfected patients and is mostly associated with metabolic factors, such as increased weight, diabetes mellitus, and more severe liver disease.....Concerning risk factors for HS in HIV/HCV-coinfected patients, metabolic factors were the most important, particularly DM, which doubled the risk of HS (OR 2.32), similar to NAFLD in the general population.....Even more important than obesity as a risk factor for HS is central obesity and ectopic fat, with a spillover of fatty acids that can then accumulate in the liver.[45] One condition associated with ectopic fat is lipodystrophy, which affects 60%-80% of HIV patients under HAART.[46] In fact, the only study evaluating the relation between lipodystrophy and HS found a strong association (OR 3.02).[21] Dyslipidemia, particularly hypertriglyceridemia, was not associated with HS prevalence, although hypertriglyceridemia is considered a risk factor for fatty liver disease"
Figure 2. Factors with a significant association with the prevalence of hepatic steatosis in HIV/HCV-coinfected patients.
Mariana Verdelho Machado 1, Antonio Gouveia Oliveira 2, Helena Cortez-Pinto 1 * 1Departmento de Gastrenterologia, Unidade de Nutricao e Metabolismo, Hospital Santa Maria, Faculdade de Medicina de Lisboa, IMM, Lisboa, Portugal 2Departamento de Bioestatistica, Faculdade de Ciencias Medicas de Lisboa, Lisboa, Portugal email: Helena Cortez-Pinto (hlcortezpinto@netcabo.pt)
Abstract
Hepatic steatosis (HS) is frequent in patients with hepatitis C virus (HCV) infection, occurring in 40%-80%, associating with metabolic and virus-related factors, namely, genotype 3 and viral load. Human immunodeficiency virus (HIV) infection and antiretroviral treatment seem to be risk factors for HS. Several studies addressed this issue in coinfected patients, with discrepant results. A meta-analysis was performed on the HS risk factors in coinfected patients. Eligible studies were identified through structured keywords including coinfection, HCV, HIV, and steatosis in relevant databases including PubMed. Pooled odds ratios (ORs) and confidence limits (CIs) were obtained with the random-effects model and the DerSimonian-Laird method. Twelve studies, including 1,989 coinfected patients, were selected. Twenty percent were infected with HCV genotype 3. The overall prevalence of HS was 50.8% (23%-72%). Four studies also included 1,540 HCV monoinfected patients, not showing an increased risk for HS in coinfected patients (OR 1.61, 95% CI 0.84-3.10, P = 0.151). In coinfected patients, HS was associated with higher body mass index (OR 1.13, 95% CI 1.07-1.19, P < 0.001), diabetes mellitus (OR 2.32, 95% CI 1.32-4.07, P = 0.003), elevated alanine aminotransferase levels (OR 1.28, 95% CI 1.02-1.61, P = 0.035), necroinflammatory activity (OR 1.72, 95% CI 1.11-2.67, P = 0.016), and fibrosis (OR 1.67, 95% CI 1.20-2.34, P = 0.003). No associations were found between HS and gender, other metabolic factors (dyslipidemia, glucose, metabolic syndrome), HCV-related factors (genotype, viral load), or HIV-related factors (viral load, CD4 count, antiretroviral therapy, and class of medication). Conclusion: In coinfected patients, HS does not seem to be more frequent than in HCV monoinfected patients and is mostly associated with metabolic factors, such as increased weight, diabetes mellitus, and more severe liver disease. The fact that no associations with HCV factors were found may be due to the small percentage of genotype 3-infected patients.
Article Text
Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection is a major health problem. Current estimations find that more than one-fourth of HIV-infected patients are coinfected with HCV,[1] and HCV-related deaths are now the third cause of death in HIV-infected patients.[2]
When compared to the general population, HCV-infected patients have a 2.5-fold increased risk of developing hepatic steatosis (HS),[3] often associated with faster fibrosis progression and more severe hepatic fibrosis,[4] an increased risk of hepatocellular carcinoma development,[5] and lower rates of sustained viral response to HCV antiviral therapy, mainly in genotype 3.[6] There are two types of HS in HCV infection, a viral-related HS and a metabolic-related HS. The first is mostly associated with genotype 3 virus and is a consequence of the direct cytopathic effect on hepatocytes. There is a direct relation with viral load and it regresses after successful HCV therapy. The metabolic type, having allegedly a dismal effect in anti-HCV therapy, is more common amid other genotypes and is primarily related to metabolic factors like obesity, alcohol, diabetes mellitus (DM), or insulin resistance.[7]
Hepatic steatosis was present in about 30% of HIV-infected patients in the era before highly active antiretroviral therapy (HAART),[8] comparable to the prevalence in the general population.[9] In HIV-infected patients in the post-HAART era, the HS prevalence is indefinite.[8] Several studies addressed the topic with a noninvasive approach and the majority did not exclude patients with HCV coinfection. Two well-designed studies, one assessing HS with ultrasonography[10] and the other with computed tomography (CT) scans,[11] found prevalences of 31% and 37%, respectively. Although the main risk factors found in these studies were metabolic, another study compared two groups of patients with HS and different HIV status; the results showed that HIV-infected patients had lower body mass index (BMI) and lower body fat percentage.[12] In HIV, the HS etiology is most likely multifactorial[13] relating to metabolic factors, e.g., insulin resistance/DM/dyslipidemia and lipodystrophy, all of which may be linked to antiretroviral therapy (ART). Protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTI) have been related to insulin resistance[14] and lipodystrophy[15]; NRTI may cause mitochondrial dysfunction with subsequent direct hepatotoxic effects.[16] Moreover, HIV infection itself may facilitate DM by way of tumor necrosis factor- stimulation and mitochondria damage.[13] Also, other coexistent morbidities such as alcohol consumption or HCV infection may enhance steatogenesis.[13]
In the last 5 years several studies concentrated on the real prevalence of HS and its risk factors in HIV/HCV-coinfected patients, but with discrepant results. Therefore, we conducted an in-depth review and meta-analysis of available studies on the prevalence and risk factors for HS in HIV/HCV-coinfected patients and hereby report their results as well as the analysis by comparison with HCV monoinfected patients.
Abbreviations:
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ART, antiretroviral therapy; BMI, body mass index; DM, diabetes mellitus; HAART; highly active antiretroviral therapy; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HS, hepatic steatosis; NAFLD, nonalcoholic fatty liver disease; NNRTI, nonnucleoside reverse transcriptase inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; PI, protease inhibitors.
Discussion
The present review found a huge discrepancy in the prevalence of HS in HIV/HCV-coinfected patients, ranging from 23%-72%, which may be related to differences in the studied populations and comorbidities such as alcohol consumption, DM, obesity, and type and duration of HCV infection, HIV infection status, and others. Several studies' biases might be pointed out. In fact, two studies[23][27] evaluated patients from a clinical trial on HCV therapy, a selected population without significant alcohol or active drug consumption and stable HIV infection, which may not translate to the real population of HIV/HCV-coinfected patients. Further, in studies not including patients from clinical trials selection depended on having a liver biopsy performed before starting HCV antiviral treatment, and those may not be representative of the HIV/HCV-coinfected population. In fact, the threshold to perform a liver biopsy may be different in HIV/HCV-coinfected patients, in whom fibrosis progression is accelerated, and in HCV monoinfected patients. Furthermore, liver biopsies per se have sampling variability limitations[36] and fat deposition is not homogenous throughout the liver. Only two studies specified that liver biopsies had to be higher than 10 mm in length[25][26]; the amount of alcohol consumption allowed was different among studies, both of which further adds to the expected bias. Moreover, whenever heavy alcohol intake was an exclusion criterion no information could be drawn regarding the potential effect of mild alcohol consumption on HS.
Overall, HS was present in half of the patients, which was not different from the HCV monoinfected patients. That was not expected because HIV factors, and most important ART, have theoretical prosteatogenic effects. It can be hypothesized that HCV steatogenic effects are so strong that they supersede any HIV-related effects. Also, in the pre-HAART era, HS in patients with HIV was not different from the general population[8] and those patients may represent some bias relating to HIV status and antiretroviral drugs exposition because they were selected from patients who were proposed for HCV treatment.
On the issue of demographic factors, HS prevalence did not show gender-related differences. Although nonalcoholic fatty liver disease (NAFLD) related to metabolic syndrome seems to associate with male gender,[37] data in HCV[4][38] and HIV[10][11][39] monoinfected patients are inconsistent. It is possible that when virus and drugs are added to metabolic factors, protection conferred by female sex is lost. The protective effect of African-American ethnicity described in NAFLD,[40] probably related to lower visceral adipose tissue,[41] was not found. Indeed, fat accumulates ectopically in response to HIV therapy, which may supersede those differences.
Concerning risk factors for HS in HIV/HCV-coinfected patients, metabolic factors were the most important, particularly DM, which doubled the risk of HS (OR 2.32), similar to NAFLD in the general population.[42] Higher BMI was also a risk factor for HS in this review, although with a small effect (OR 1.13). This could be due to the fact that HIV infection after the introduction of HAART has transformed in a chronic illness increasingly accompanied by obesity,[43] with HIV-infected individuals approaching weight levels seen in the general population, with a 14% obesity prevalence and 31% overweight.[44] Even more important than obesity as a risk factor for HS is central obesity and ectopic fat, with a spillover of fatty acids that can then accumulate in the liver.[45] One condition associated with ectopic fat is lipodystrophy, which affects 60%-80% of HIV patients under HAART.[46] In fact, the only study evaluating the relation between lipodystrophy and HS found a strong association (OR 3.02).[21] Dyslipidemia, particularly hypertriglyceridemia, was not associated with HS prevalence, although hypertriglyceridemia is considered a risk factor for fatty liver disease.[47] In comparison to the general population, HIV-infected patients present a dismal lipid profile, with hypertriglyceridemia and hypercholesterolemia, particularly higher LDL and lower HDL cholesterol levels,[48] which worsens in patients under ART.[49] However, HCV infection, in particular with genotype 3, has a beneficial influence on antiretroviral-related lipid changes,[50] as HCV disturbs the assembly and excretion of lipid complexes from the hepatocyte,[51] thus potentially explaining the lack of association between dyslipidemia and HS in HIV/HCV-coinfected patients.
HCV-related factors, namely, genotype 3 or viral load, did not associate with HS, possibly due to the low overall prevalence of genotype 3 (20%), probably resulting from the fact that the majority of the cohorts come from the United States, where an 8% prevalence is estimated.[52] In contrast, genotype 3 European prevalence varies from 10% to more than 50% in Eastern countries.[53] In conformity, a subanalysis of the European studies with higher genotype 3 prevalence did in fact demonstrate a significant association with HS (OR 2.5).
Similarly, HIV-related factors, namely, viral load, CD4 cell count, ART, and class of medication, were not associated with HS. In the analyzed studies the same parameters were differently evaluated, with different cutoffs, allowing a meta-analysis only in a limited number of studies and decreasing its power to analyze that particular data.
In conclusion, HS was present in half of HIV/HCV-coinfected patients and does not seem to be more frequent when compared to HCV monoinfected patients. In coinfected patients, HS is associated with metabolic factors, namely, DM and BMI, and with more severe liver disease (necroinflammation and fibrosis). The fact that no associations with HCV factors were found may be due to the small percentage of patients with genotype 3 HCV infection, because a strong association was found in the studies with higher genotype 3 prevalence.
Results
Twelve studies were included[19-30] addressing a total of 1,989 HIV/HCV-coinfected patients. In four of these studies[20][24][25][28] data regarding HCV-monoinfected patients were presented separately, with a total of 1,540 patients. Three studies had a retrospective recruitment[21][22][25]; the remaining were prospective. HS was always evaluated by liver biopsy. Their main characteristics are summarized in Tables 1 and 2. Studies with a noninvasive assessment of HS were not found.
Inclusion criteria were similar in all studies, which enrolled patients with known HIV/HCV coinfection, detectable HCV RNA assessed by way of sensitive polymerase chain reaction-based techniques, and liver biopsy performed to evaluate liver damage in HCV antiviral therapy candidates. Two studies[23][27] were subanalyses of major controlled randomized trials of HCV anti-viral treatment in coinfected populations, namely, the ANRS HC02[31] and APRICOT trials.[32] In these trials HIV infection was required to be stable, with good immune system status and under no ART or on a stable schedule for the 3 months preceding the study.
Exclusion criteria were similar but not identical across studies. All of them required patients to be HCV treatment-naives and negative for hepatitis B surface antigen. Except for significant alcohol consumption, greater than 40-50 g per day, which was an exclusion criterion in only five studies,[23-25][27][28] other causes of liver disease were systematically excluded. Liver biopsies with less than 10 mm length were considered as an exclusion criterion in just two studies.[25][26] Decompensated liver cirrhosis was a transversal exclusion criterion.
Definitions and grading of HS were not homogeneous in all studies, although the majority[19-24][27-30] used Brunt's criteria or similar.[33] Two studies[25][26] used the chronic hepatitis C validated METAVIR classification system,[34] in which steatosis is considered mild if present in 1%-10% of the hepatocytes, moderate in 11%-30%, and severe when in more than 30%. Necroinflammation and fibrosis were graded or staged by METAVIR[20][21][23][25][26] or Ishak classifications.[35]
Steatosis Prevalence.
In HIV/HCV-coinfected patients the overall prevalence of HS was 50.8%, ranging from 23%-72%. In the four studies that also evaluated patients with HCV monoinfection, the overall prevalence of HS was 48.6%, ranging from 33%-59%.
Evaluating all data together, HIV did not confer an increased risk for HS when compared to HCV monoinfection (pooled odds ratio [OR] 1.67, 95% confidence interval [CI] 0.84-2.10, P = 0.151) (Fig. 1).
Demographic Associations.
There was no association between gender and the prevalence of HS in HIV/HCV-coinfected patients, either in individual studies or in the pooled data: pooled OR for female sex was 0.85, 95% CI 0.60-1.21, P = 0.365, in 10 studies.[19-22][24][26][27][29][30] Similarly, HS prevalence was not different in African-American patients: pooled OR was 0.76, 95% CI 0.24-2.48, P = 0.668, in two studies.[21][24] As verified in seven studies,[19-22][24][29][30] alcohol consumption was not associated with an increased risk of HS (pooled OR 0.95, 95% CI 0.70-1.30, P = 0.761). It should be noted that among these studies only Gaslightwala and Bini[24] was restricted to patients who were drinking less than 2 beverages per day.
Metabolic Factors.
BMI, assessed in four studies,[22][23][25][26] was associated with an increased risk for HS; however, with small magnitude (pooled OR 1.13, 95% CI 1.07-1.19, P < 0.001) (Fig. 2).
Regarding the presence of DM, seven studies[20-22][24][27][29][30] analyzed a possible association with increased risk for HS, although only two showed a significant association.[24][30] However, in the pooled data analysis there was a strong statistically significant association (pooled OR 2.32, 95% CI 1.32-4.07, P = 0.003) (Fig. 2). When analyzing the presence of increased fasting glucose levels, although there seemed to be an association in each of three studies,[19][22][27] this was not confirmed in the pooled data (pooled OR 1.52, 95% CI 0.58-4.02, P = 0.396).
A possible association between HS and hypertriglyceridemia was evaluated in four studies[19][22][24][27]; only two revealed a weak though statistically significant association.[22][24] The pooled data failed to show any association (pooled OR 1.00, 95% CI 0.97-1.05, P = 0.796).
The presence of metabolic syndrome was evaluated as a risk factor for HS in two studies,[27][30] and although one of the studies showed a positive association, the pooled data failed to confirm it (pooled OR 1.07, 95% CI 0.13-8.83, P = 0.949).
Lipodystrophy was studied only once,[21] and a positive association with HS was found (OR 3.02, 95% CI 1.06-8.51).
Biochemical Abnormalities.
Individually, just one[27] out of seven studies[19][24][25][27][29][30] found a positive association between alanine aminotransferase (ALT) elevation and HS. Yet in the pooled data there was a weak but positive association (pooled OR 1.28, 95% CI 1.02-1.61, P = 0.035) (Fig. 2).
Two studies[19][26] presented conflicting results regarding aspartate aminotransferase (AST) elevation, and the pooled data failed to confirm an association (pooled OR 1.76, 95% CI 0.61-5.03, P = 0.292).
Histological Correlations.
When nine studies were evaluated together,[19-23][26][27][29][30] advanced fibrosis, i.e., bridging fibrosis or hepatic cirrhosis, presented a positive association with HS in the pooled data (pooled OR 1.67, 95% CI 2.34-3.01, P = 0.003) (Fig. 2). Severe necroinflammatory activity also presented a positive association with HS in the meta-analysis of seven studies[19-22][25-27] (pooled OR 1.72, 95% CI 1.11-2.67, P = 0.016), although that association was only statistically significant in three studies[19][25][26] (Fig. 2).
HCV Factors Associations.
Regarding HCV infection, the pooled data did not corroborate any association with possible risk factors for HS. In fact, the analysis of nine studies[20-27][30] failed to demonstrate genotype 3 as a risk factor (pooled OR 2.00, 95% CI 0.82-4.87, P = 0.127). However, a subanalysis of the three European studies with a genotype 3 prevalence higher than 30%[23][25][26] showed a strong association with HS (pooled OR 2.52, 95% CI 1.77-3.59, P < 0.001).
HCV viral load was assessed as a risk factor for HS in seven studies,[19][20][22-24][27][29] with only two showing a positive association.[23][27] The Bani-Sadr et al.[23] data suggested an increase of more than 50% in the risk for HS (OR 1.65, 95% CI 1.22-2.23) by each increase of 1 log10 IU/L in the HCV viral load. However, a meta-analysis of three studies[20][22][24] evaluating the risk of high viral load did not confirm an association (pooled OR 0.92, 95% CI 0.92-1.07, P = 0.819). The definition of high viral load was not exactly the same between studies.
HIV Factor Associations.
Immune status, assessed by CD4 cells count, did not seem to relate to HS because four out of five studies that evaluated that association presented negative results.[24-26][29][30] Only Gaslightwala and Bini[24] found a higher prevalence of HS when CD4 cell counts were higher than 350 cells/mm3 (72% versus 51%, P = 0.004). A meta-analysis of two studies[25][30] that used the same cutoff of CD4 cells count higher than 200 cells /mm3 also failed to show a statistically significant association (pooled OR 0.83, 95% CI 0.39-1.79, P = 0.637).
The effect of the duration of HIV infection on the prevalence of HS was evaluated in three studies.[20][21][30] Although Sterling et al.[30] found a slightly lower duration of infection in patients with HS (18.5 ± 0.95 years versus 22.6 ± 0.75 years, P = 0.036), each year of HIV infection duration[21] or being infected by HIV for more than 7 years[20] were not associated with a different risk for HS.
Using different approaches, many studies evaluated a potential effect of the HIV viral load[19-22][24-26][29][30]; seven, however, did not show a difference. Regarding having detectable versus nondetectable viral load, the McGovern et al.[22] results suggested that patients with detectable viral load had less HS (OR 0.86, 95% CI 0.76-0.98). However, a meta-analysis of four studies[20][22][24][25] did not confirm an association (pooled OR 0.95, 95% CI 0.61-1.47, P = 0.815). Regarding the fact of having a viral load higher than 400 copies per mL, the pooled data of two studies[19][30] also did not find an association (pooled OR 0.29, 95% CI 0.80-2.09, P = 0.295).
Being under ART did not seem to affect the risk for HS in the pooled data of six studies[20-22][26][29][30] (pooled OR 1.04, 95% CI 0.56-1.95, P = 0.903). In fact, individually, only two of these studies[22][30] detected a marginal statistically significant difference, although in opposite directions.
Analyzing the class of medications, no differences in the use of PI, NRTI, or nonnucleoside reverse transcriptase inhibitors (NNRTI) were found in relation to HS. In fact, only one[30] out of eight studies[20-22][24-26][29][30] that evaluated PI showed a weak association. The pooled data of seven studies[21][22][24-26][29][30] was also negative (pooled OR 1.05, 95% CI 0.72-1.52, P = 0.799). In addition, out of six studies,[22][24-26][29][30] only McGovern et al.[22] found a positive association between the use of NRTI and HS, with a more than 2-fold increased risk (OR 2.14, 95% CI 1.10-4.14). The pooled data of the remaining six studies also found no increased risk (pooled OR 0.89, 95% CI 0.35-2.24, P = 0.808). Lastly, concerning NNRTI therapy, out of seven studies[21][22][24-26][29][30] only Neau et al.[26] found it to have protective properties against HS (OR 0.40, 95% CI 0.20-0.90). The pooled data of these seven studies failed to find an association (pooled OR 0.86, 95% CI 0.61-1.19, P = 0.353).
Materials and Methods
This analysis was performed with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) criteria.[17] MEDLINE and Current Contents were searched by one investigator to identify relevant articles published until May 2009. In the electronic scrutiny, study references and relevant review articles on HIV/HCV coinfection were manually searched; eligible studies were identified through structured keywords: steatosis, fatty liver, VHC, HIV, and coinfection. All analyzed studies had to be published in English and to comprise a series of consecutive eligible patients, although allowing for exclusions due to other concomitant liver diseases and not necessarily excluding alcohol consumption.
The abstracts of all articles identified by the initial search were reviewed by another author and both authors reviewed the full text of all eligible studies reporting the prevalence of HS and its risk factors. Data elements sought from each included study were protocol-specified including steatosis prevalence, HCV monoinfection steatosis prevalence comparison data, study location, demographic data, HCV genotype, alcohol consumption, and other risk factors for HS.
Statistical Analysis.
For calculations, we computed the actual number of subjects from each study and performed a pooled analysis of the data. Pooled estimation of the prevalence of HS in HIV/HCV-coinfected patients and confidence limits were obtained with the random-effects model and the DerSimonian-Laird method.[18] Analysis of the heterogeneity of prevalence across studies was done with 2 tests. As all tests showed great heterogeneity, random effects models were preferred regarding fixed effects models.
Statistical analysis was conducted with STATA software (College Station, TX), version 10. Significance was established for P < 0.05.
Hepatology July 2010
(from Jules: the key message here is that in certain patients steatosis is more pre prevalent so in coinfected patients diabetes, high BMI are associated with fatty liver). "the overall prevalence of HS was 50.8% (23%-72%).... In coinfected patients, HS does not seem to be more frequent than in HCV monoinfected patients and is mostly associated with metabolic factors, such as increased weight, diabetes mellitus, and more severe liver disease.....Concerning risk factors for HS in HIV/HCV-coinfected patients, metabolic factors were the most important, particularly DM, which doubled the risk of HS (OR 2.32), similar to NAFLD in the general population.....Even more important than obesity as a risk factor for HS is central obesity and ectopic fat, with a spillover of fatty acids that can then accumulate in the liver.[45] One condition associated with ectopic fat is lipodystrophy, which affects 60%-80% of HIV patients under HAART.[46] In fact, the only study evaluating the relation between lipodystrophy and HS found a strong association (OR 3.02).[21] Dyslipidemia, particularly hypertriglyceridemia, was not associated with HS prevalence, although hypertriglyceridemia is considered a risk factor for fatty liver disease"
Figure 2. Factors with a significant association with the prevalence of hepatic steatosis in HIV/HCV-coinfected patients.
Mariana Verdelho Machado 1, Antonio Gouveia Oliveira 2, Helena Cortez-Pinto 1 * 1Departmento de Gastrenterologia, Unidade de Nutricao e Metabolismo, Hospital Santa Maria, Faculdade de Medicina de Lisboa, IMM, Lisboa, Portugal 2Departamento de Bioestatistica, Faculdade de Ciencias Medicas de Lisboa, Lisboa, Portugal email: Helena Cortez-Pinto (hlcortezpinto@netcabo.pt)
Abstract
Hepatic steatosis (HS) is frequent in patients with hepatitis C virus (HCV) infection, occurring in 40%-80%, associating with metabolic and virus-related factors, namely, genotype 3 and viral load. Human immunodeficiency virus (HIV) infection and antiretroviral treatment seem to be risk factors for HS. Several studies addressed this issue in coinfected patients, with discrepant results. A meta-analysis was performed on the HS risk factors in coinfected patients. Eligible studies were identified through structured keywords including coinfection, HCV, HIV, and steatosis in relevant databases including PubMed. Pooled odds ratios (ORs) and confidence limits (CIs) were obtained with the random-effects model and the DerSimonian-Laird method. Twelve studies, including 1,989 coinfected patients, were selected. Twenty percent were infected with HCV genotype 3. The overall prevalence of HS was 50.8% (23%-72%). Four studies also included 1,540 HCV monoinfected patients, not showing an increased risk for HS in coinfected patients (OR 1.61, 95% CI 0.84-3.10, P = 0.151). In coinfected patients, HS was associated with higher body mass index (OR 1.13, 95% CI 1.07-1.19, P < 0.001), diabetes mellitus (OR 2.32, 95% CI 1.32-4.07, P = 0.003), elevated alanine aminotransferase levels (OR 1.28, 95% CI 1.02-1.61, P = 0.035), necroinflammatory activity (OR 1.72, 95% CI 1.11-2.67, P = 0.016), and fibrosis (OR 1.67, 95% CI 1.20-2.34, P = 0.003). No associations were found between HS and gender, other metabolic factors (dyslipidemia, glucose, metabolic syndrome), HCV-related factors (genotype, viral load), or HIV-related factors (viral load, CD4 count, antiretroviral therapy, and class of medication). Conclusion: In coinfected patients, HS does not seem to be more frequent than in HCV monoinfected patients and is mostly associated with metabolic factors, such as increased weight, diabetes mellitus, and more severe liver disease. The fact that no associations with HCV factors were found may be due to the small percentage of genotype 3-infected patients.
Article Text
Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection is a major health problem. Current estimations find that more than one-fourth of HIV-infected patients are coinfected with HCV,[1] and HCV-related deaths are now the third cause of death in HIV-infected patients.[2]
When compared to the general population, HCV-infected patients have a 2.5-fold increased risk of developing hepatic steatosis (HS),[3] often associated with faster fibrosis progression and more severe hepatic fibrosis,[4] an increased risk of hepatocellular carcinoma development,[5] and lower rates of sustained viral response to HCV antiviral therapy, mainly in genotype 3.[6] There are two types of HS in HCV infection, a viral-related HS and a metabolic-related HS. The first is mostly associated with genotype 3 virus and is a consequence of the direct cytopathic effect on hepatocytes. There is a direct relation with viral load and it regresses after successful HCV therapy. The metabolic type, having allegedly a dismal effect in anti-HCV therapy, is more common amid other genotypes and is primarily related to metabolic factors like obesity, alcohol, diabetes mellitus (DM), or insulin resistance.[7]
Hepatic steatosis was present in about 30% of HIV-infected patients in the era before highly active antiretroviral therapy (HAART),[8] comparable to the prevalence in the general population.[9] In HIV-infected patients in the post-HAART era, the HS prevalence is indefinite.[8] Several studies addressed the topic with a noninvasive approach and the majority did not exclude patients with HCV coinfection. Two well-designed studies, one assessing HS with ultrasonography[10] and the other with computed tomography (CT) scans,[11] found prevalences of 31% and 37%, respectively. Although the main risk factors found in these studies were metabolic, another study compared two groups of patients with HS and different HIV status; the results showed that HIV-infected patients had lower body mass index (BMI) and lower body fat percentage.[12] In HIV, the HS etiology is most likely multifactorial[13] relating to metabolic factors, e.g., insulin resistance/DM/dyslipidemia and lipodystrophy, all of which may be linked to antiretroviral therapy (ART). Protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTI) have been related to insulin resistance[14] and lipodystrophy[15]; NRTI may cause mitochondrial dysfunction with subsequent direct hepatotoxic effects.[16] Moreover, HIV infection itself may facilitate DM by way of tumor necrosis factor- stimulation and mitochondria damage.[13] Also, other coexistent morbidities such as alcohol consumption or HCV infection may enhance steatogenesis.[13]
In the last 5 years several studies concentrated on the real prevalence of HS and its risk factors in HIV/HCV-coinfected patients, but with discrepant results. Therefore, we conducted an in-depth review and meta-analysis of available studies on the prevalence and risk factors for HS in HIV/HCV-coinfected patients and hereby report their results as well as the analysis by comparison with HCV monoinfected patients.
Abbreviations:
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ART, antiretroviral therapy; BMI, body mass index; DM, diabetes mellitus; HAART; highly active antiretroviral therapy; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HS, hepatic steatosis; NAFLD, nonalcoholic fatty liver disease; NNRTI, nonnucleoside reverse transcriptase inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; PI, protease inhibitors.
Discussion
The present review found a huge discrepancy in the prevalence of HS in HIV/HCV-coinfected patients, ranging from 23%-72%, which may be related to differences in the studied populations and comorbidities such as alcohol consumption, DM, obesity, and type and duration of HCV infection, HIV infection status, and others. Several studies' biases might be pointed out. In fact, two studies[23][27] evaluated patients from a clinical trial on HCV therapy, a selected population without significant alcohol or active drug consumption and stable HIV infection, which may not translate to the real population of HIV/HCV-coinfected patients. Further, in studies not including patients from clinical trials selection depended on having a liver biopsy performed before starting HCV antiviral treatment, and those may not be representative of the HIV/HCV-coinfected population. In fact, the threshold to perform a liver biopsy may be different in HIV/HCV-coinfected patients, in whom fibrosis progression is accelerated, and in HCV monoinfected patients. Furthermore, liver biopsies per se have sampling variability limitations[36] and fat deposition is not homogenous throughout the liver. Only two studies specified that liver biopsies had to be higher than 10 mm in length[25][26]; the amount of alcohol consumption allowed was different among studies, both of which further adds to the expected bias. Moreover, whenever heavy alcohol intake was an exclusion criterion no information could be drawn regarding the potential effect of mild alcohol consumption on HS.
Overall, HS was present in half of the patients, which was not different from the HCV monoinfected patients. That was not expected because HIV factors, and most important ART, have theoretical prosteatogenic effects. It can be hypothesized that HCV steatogenic effects are so strong that they supersede any HIV-related effects. Also, in the pre-HAART era, HS in patients with HIV was not different from the general population[8] and those patients may represent some bias relating to HIV status and antiretroviral drugs exposition because they were selected from patients who were proposed for HCV treatment.
On the issue of demographic factors, HS prevalence did not show gender-related differences. Although nonalcoholic fatty liver disease (NAFLD) related to metabolic syndrome seems to associate with male gender,[37] data in HCV[4][38] and HIV[10][11][39] monoinfected patients are inconsistent. It is possible that when virus and drugs are added to metabolic factors, protection conferred by female sex is lost. The protective effect of African-American ethnicity described in NAFLD,[40] probably related to lower visceral adipose tissue,[41] was not found. Indeed, fat accumulates ectopically in response to HIV therapy, which may supersede those differences.
Concerning risk factors for HS in HIV/HCV-coinfected patients, metabolic factors were the most important, particularly DM, which doubled the risk of HS (OR 2.32), similar to NAFLD in the general population.[42] Higher BMI was also a risk factor for HS in this review, although with a small effect (OR 1.13). This could be due to the fact that HIV infection after the introduction of HAART has transformed in a chronic illness increasingly accompanied by obesity,[43] with HIV-infected individuals approaching weight levels seen in the general population, with a 14% obesity prevalence and 31% overweight.[44] Even more important than obesity as a risk factor for HS is central obesity and ectopic fat, with a spillover of fatty acids that can then accumulate in the liver.[45] One condition associated with ectopic fat is lipodystrophy, which affects 60%-80% of HIV patients under HAART.[46] In fact, the only study evaluating the relation between lipodystrophy and HS found a strong association (OR 3.02).[21] Dyslipidemia, particularly hypertriglyceridemia, was not associated with HS prevalence, although hypertriglyceridemia is considered a risk factor for fatty liver disease.[47] In comparison to the general population, HIV-infected patients present a dismal lipid profile, with hypertriglyceridemia and hypercholesterolemia, particularly higher LDL and lower HDL cholesterol levels,[48] which worsens in patients under ART.[49] However, HCV infection, in particular with genotype 3, has a beneficial influence on antiretroviral-related lipid changes,[50] as HCV disturbs the assembly and excretion of lipid complexes from the hepatocyte,[51] thus potentially explaining the lack of association between dyslipidemia and HS in HIV/HCV-coinfected patients.
HCV-related factors, namely, genotype 3 or viral load, did not associate with HS, possibly due to the low overall prevalence of genotype 3 (20%), probably resulting from the fact that the majority of the cohorts come from the United States, where an 8% prevalence is estimated.[52] In contrast, genotype 3 European prevalence varies from 10% to more than 50% in Eastern countries.[53] In conformity, a subanalysis of the European studies with higher genotype 3 prevalence did in fact demonstrate a significant association with HS (OR 2.5).
Similarly, HIV-related factors, namely, viral load, CD4 cell count, ART, and class of medication, were not associated with HS. In the analyzed studies the same parameters were differently evaluated, with different cutoffs, allowing a meta-analysis only in a limited number of studies and decreasing its power to analyze that particular data.
In conclusion, HS was present in half of HIV/HCV-coinfected patients and does not seem to be more frequent when compared to HCV monoinfected patients. In coinfected patients, HS is associated with metabolic factors, namely, DM and BMI, and with more severe liver disease (necroinflammation and fibrosis). The fact that no associations with HCV factors were found may be due to the small percentage of patients with genotype 3 HCV infection, because a strong association was found in the studies with higher genotype 3 prevalence.
Results
Twelve studies were included[19-30] addressing a total of 1,989 HIV/HCV-coinfected patients. In four of these studies[20][24][25][28] data regarding HCV-monoinfected patients were presented separately, with a total of 1,540 patients. Three studies had a retrospective recruitment[21][22][25]; the remaining were prospective. HS was always evaluated by liver biopsy. Their main characteristics are summarized in Tables 1 and 2. Studies with a noninvasive assessment of HS were not found.
Inclusion criteria were similar in all studies, which enrolled patients with known HIV/HCV coinfection, detectable HCV RNA assessed by way of sensitive polymerase chain reaction-based techniques, and liver biopsy performed to evaluate liver damage in HCV antiviral therapy candidates. Two studies[23][27] were subanalyses of major controlled randomized trials of HCV anti-viral treatment in coinfected populations, namely, the ANRS HC02[31] and APRICOT trials.[32] In these trials HIV infection was required to be stable, with good immune system status and under no ART or on a stable schedule for the 3 months preceding the study.
Exclusion criteria were similar but not identical across studies. All of them required patients to be HCV treatment-naives and negative for hepatitis B surface antigen. Except for significant alcohol consumption, greater than 40-50 g per day, which was an exclusion criterion in only five studies,[23-25][27][28] other causes of liver disease were systematically excluded. Liver biopsies with less than 10 mm length were considered as an exclusion criterion in just two studies.[25][26] Decompensated liver cirrhosis was a transversal exclusion criterion.
Definitions and grading of HS were not homogeneous in all studies, although the majority[19-24][27-30] used Brunt's criteria or similar.[33] Two studies[25][26] used the chronic hepatitis C validated METAVIR classification system,[34] in which steatosis is considered mild if present in 1%-10% of the hepatocytes, moderate in 11%-30%, and severe when in more than 30%. Necroinflammation and fibrosis were graded or staged by METAVIR[20][21][23][25][26] or Ishak classifications.[35]
Steatosis Prevalence.
In HIV/HCV-coinfected patients the overall prevalence of HS was 50.8%, ranging from 23%-72%. In the four studies that also evaluated patients with HCV monoinfection, the overall prevalence of HS was 48.6%, ranging from 33%-59%.
Evaluating all data together, HIV did not confer an increased risk for HS when compared to HCV monoinfection (pooled odds ratio [OR] 1.67, 95% confidence interval [CI] 0.84-2.10, P = 0.151) (Fig. 1).
Demographic Associations.
There was no association between gender and the prevalence of HS in HIV/HCV-coinfected patients, either in individual studies or in the pooled data: pooled OR for female sex was 0.85, 95% CI 0.60-1.21, P = 0.365, in 10 studies.[19-22][24][26][27][29][30] Similarly, HS prevalence was not different in African-American patients: pooled OR was 0.76, 95% CI 0.24-2.48, P = 0.668, in two studies.[21][24] As verified in seven studies,[19-22][24][29][30] alcohol consumption was not associated with an increased risk of HS (pooled OR 0.95, 95% CI 0.70-1.30, P = 0.761). It should be noted that among these studies only Gaslightwala and Bini[24] was restricted to patients who were drinking less than 2 beverages per day.
Metabolic Factors.
BMI, assessed in four studies,[22][23][25][26] was associated with an increased risk for HS; however, with small magnitude (pooled OR 1.13, 95% CI 1.07-1.19, P < 0.001) (Fig. 2).
Regarding the presence of DM, seven studies[20-22][24][27][29][30] analyzed a possible association with increased risk for HS, although only two showed a significant association.[24][30] However, in the pooled data analysis there was a strong statistically significant association (pooled OR 2.32, 95% CI 1.32-4.07, P = 0.003) (Fig. 2). When analyzing the presence of increased fasting glucose levels, although there seemed to be an association in each of three studies,[19][22][27] this was not confirmed in the pooled data (pooled OR 1.52, 95% CI 0.58-4.02, P = 0.396).
A possible association between HS and hypertriglyceridemia was evaluated in four studies[19][22][24][27]; only two revealed a weak though statistically significant association.[22][24] The pooled data failed to show any association (pooled OR 1.00, 95% CI 0.97-1.05, P = 0.796).
The presence of metabolic syndrome was evaluated as a risk factor for HS in two studies,[27][30] and although one of the studies showed a positive association, the pooled data failed to confirm it (pooled OR 1.07, 95% CI 0.13-8.83, P = 0.949).
Lipodystrophy was studied only once,[21] and a positive association with HS was found (OR 3.02, 95% CI 1.06-8.51).
Biochemical Abnormalities.
Individually, just one[27] out of seven studies[19][24][25][27][29][30] found a positive association between alanine aminotransferase (ALT) elevation and HS. Yet in the pooled data there was a weak but positive association (pooled OR 1.28, 95% CI 1.02-1.61, P = 0.035) (Fig. 2).
Two studies[19][26] presented conflicting results regarding aspartate aminotransferase (AST) elevation, and the pooled data failed to confirm an association (pooled OR 1.76, 95% CI 0.61-5.03, P = 0.292).
Histological Correlations.
When nine studies were evaluated together,[19-23][26][27][29][30] advanced fibrosis, i.e., bridging fibrosis or hepatic cirrhosis, presented a positive association with HS in the pooled data (pooled OR 1.67, 95% CI 2.34-3.01, P = 0.003) (Fig. 2). Severe necroinflammatory activity also presented a positive association with HS in the meta-analysis of seven studies[19-22][25-27] (pooled OR 1.72, 95% CI 1.11-2.67, P = 0.016), although that association was only statistically significant in three studies[19][25][26] (Fig. 2).
HCV Factors Associations.
Regarding HCV infection, the pooled data did not corroborate any association with possible risk factors for HS. In fact, the analysis of nine studies[20-27][30] failed to demonstrate genotype 3 as a risk factor (pooled OR 2.00, 95% CI 0.82-4.87, P = 0.127). However, a subanalysis of the three European studies with a genotype 3 prevalence higher than 30%[23][25][26] showed a strong association with HS (pooled OR 2.52, 95% CI 1.77-3.59, P < 0.001).
HCV viral load was assessed as a risk factor for HS in seven studies,[19][20][22-24][27][29] with only two showing a positive association.[23][27] The Bani-Sadr et al.[23] data suggested an increase of more than 50% in the risk for HS (OR 1.65, 95% CI 1.22-2.23) by each increase of 1 log10 IU/L in the HCV viral load. However, a meta-analysis of three studies[20][22][24] evaluating the risk of high viral load did not confirm an association (pooled OR 0.92, 95% CI 0.92-1.07, P = 0.819). The definition of high viral load was not exactly the same between studies.
HIV Factor Associations.
Immune status, assessed by CD4 cells count, did not seem to relate to HS because four out of five studies that evaluated that association presented negative results.[24-26][29][30] Only Gaslightwala and Bini[24] found a higher prevalence of HS when CD4 cell counts were higher than 350 cells/mm3 (72% versus 51%, P = 0.004). A meta-analysis of two studies[25][30] that used the same cutoff of CD4 cells count higher than 200 cells /mm3 also failed to show a statistically significant association (pooled OR 0.83, 95% CI 0.39-1.79, P = 0.637).
The effect of the duration of HIV infection on the prevalence of HS was evaluated in three studies.[20][21][30] Although Sterling et al.[30] found a slightly lower duration of infection in patients with HS (18.5 ± 0.95 years versus 22.6 ± 0.75 years, P = 0.036), each year of HIV infection duration[21] or being infected by HIV for more than 7 years[20] were not associated with a different risk for HS.
Using different approaches, many studies evaluated a potential effect of the HIV viral load[19-22][24-26][29][30]; seven, however, did not show a difference. Regarding having detectable versus nondetectable viral load, the McGovern et al.[22] results suggested that patients with detectable viral load had less HS (OR 0.86, 95% CI 0.76-0.98). However, a meta-analysis of four studies[20][22][24][25] did not confirm an association (pooled OR 0.95, 95% CI 0.61-1.47, P = 0.815). Regarding the fact of having a viral load higher than 400 copies per mL, the pooled data of two studies[19][30] also did not find an association (pooled OR 0.29, 95% CI 0.80-2.09, P = 0.295).
Being under ART did not seem to affect the risk for HS in the pooled data of six studies[20-22][26][29][30] (pooled OR 1.04, 95% CI 0.56-1.95, P = 0.903). In fact, individually, only two of these studies[22][30] detected a marginal statistically significant difference, although in opposite directions.
Analyzing the class of medications, no differences in the use of PI, NRTI, or nonnucleoside reverse transcriptase inhibitors (NNRTI) were found in relation to HS. In fact, only one[30] out of eight studies[20-22][24-26][29][30] that evaluated PI showed a weak association. The pooled data of seven studies[21][22][24-26][29][30] was also negative (pooled OR 1.05, 95% CI 0.72-1.52, P = 0.799). In addition, out of six studies,[22][24-26][29][30] only McGovern et al.[22] found a positive association between the use of NRTI and HS, with a more than 2-fold increased risk (OR 2.14, 95% CI 1.10-4.14). The pooled data of the remaining six studies also found no increased risk (pooled OR 0.89, 95% CI 0.35-2.24, P = 0.808). Lastly, concerning NNRTI therapy, out of seven studies[21][22][24-26][29][30] only Neau et al.[26] found it to have protective properties against HS (OR 0.40, 95% CI 0.20-0.90). The pooled data of these seven studies failed to find an association (pooled OR 0.86, 95% CI 0.61-1.19, P = 0.353).
Materials and Methods
This analysis was performed with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) criteria.[17] MEDLINE and Current Contents were searched by one investigator to identify relevant articles published until May 2009. In the electronic scrutiny, study references and relevant review articles on HIV/HCV coinfection were manually searched; eligible studies were identified through structured keywords: steatosis, fatty liver, VHC, HIV, and coinfection. All analyzed studies had to be published in English and to comprise a series of consecutive eligible patients, although allowing for exclusions due to other concomitant liver diseases and not necessarily excluding alcohol consumption.
The abstracts of all articles identified by the initial search were reviewed by another author and both authors reviewed the full text of all eligible studies reporting the prevalence of HS and its risk factors. Data elements sought from each included study were protocol-specified including steatosis prevalence, HCV monoinfection steatosis prevalence comparison data, study location, demographic data, HCV genotype, alcohol consumption, and other risk factors for HS.
Statistical Analysis.
For calculations, we computed the actual number of subjects from each study and performed a pooled analysis of the data. Pooled estimation of the prevalence of HS in HIV/HCV-coinfected patients and confidence limits were obtained with the random-effects model and the DerSimonian-Laird method.[18] Analysis of the heterogeneity of prevalence across studies was done with 2 tests. As all tests showed great heterogeneity, random effects models were preferred regarding fixed effects models.
Statistical analysis was conducted with STATA software (College Station, TX), version 10. Significance was established for P < 0.05.
Medivir Announces Phase 2b 24-week Interim Results of TMC435 in Treatment-naïve Patients
Medivir Announces Phase 2b 24-week Interim Results of TMC435 in Treatment-naïve Patients Chronically Infected with Genotype-1 Hepatitis C Virus
BusinessWire · Monday, Jul. 12, 2010
Potent and consistent antiviral efficacy was demonstrated at 24-week end-of-treatment and in interim SVR4 and SVR12 results. There were no clinically relevant differences between TMC435 treatment groups and placebo for adverse events.
Medivir (STO:MVIRB) announced today 24-week end-of-treatment interim results from the 5-arm phase 2b response guided PILLAR study in 386 treatment-naïve patients with hepatitis C virus (HCV) genotype-1 (TMC435-C205).
TMC435 is a protease inhibitor jointly developed by Medivir and Tibotec Pharmaceuticals, dosed as one pill once daily (q.d.) to treat hepatitis C virus infections (HCV).
In the PILLAR study, 75mg or 150mg TMC435 was given for either 12 weeks or 24 weeks in combination with 24 weeks of ribavirin and pegIFNalpha-2A, the current standard of care (SOC). Patients stopped all treatment at week 24 when HCV RNA levels at week 4 were < 25 log10 IU/mL detectable or undetectable and HCV RNA levels at week 12, week 16 and week 20 were < 25 log10 IU/mL undetectable. Patients who did not meet the above response-guided criteria continued with SOC until week 48. The results showed that in the TMC435 treatment groups 83% of patients were able to stop all therapy at Week 24.
Potent and consistent antiviral efficacy was demonstrated at 24-week end-of-treatment and in interim SVR4 and SVR12 rates with no major differences between TMC435 doses or length of triple therapy. 92% of patients taking TMC435 and Peg-IFN/RBV (SoC) achieved undetectable HCV RNA levels at week 4 and 92% at week 12 after cessation of treatment, i.e. SVR4 and SVR12. SVR4 and SVR12 data were available for 82% and 42% of the TMC435-treated patients respectively who had stopped all therapy before or at Week 24 and had completed the follow-up visits. Both the viral breakthrough rate (4.9%) and relapse rate (1.6%) were low in the TMC435 treatment groups.
TMC435 was generally safe and well tolerated with no relevant differences in adverse events (AEs) between placebo and TMC435 treatment groups. Most AEs were mild to moderate in severity and the discontinuation rate due to AEs was low and not different from placebo.
When looking at particular adverse events of interest, the incidence of rash, pruritis, GI side effects and anemia were similar in TMC435 groups and placebo and were generally mild to moderate in nature. Use of erythropoetin-stimulating agents (ESAs) was not allowed during the trial.
In laboratory parameters, there were no clinically relevant differences between any TMC435 groups and placebo except for mild bilirubin elevations. Significant decreases in transaminases (ALT and AST) were observed in all treatment groups.
Further safety and efficacy data will be presented at future scientific meetings later in 2010.
"We are extremely encouraged and excited by the efficacy and safety demonstrating that TMC435 is truly a second-generation HCV protease inhibitor," stated Bertil Samuelsson, CSO of Medivir. "We also are looking forward to the top-line data coming up from the phase 2b trial C206 (ASPIRE) in treatment-experienced patients later this year as well as start of phase 3 clinical trials in treatment-naïve patients early next year.”
Frequency of Undetectable* HCV RNA Levels During and After Treatment
Screen shot 2010-07-12 at 9.33.02 AM.png
* < 25 log10 IU/mL undetectable
** End of treatment
***EoT: End of Treatment
**** Patients in the control arm continue SoC till Week 48 and SVR data are not available
q.d.: once daily, PR: pegIFNalpha-2A and ribavirin, SVR4: undetectable HCV RNA at EoT & undetectable HCV RNA 4 weeks after planned EoT, SVR12: undetectable HCV RNA at EoT & undetectable HCV RNA 12 weeks after planned EoT
About TMC435 clinical trial programs
TMC435 is a protease inhibitor jointly developed by Medivir and Tibotec Pharmaceuticals to treat hepatitis C virus infections (HCV).
TMC435 is currently being developed in three phase 2b clinical trials (TMC435-C205, TMC435-C206 and TMC435-C215) in G1 treatment-naïve and in G1 patients that failed previous IFN-based treatment. Safety and efficacy data from the phase 2b trials will be presented at scientific meetings later in 2010.
TMC435-C205 is a global phase 2b study in 386 genotype-1 treatment-naïve patients. It is a once daily treatment of TMC435 with different doses and durations given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.
TMC435-C215 is a Japan phase 2b study in 92 genotype-1 treatment-naïve patients. It is a once daily treatment of TMC435 with different doses and durations given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.
TMC435-C206 is a global phase 2b study in 463 genotype-1 treatment-experienced patients. It is a once daily treatment of TMC435 in with different doses of given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.
About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.
Invitation to a Press Conference
Medivir will host a teleconference today at 15:00 (Central European summer time) focusing on the phase 2b 24-week interim results.
To participate in the teleconference, please call +46 8 619 75 30 using the participant code 195272#.
For more information on Medivir, please see the company website: www.medivir.se (http://www.medivir.se)
Contacts
Medivir
Rein Piir, CFO & VP Investor Relations
Tel: +46 8 54683123
BusinessWire · Monday, Jul. 12, 2010
Potent and consistent antiviral efficacy was demonstrated at 24-week end-of-treatment and in interim SVR4 and SVR12 results. There were no clinically relevant differences between TMC435 treatment groups and placebo for adverse events.
Medivir (STO:MVIRB) announced today 24-week end-of-treatment interim results from the 5-arm phase 2b response guided PILLAR study in 386 treatment-naïve patients with hepatitis C virus (HCV) genotype-1 (TMC435-C205).
TMC435 is a protease inhibitor jointly developed by Medivir and Tibotec Pharmaceuticals, dosed as one pill once daily (q.d.) to treat hepatitis C virus infections (HCV).
In the PILLAR study, 75mg or 150mg TMC435 was given for either 12 weeks or 24 weeks in combination with 24 weeks of ribavirin and pegIFNalpha-2A, the current standard of care (SOC). Patients stopped all treatment at week 24 when HCV RNA levels at week 4 were < 25 log10 IU/mL detectable or undetectable and HCV RNA levels at week 12, week 16 and week 20 were < 25 log10 IU/mL undetectable. Patients who did not meet the above response-guided criteria continued with SOC until week 48. The results showed that in the TMC435 treatment groups 83% of patients were able to stop all therapy at Week 24.
Potent and consistent antiviral efficacy was demonstrated at 24-week end-of-treatment and in interim SVR4 and SVR12 rates with no major differences between TMC435 doses or length of triple therapy. 92% of patients taking TMC435 and Peg-IFN/RBV (SoC) achieved undetectable HCV RNA levels at week 4 and 92% at week 12 after cessation of treatment, i.e. SVR4 and SVR12. SVR4 and SVR12 data were available for 82% and 42% of the TMC435-treated patients respectively who had stopped all therapy before or at Week 24 and had completed the follow-up visits. Both the viral breakthrough rate (4.9%) and relapse rate (1.6%) were low in the TMC435 treatment groups.
TMC435 was generally safe and well tolerated with no relevant differences in adverse events (AEs) between placebo and TMC435 treatment groups. Most AEs were mild to moderate in severity and the discontinuation rate due to AEs was low and not different from placebo.
When looking at particular adverse events of interest, the incidence of rash, pruritis, GI side effects and anemia were similar in TMC435 groups and placebo and were generally mild to moderate in nature. Use of erythropoetin-stimulating agents (ESAs) was not allowed during the trial.
In laboratory parameters, there were no clinically relevant differences between any TMC435 groups and placebo except for mild bilirubin elevations. Significant decreases in transaminases (ALT and AST) were observed in all treatment groups.
Further safety and efficacy data will be presented at future scientific meetings later in 2010.
"We are extremely encouraged and excited by the efficacy and safety demonstrating that TMC435 is truly a second-generation HCV protease inhibitor," stated Bertil Samuelsson, CSO of Medivir. "We also are looking forward to the top-line data coming up from the phase 2b trial C206 (ASPIRE) in treatment-experienced patients later this year as well as start of phase 3 clinical trials in treatment-naïve patients early next year.”
Frequency of Undetectable* HCV RNA Levels During and After Treatment
Screen shot 2010-07-12 at 9.33.02 AM.png
* < 25 log10 IU/mL undetectable
** End of treatment
***EoT: End of Treatment
**** Patients in the control arm continue SoC till Week 48 and SVR data are not available
q.d.: once daily, PR: pegIFNalpha-2A and ribavirin, SVR4: undetectable HCV RNA at EoT & undetectable HCV RNA 4 weeks after planned EoT, SVR12: undetectable HCV RNA at EoT & undetectable HCV RNA 12 weeks after planned EoT
About TMC435 clinical trial programs
TMC435 is a protease inhibitor jointly developed by Medivir and Tibotec Pharmaceuticals to treat hepatitis C virus infections (HCV).
TMC435 is currently being developed in three phase 2b clinical trials (TMC435-C205, TMC435-C206 and TMC435-C215) in G1 treatment-naïve and in G1 patients that failed previous IFN-based treatment. Safety and efficacy data from the phase 2b trials will be presented at scientific meetings later in 2010.
TMC435-C205 is a global phase 2b study in 386 genotype-1 treatment-naïve patients. It is a once daily treatment of TMC435 with different doses and durations given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.
TMC435-C215 is a Japan phase 2b study in 92 genotype-1 treatment-naïve patients. It is a once daily treatment of TMC435 with different doses and durations given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.
TMC435-C206 is a global phase 2b study in 463 genotype-1 treatment-experienced patients. It is a once daily treatment of TMC435 in with different doses of given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.
About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.
Invitation to a Press Conference
Medivir will host a teleconference today at 15:00 (Central European summer time) focusing on the phase 2b 24-week interim results.
To participate in the teleconference, please call +46 8 619 75 30 using the participant code 195272#.
For more information on Medivir, please see the company website: www.medivir.se (http://www.medivir.se)
Contacts
Medivir
Rein Piir, CFO & VP Investor Relations
Tel: +46 8 54683123
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