September 28, 2012

A new model that includes alpha-fetoprotein level predicts 5-year recurrence of posttransplant HCC better than the standard Milan criteria.

Liver transplantation is the best treatment option for early stages of hepatocellular carcinoma (HCC). Currently, the Milan criteria are used to identify transplantation-eligible patients with a low risk (10%–15%) for posttransplantation tumor recurrence. However, recent evidence has raised concern that these criteria might be too restrictive.

Using data from a cohort of 537 patients in France who received a liver transplant for HCC, researchers developed a new predictive model that included alpha-fetoprotein (AFP) level. This AFP model was then validated in a separate cohort of 435 liver transplant recipients with HCC who were part of a national transplantation program in France and were followed prospectively.

Regression analysis showed that the number of tumors, tumor size, and AFP level were independent predictors of 5-year tumor recurrence (the primary endpoint). Three combinations of these variables defined patients as low risk:

  • One to three nodules with maximum tumor diameter <3 cm and AFP ≤1000 ng/mL
  • One to three nodules with maximum tumor diameter 3 to 6 cm and AFP ≤100 ng/mL
  • More than four nodules with maximum tumor diameter <3 cm and AFP ≤100 ng/mL

In a simplified model, researchers transformed Beta coefficients of variables from the regression model into points, adding these to obtain a score. A score of 2 was the cutoff for low versus high risk. In the validation cohort, a score >2 (vs. ≤2) was associated with a higher 5-year recurrence rate (50.6% vs. 8.8%, P<0.001) and a lower 5-year survival rate (47.5% vs. 67.8%, P=0.002). The AFP model was superior to the Milan criteria in predictive performance based on a comparison of predicted and observed recurrence events with each. Some patients identified by the AFP model as low risk (e.g., patients with AFP ≤100 ng/mL) did not meet Milan criteria, and some identified as high risk (e.g., patients with AFP >1000 ng/mL) did meet the Milan criteria.

Comment: These new selection criteria identified not only transplantation candidates with low risk for HCC recurrence who would have been excluded using the standard Milan criteria, but also those at high risk for HCC recurrence who would have been eligible under those criteria. With the rise in the number of patients with HCC listed for transplantation, continual refinement of the selection criteria is critical. This AFP model could be the next iteration of those criteria.

Atif Zaman, MD, MPH

Published in Journal Watch Gastroenterology September 28, 2012

Citation(s):

Duvoux C et al. Liver transplantation for hepatocellular carcinoma: A model including alpha-fetoprotein improves the performance of Milan criteria. Gastroenterology 2012 Oct; 143:986.

Medline abstract (Free)

Source

Vertex

September 25, 2012

- ALS-2158: Well-tolerated in a seven-day viral kinetic study; development discontinued due to lack of efficacy -

- ALS-2200: Data from additional cohort of seven-day viral kinetic study with ALS-2200 (200 mg, QD) in combination with ribavirin show median 4.18 log10 reduction in HCV RNA with 5 of 8 people below the limit of quantification; treatment was well-tolerated -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and its collaborator Alios BioPharma, Inc. today announced results from a viral kinetic study of the adenosine nucleotide analogue pro-drug ALS-2158 for the treatment of hepatitis C. Data showed that seven days of dosing with up to 900 mg of ALS-2158 was well-tolerated in people with genotype 1 chronic hepatitis C, but that there was insufficient antiviral activity to warrant proceeding with further clinical development. The companies also announced new data from an additional cohort of an ongoing viral kinetic study of the uridine nucleotide analogue pro-drug ALS-2200 in combination with ribavirin. There was a median 4.18 log10 reduction from baseline in HCV RNA after seven days of dosing with a once-daily 200 mg dose of ALS-2200 in combination with ribavirin in people with genotype 1 chronic hepatitis C who were new to treatment (n=8). Five patients achieved HCV RNA levels below the limit of quantification ( < LOQ = < 25 IU/mL) and two of these five achieved HCV RNA levels below the limit of detection (Roche COBAS Taqman HCV test, Version 2) after seven days of treatment.

Similar to previously announced data from the monotherapy cohort, ALS-2200 was well-tolerated, no patients discontinued due to adverse events and there were no serious adverse events. Data from the ALS-2200 study will be presented in an oral presentation at The Liver Meeting®, the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, November 9 to 13, 2012.

"Our goal is to develop all-oral regimens that are well-tolerated and provide a high rate of viral cure in a broad population of people with chronic hepatitis C," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer at Vertex. "We're making good progress and expect to begin all-oral Phase 2 combination studies by the end of this year."

Pending discussions with regulatory agencies, Vertex is planning one Phase 2 study to evaluate ALS-2200 (VX-135) in combination with ribavirin, and one to evaluate ALS-2200 (VX-135) in combination with INCIVEK® (telaprevir), the company's approved protease inhibitor for people with genotype 1 chronic hepatitis C. These studies will evaluate 12 total weeks of treatment with a primary endpoint of SVR12 (sustained viral response: undetectable hepatitis C virus 12 weeks after the end of treatment) in people with genotype 1 chronic hepatitis C.

About ALS-2200

ALS-2200 is a uridine nucleotide analogue pro-drug that appears to have a high barrier to drug resistance based on in vitro studies. It is designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. In vitro studies of the compound showed antiviral activity across all genotypes, or forms, of the hepatitis C virus, including genotypes more prevalent outside of the United States.

Vertex gained worldwide rights to ALS-2200 through an exclusive licensing agreement signed with Alios BioPharma, Inc. in June 2011. The agreement also includes a research program that will focus on the discovery of additional nucleotide analogues that act on hepatitis C polymerase. Vertex has the option to select additional compounds for development emerging from the research program.

About INCIVEK

INCIVEK® (telaprevir) tablets is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication.

INCIVEK was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and by Health Canada in August 2011 for use in combination with pegylated-interferon and ribavirin for adults with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK is approved for people who are new to treatment, and for people who were treated previously with interferon-based treatment but who did not achieve a sustained viral response, or viral cure (relapsers, partial responders and null responders).

Vertex developed telaprevir in collaboration with Janssen and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America where it is being marketed under the brand name INCIVEK (in-SEE-veck). Janssen has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. In September 2011, telaprevir was approved in the European Union and Switzerland. Telaprevir is known as INCIVO® in Europe. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries. In September 2011, telaprevir was approved in Japan and is known as Telavic®.

IMPORTANT SAFETY INFORMATION

Indication

INCIVEK® (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.

Important Safety Information

INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Patients must use two forms of effective birth control during treatment and for the 6 months after treatment with these medicines. Hormonal forms of birth control, including birth control pills, vaginal rings, implants or injections, may not work during treatment with INCIVEK.

INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.

INCIVEK can cause serious side effects including skin reactions, rash and anemia that can be severe. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare providers about any side effect that bothers them or doesn't go away.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1

Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.2 However, approximately 60 percent of people do not achieve SVR,3,4,5 or viral cure,6 after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8

More than 170 million people worldwide are chronically infected with hepatitis C.6 In the United States, up to 5 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.9,10 Hepatitis C is four times more prevalent in the United States compared to HIV.10 The majority of people with hepatitis C in the United States were born between 1945 and 1965, accounting 82 percent of people with the disease.11 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 15,000 deaths annually.12,13 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.10

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, Mass., we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, and for three years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences.

Vertex's press releases are available at www.vrtx.com.

About Alios BioPharma

Alios BioPharma is a biotechnology company located in South San Francisco, California, that is developing novel medicines aimed at the treatment of viral diseases. Alios has an innovative team of highly experienced scientists and clinical researchers who are developing direct acting antiviral agents against several human viral pathogens of public health importance including HCV, RSV, Influenza and other chronic, acute and emerging viral diseases. The overall goal for the Alios therapeutic platform is to maximize patient benefits in areas of high unmet medical need through optimization of potency, safety and tolerability.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, Dr. Kauffman's statements in the third paragraph of this press release and statements regarding (i) data supporting the advancement of ALS-2200 into Phase 2 all-oral studies this year and (ii) Vertex's plans regarding the design of these Phase 2 studies. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the initiation of Phase 2 studies of ALS-2200 may be delayed or prevented, outcomes from any future studies of ALS-2200 may not be favorable and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

References:

1 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf Updated June 2010. Accessed September 21, 2012.

2 Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.

3 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

4 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

5 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

6 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).

8 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

9 Chak, E, et. al. Hepatitis C Virus Infection In USA: An Estimate of True Prevalence. Liver Intl. 2011;1096 -1098.

10 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx Updated January 11, 2010. Accessed September 21, 2012.

11 Smith, BD, et al. Hepatitis C Virus Antibody Prevalence, Correlates and Predictors among Persons Born from 1945 through 1965, United States, 1999-2008. AASLD 2011 Annual Meeting.

12 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

13 S.D. Holmberg, K.N. Ly., et.al. The Growing Burden of Mortality Associated with Viral Hepatitis in the United States, 1999-2007. AASLD 2011 Annual Meeting.

Vertex Pharmaceuticals Incorporated
Media:
Zach Barber
Erin Emlock
Dawn Kalmar
617-444-6992
mediainfo@vrtx.com
or
Investors:
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Michael Partridge, 617-444-6108

Source: Vertex Pharmaceuticals Incorporated

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September 27, 2012

Incarcerated patients with chronic hepatitis C virus (HCV) infection are just as likely to respond to treatment for the disease as patients in the community, according to findings published in the October issue of Hepatology, a peer-reviewed journal of the American Association for the Study of Liver Diseases. The study from the University of Wisconsin School of Medicine and Public Health (SMPH) in Madison found that HCV patients in prison were just as likely to achieve a sustained viral response (SVR) as non-incarcerated patients.

Medical evidence reports that chronic HCV is the leading cause of end-stage liver disease (ESLD) and liver disease mortality in the U.S. Further studies have shown the risk of developing cirrhosis due to chronic HCV ranges between 5 and 25 percent over a 25 to 30 year period. Consequences caused by chronic HCV are major public health concerns within the U.S. prison system, with research conducted by the Centers for Disease Control and Prevention (CDC) estimating up to 31 percent of U.S. inmates have chronic HCV, compared to just two percent of the general population in this country.

"Given that a history of intravenous drug use is more frequent among inmates, there is a higher prevalence of HCV infection in the prison population," explains lead author Dr. Michael Lucey, Chief of the Division of Gastroenterology and Hepatology at the SMPH. "HCV treatment during incarceration provides an opportunity to make a significant improvement to public health."

Incarcerated and non-incarcerated patients with HCV who were seen at the University of Wisconsin Hepatology or Infectious Diseases Clinic between January 2002 and December 2007, were evaluated for antiviral therapy. Researchers identified 521 general-population patients and 388 from the prison population who were evaluated for HCV therapy.

Results show that 61 percent of non-incarcerated and 60 percent of incarcerated patients received treatment with pegylated interferon and ribavirin. Those from the prison population were more likely to be African-American males with a history of alcohol or intravenous drug use. The team reported that SVR was achieved in 43 percent of prisoners compared to 38 percent of patients in the general-population group.

"Our findings highlight the effectiveness of antiviral therapy in HCV-infected prisoners, and show that it is as successful as treatment for HCV patients in the general population," says Lucey. "With previous studies citing poor results of HCV treatment in high-risk groups on an outpatient basis, a correctional setting may be an optimal setting for treatment that will help curb the hepatitis C public health crisis."

This research was funded by the American Cancer Society Research Scholar Grant, the National Institutes of Health (NIH) Clinical and Translational Science Award, and by the Clinical and Translational Science Award (CTSA) program of the National Center for Research Resources at NIH.

Reference: Rice JP, et al. Comparison of Hepatitis C Virus Treatment Between Incarcerated and Community Patients. Hepatology; (DOI: 10.1002/hep.25770; Print Issue Date: October, 2012.

Source

September 27, 2012

(Phys.org)—Lymph nodes can provide a suitable home for a variety of cells and tissues from other organs, suggesting that a cell-based alternative to whole organ transplantation might one day be feasible, according to researchers at the University of Pittsburgh School of Medicine and its McGowan Institute for Regenerative Medicine. In a report recently published online in Nature Biotechnology, the research team showed for the first time that liver cells, thymus tissue and insulin-producing pancreatic islet cells, in an animal model, can thrive in lymph nodes despite being displaced from their natural sites.

Hepatitis virus infection, alcoholic cirrhosis and other diseases can cause so much damage that liver transplantation is the only way to save the patient, noted senior investigator Eric Lagasse, Pharm. D., Ph.D., associate professor, Department of Pathology, Pitt School of Medicine. Children with DiGeorge syndrome lack functional thymus glands to produce essential immune cells, and diabetes can be cured with a pancreas transplant.

"However, the scarcity of donor organs means many people will not survive the wait for transplantation," said Dr. Lagasse, whose lab is at the McGowan Institute. "Cell therapies are being explored, but introducing cells into tissue already ravaged by disease decreases the likelihood of successful engraftment and restoration of function."

In the study, his team tested the possibility of using lymph nodes, which are abundant throughout the body and have a rich blood supply, as a new home for cells from other organs in what is called an "ectopic" transplant.

They injected healthy liver cells from a genetically-identical donor animal into lymph nodes of mice at various locations. The result was an enlarged, liver-like node that functioned akin to the liver; in fact, a single hepatized lymph node rescued mice that were in danger of dying from a lethal metabolic liver disease. Likewise, thymus tissue transplanted into the lymph node of mice that lacked the organ generated functional immune systems, and pancreatic islet cell transplants restored normal blood sugar control in diabetic animals.

"Our goal is not necessarily to replace the entire liver, for example, but to provide sufficient cell mass to stabilize liver function and sustain the patient's life," Dr. Lagasse said. "That could buy time until a donor organ can be transplanted. Perhaps, in some cases, ectopic cell transplantation in the lymph node might allow the diseased organ to recover."

Journal reference: Nature Biotechnology

Provided by University of Pittsburgh Schools of the Health Sciences

Source

Also See: Growing Surrogate Organs in Lymph Nodes

Achillion Announces Positive Proof-of-Concept Data With ACH-3102

ACH

September 27, 2012

-Second-Generation Pan-Genotypic NS5A Inhibitor Achieves Potent Antiviral Activity
of Mean Maximum 3.74 Log
10 Reduction Following a Single Dose -

- Initiated Enrollment in a Phase 2 Clinical Trial Evaluating ACH-3102 Plus Ribavirin for the Treatment of HCV Genotype 1b-

- Hosting Analyst Day Today With Live Webcast Beginning at 1:00 p.m. ET -

NEW HAVEN, Conn., Sept. 27, 2012 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced positive proof-of-concept results with ACH-3102, a second-generation pan-genotypic NS5A inhibitor being developed for the treatment of chronic hepatitis C viral infections (HCV). Administration of a single-dose of ACH-3102 to genotype (GT) 1a HCV-infected subjects resulted in a mean maximum 3.74 log10 reduction in HCV RNA (range 2.9 — 4.6 log10). Significant reductions in HCV RNA were achieved in subjects with resistant variants at baseline, including L31M and Y93C variants.

Based on these data, combined with safety and tolerability results from the Phase 1a trial in healthy subjects evaluating up to 14 days of ACH-3102, Achillion has initiated a pilot Phase 2 clinical trial evaluating ACH-3102 in combination with ribavirin for the treatment of patients with chronic GT 1b HCV.

"We believe these proof-of-concept results demonstrate the differentiation of ACH-3102 from first-generation NS5A inhibitors. The potency of ACH-3102 was successfully shown against genotype 1a, historically the hardest to treat HCV subtype," commented Michael Kishbauch, President and Chief Executive Officer of Achillion. "Furthermore, we believe the enhanced resistance profile of ACH-3102 observed in vitro has been validated in the clinic with robust antiviral activity against baseline mutations such as L31M. These results support our belief that this second-generation pan-genotypic NS5A inhibitor has the potential to become a cornerstone compound."

ACH-3102: Phase 1 Program

In May 2012, Achillion initiated a Phase 1a clinical trial evaluating the safety and tolerability of single and multiple ascending doses of ACH-3102 in healthy volunteers. To date, 42 healthy volunteers have received a single dose of ACH-3102, ranging from 25 mg to 1,000 mg. An additional 32 healthy volunteers have received 14 days of ACH-3102 once-daily evaluating various dosing regimens. Preliminary data from the single and multiple ascending dose groups demonstrated that ACH-3102 was well tolerated at all doses evaluated. There were no serious adverse events and no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. All reported adverse events were classified as mild or moderate and were transient in nature.

In August 2012, Achillion initiated a Phase 1b clinical trial enrolling a total of 14 patients infected with GT 1a chronic HCV, of which 2 received placebo and 12 received a single dose of 50 mg, 150 mg or 300 mg ACH-3102. No serious adverse events were reported and there were no patient discontinuations.

The mean maximum HCV RNA decline for each dose group is provided below:

Capture

An assessment of clinical virology was conducted on baseline samples from all 12 patients receiving a single-dose of ACH-3102. Sequencing revealed one patient had a baseline L31M mutation (300 mg dose group, maximum HCV RNA decline of 3.4 log10) and another patient had a baseline Y93C mutation (300 dose group, maximum HCV RNA decline of 4.6 log10). These mutations have been previously reported to convey a high level of resistance to first-generation NS5A inhibitors which was not observed following exposure to ACH-3102.

ACH-3102: All-oral, interferon-free pilot Phase 2 12-week trial of ACH-3102 and ribavirin for the treatment of HCV GT 1b

Achillion has initiated patient enrollment in an open-label Phase 2 pilot trial evaluating 12-weeks of once-daily ACH-3102 in combination with ribavirin for the treatment of HCV GT 1b. This study will initially enroll up to 16 treatment-naïve patients with GT 1b IL28B CC HCV. Patients will receive 225 mg of ACH-3102 on day 1 followed by 75 mg of ACH-3102 once daily on subsequent days in combination with twice daily ribavirin. The primary objective of the trial is to determine the safety and sustained virologic response 12 weeks after the completion of treatment (SVR12) with secondary endpoints assessing safety, pharmacokinetics, pharmacodynamics, and virologic endpoints including rapid virologic response (RVR) and extended RVR (eRVR). Achillion expects to report initial RVR results from this study during the fourth quarter of 2012.

Mr. Kishbauch further commented, "With the initiation of this all-oral 12-week study evaluating ACH-3102 and ribavirin for the treatment of HCV genotype 1b, we have rapidly advanced our portfolio and believe the attributes of ACH-3102, as well as sovaprevir, our Phase 2 protease inhibitor, have the potential to provide optimized compounds for the broad treatment of HCV."

Analyst Day Webcast

Achillion is hosting its inaugural Analyst Day and simultaneous webcast on Thursday, September 27, 2012 at 1:00 p.m. Eastern Time. To access a copy of the presentation and the live audio webcast of the event, please visit www.achillion.com. Please connect to Achillion's website several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary. A replay of the webcast will be available on www.achillion.com beginning approximately 2 hours after the conclusion of the event.

About HCV

The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide including more than 5 million people in the United States, more than twice as widespread as HIV. Three-fourths of the HCV patient population is undiagnosed; it is a silent epidemic and a major global health threat. Chronic hepatitis, if left untreated, can lead to permanent liver damage that can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including HCV and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000 begin_of_the_skype_highlighting 1-203-624-7000 end_of_the_skype_highlighting.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to the favorable activity and potential benefits of ACH-3102 and sovaprevir, and expectations about milestone achievement including the potential to report RVR results during the fourth quarter of 2012. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things, Achillion's ability to: replicate in later clinical trials the positive results found in nonclinical studies and earlier stage clinical studies of sovaprevir, ACH-2684, and ACH-3102; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2011 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.

Source

Growing Surrogate Organs in Lymph Nodes

GENNewsHighlights

Sep 28, 2012

A patient’s lymph nodes may offer an ideal transplantation site for cell- or tissue-based therapies against a range of diseases that currently necessitate whole-organ transplantation, or the transfer and engraftment of cells into already damaged tissue, scientists claim. Studies in mice by University of Pittsburgh scientists have shown that healthy lymph nodes will support engraftment of diverse cell types such as hepatocytes, thymic tissue, and pancreatic islet cells, and that the transplanted cells generate functional surrogate organs in the lymph nodes that can reverse the pathology of diseases such as liver failure and diabetes.

The human body contains over 500 lymph nodes, and the concept that these sites can provide a foster home for a wide range of cell types is supported by the fact multiple cancer cell types will often metastasise first to lymph nodes, where they can continue to grow and proliferate. The latest work by Eric Lagasse, Ph.D., and colleagues now suggests that this hospitable environment could be harnessed for regenerative therapy.

The team tested to see whether the lymph node environment could also support the engraftment and function of different cell types for cell therapy application. For the first set of experiments, the researchers transferred syngeneic hepatocytes into a single jejuna lymph node of a mouse model of lethal metabolic liver failure. Twelve weeks later they found that the cells had engrafted in the lymph node and effectively generated a functional ectopic liver that rescued the recipient animals from lethal liver failure. In fact, in the Fah-/- mouse model used, hepatocytes transplanted into just one jejunal lymph node developed into tissue representing about 70% of the mass of a mouse liver. Encouragingly, the technique was equally effective when other lymph nodes were used as the transplantation site.

Projecting the future use of this approach for treating liver disease in humans, the investigators say the overall aim wouldn’t necessarily be to replace the patient’s liver, rather the ectopic tissue would hopefully provide enough cell mass to stabilize liver function until an organ donor is found, or help the patient’s own liver regenerate.

For the second set of experiments the team transplanted thymuses taken from healthy newborn mice into jejuna lymph nodes of athymic (BALB/c) nude mice. A month later the recipient animals were producing CD4+ and CD8+ cells from their own bone marrow, and these immune cells were still being generated 10 months later. Notably, when the ectopic thymus tissue was analyzed, it was found that the transplanted cells had organized into thymic medullary and cortical epithelia, and that the T cell population induced a full complement of regulatory, naive, central memory, and effector T cells that could mount T cell-mediated immune responses to skin allografts and tumor xenografts.

In a third set of studies, the investigators harvested pancreatic islets from C57BL/6 mice and transplanted these into the jejuna lymph nodes of C57BL/6 wild type mice treated with streptozotocin, a compound that induces diabetes. Encouragingly, the transplanted islets expressed C-peptide and glucagon, which are indicators of pancreatic β-cell and α-cell function. Importantly, the transplanted islets functioned to restore glucose concentrations in the recipient animals to normal levels within six weeks, and, in one animal evaluated, normoglycemia was maintained for at least six months after lymph node transplantation.

Describing their work in Nature Biotechnology, the Pittsburgh investigators say that to their knowledge this is the first time that lymph node evaluation as a site for functional cellular transplantation has been reported. “By directly injecting the lymph node with hepatocytes, thymuses, or pancreatic islets, we demonstrate engraftment of the donor cells and subsequent organ function,” they state. “This new approach of using the lymph node as an in vivo bioreactor in which to regenerate functional organs may be beneficial to the field of regenerative medicine.”

Source

Poor HIV patients improve with care beyond drugs: study

r

AIDS activists take part in a rally across from the White House in Washington July 24, 2012. Credit: Reuters/Kevin Lamarque

By Susan Heavey

WASHINGTON | Fri Sep 28, 2012 2:56am EDT

(Reuters) - Patients stepping into Johns Hopkins University's HIV clinic in east Baltimore do not just see a doctor or get prescriptions for their antiretroviral drugs. Many also get help finding a place to live or bus fare to make it to their next appointment.

Such care that goes beyond the examination table and into patients' often challenging lives has been key to helping poorer HIV patients - particularly blacks and women - live long, healthier lives, according to a 15-year study published on Thursday in the journal Clinical Infectious Diseases.

Researchers at the university followed 6,366 patients in the mostly black, low-income part of a city marked by abandoned buildings and plagued by an illegal drug trade that drew national attention on the gritty television series "The Wire."

From 1995 to 2010, doctors at Hopkins joined with social workers and other experts to treat HIV, the human immunodeficiency virus that causes AIDs, and address other aspects of care that can often derail patients, such as being able to fill prescriptions or access health insurance programs for the needy.

They found that with additional assistance, patients at the clinic could expect to live to about age 73 despite their background. Researchers found no difference in patients' health over time despite their gender, race, risk group, or socioeconomic status - a finding they said showed comprehensive care could eliminate disparities that arise among at-risk groups.

"Just like over time we have developed medications that are easier to take, have fewer toxicities and are more effective, I think we've done exactly the same things in our ability to deliver quality care to this particular population," Dr. Richard Moore, the study's lead author, said in an interview.

Moore, a professor of infectious diseases and director of the university's clinic, said the program showed it was possible to counter the impact of economic disparities on healthcare.

Even though HIV medications have significantly improved since the virus emerged in the United States decades ago, accessing those medications, receiving consistent care and follow-up appointments for the chronic condition are key, he said.

HIV still hits certain populations harder than others, and rising infection rates among gay black men, for example, remain a major worry among public health experts.

IMPROVING OUTCOMES

"Our results emphasize that advances in HIV treatment have had a positive impact on all affected demographic and behavioral risk groups in an HIV clinical setting," Moore and his colleagues wrote.

Previous studies have shown that certain groups of HIV patients - the poor, minorities, women and drug users - tended to have worse outcomes and die earlier.

Moore found that more comprehensive care that addresses problems such as homelessness and a lack of reliable transportation could help an average 28-year-old with HIV live roughly 45 more years with no significantly higher risk of various infections or other complications, a result that "did not differ by demographic or behavioral risk group."

Moore also credited the roughly $2 billion Ryan White CARE Act, the largest federal program solely aimed at paying for care for low-income HIV patients who are uninsured or have inadequate coverage. The program, which President Barack Obama extended in 2009, is up for renewal next year.

About 92 percent of the clinic's patients are low-income, according to the study.

Michael Saag, head of the University of Alabama at Birmingham's Center for AIDS Research, said the new findings underscored the need to revamp the nation's healthcare system so that all people get quality care. HIV patients are lucky to have access to Ryan White funds, but others do not.

"This is likely a fundamental reason why the poor and disadvantaged in the United States have health disparities that cause disproportionately worse clinical outcomes than those with means," Saag said in an editorial accompanying the study.

To be sure, researchers only followed patients who continued with the clinic over time. Patients who dropped out for various reasons, even despite staff effort to contact them, were not included in the data.

Over the years, Moore said he and his colleagues had learned what tends to work, and what does not, when it comes to their patients.

Moore, who has worked at the Hopkins clinic for 24 years, said patients were immediately connected to a case worker who sometimes started counseling them even before their first appointment.

Other clinics have also started similar efforts in recent year, but this more comprehensive type of care is not yet available nationwide.

"Medical care, particularly for a lot of people who aren't necessarily well-insured or living in a stable situation, you have to just as much deal with all that aspect of assisting them with their lives," Moore said. "I wish that wasn't the case."

(Editing by Peter Cooney Steenhuysen)

Source

HIV Therapy Universally Effective

35009

By Michael Smith, North American Correspondent, MedPage Today

Published: September 28, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

HIV therapy is equally effective regardless of race, ethnicity, sex, or economic class -- as long as patients can be engaged and retained in care.

The finding -- apparently at odds with reports of major disparities in HIV across the U.S. -- comes from a 15-year analysis of data from a long-standing and highly regarded Baltimore clinic.

Over that time, outcome differences along race, sex, or economic lines have steadily fallen, according to Richard Moore, MD, and colleagues at Johns Hopkins University.

By 2010, the proportion of patients getting triple-drug therapy, the average viral load, the rate of opportunistic infections, the average count of CD4-positive T cells, and the risk of dying were all similar across all demographic and HIV risk categories, Moore and colleagues found.

And a 28-year-old patient in care in 2009 in the Johns Hopkins HIV/AIDS Service could expect an additional 45 years of life, the researchers reported online and in the Nov. 1 issue of Clinical Infectious Diseases.

"What we have found is very optimistic," Moore told MedPage Today. "Our treatments really can work for everyone who's HIV-infected."

The catch is overcoming barriers that prevent patients from remaining in care, Moore said. Most disparities in outcomes arise from a failure to retain patients, and the current study only applies to the 6,366 patients who were engaged in care at Johns Hopkins from 1995 to 2010.

But in many cases, he said, "I think it would generalize" -- especially to other specialized centers that have been able to use federal money available under the Ryan White Care Act, to overcome patient barriers to care.

Using that resource, the Baltimore clinic is able to offer -- along with HIV care -- primary care, specialties such as substance abuse and mental health, and supportive services, including nutrition, treatment adherence, emergency services, and transportation.

In 2010, 92% of the clinic's patients were low-income and 75% were black -- two groups that are hardest-hit by HIV.

Indeed, the "remarkable outcomes" in Baltimore and similar centers are likely a result of Ryan White support, commented Michael Saag, MD, of the University of Alabama at Birmingham.

In an accompanying editorial comment, he noted that Ryan White support can be used to cover the cost of outpatient care and medications, including such things as psychology/psychiatry, substance use treatment, adherence counseling, and social services.

Most other disease-specific and primary care clinics don't have such extra support, Saag noted, "and this is likely a fundamental reason why the poor and disadvantaged in the U.S. have health disparities that cause disproportionately worse clinical outcomes than those with means."

Moore said other factors also play a role -- including improved treatments and better clinical understanding of HIV. But the absence of Ryan White support, he said, "would be a big blow to our program" assuming there were no compensating changes to healthcare.

The Ryan White act is due for reauthorization next year, Saag noted. The entire healthcare system needs an overhaul, he said, but until then "we will desperately need the support from (the act) to continue filling the holes in our primary care safety net for HIV patients."

Moore and colleagues reported that, as of 2010:

  • 87% of their patients were receiving antiretroviral therapy.
  • The median serum viral load was less than 200 copies of HIV RNA/mL.
  • The median CD4 was 475 cells/mm2 of blood.
  • The rate of opportunistic illnesses was 2.4 per 100 patient-years.
  • The mortality rate was 2.1 per 100 patient-years.

By and large, they reported, there were no differences by demographic or HIV risk group. The exception was that people infected through injection drug use had a lower CD4 count and a higher viral load than other risk groups.

The researchers cautioned that the study focused on a single center and may not apply more widely. In any case, they added, the results "certainly do not generalize to HIV-infected people in the U.S. who have not engaged in HIV care."

"Nevertheless," they concluded, "we believe that our results are an important demonstration of what can be achieved by contemporary HIV care in patients who are retained in care."

The study was supported by the National Institutes of Health. The journal said the authors reported no potential conflicts.

The journal said Saag reported no potential conflicts.

Primary source: Clinical Infectious Diseases
Source reference:
Moore RD, et al. "Improvement in the health of HIV-infected persons in care: Reducing Disparities" Clin Inf Dis 2012; DOI: 10.1093/cid/cis654.

Additional source: Clinical Infectious Diseases
Source reference:
Saag MS. "Viva no différence!" Clin Inf Dis 2012; DOI: 10.1093/cid/cis656.

Source

From Journal of Viral Hepatitis

J. A. Holmes; P. V. Desmond; A. J. Thompson

Posted: 09/28/2012; J Viral Hepat. 2012;19(10):677-684. © 2012 Blackwell Publishing

Abstract and Introduction
Abstract

IL28B genotype has been shown to be the strongest pretreatment predictor of sustained virological response (SVR) in patients with genotype 1 chronic hepatitis C infection (CHC) treated with pegylated interferon (peg-IFN) and ribavirin (RBV). Patients carrying the good response genotype have a two- to threefold higher chance of SVR than those with a poor response genotype, manifest as dramatically improved early viral kinetics. However, the treatment paradigm for CHC is changing with the introduction of potent direct-acting antivirals (DAAs). IL28B genotype remains relevant to both telaprevir and boceprevir treatment regimens, although the strength of association with virological response is attenuated. The association between IL28B genotype and outcomes of treatment regimens that involve peg-IFN plus combination DAA therapy, or IFN-free regimens, is currently being evaluated. IL28B genotype may remain relevant to individualizing the choice of treatment regimen in the future.

Introduction

Chronic infection with the hepatitis C virus (HCV) is a global epidemic affecting 130 to 170 million individuals, who are at risk of progressive liver fibrosis, decompensation and hepatocellular carcinoma. These complications have been shown to be reduced by viral eradication. Pegylated-interferon-alpha (peg-IFN) combined with ribavirin (RBV) has been the standard-of-care therapy for chronic hepatitis C (CHC) since 2003. However, the rate of response is suboptimal for genotype 1 HCV (HCV-1), with only 40–50% of patients being cured by dual therapy. Furthermore, the ability to identify which individuals would respond to treatment was limited. In the last 3 years, the field has made two major advances. In late 2009, genome-wide association studies (GWAS) identified genetic variants in the region of the IL28B gene that are strongly associated with the outcome of peg-IFN and RBV (PR) therapy.[1–3] In the IDEAL study pharmacogenetics cohort, carriage of the favourable IL28B genotype was associated with sustained virological response (SVR) rates of 70–80% in Caucasian patients treated with 48 weeks of PR, compared to 30–40% in patients carrying one of the unfavourable genotypes. Difference in population frequency of the favourable IL28B genotype explained much of the recognized ethnic disparity in PR response rates. IL28B genotyping immediately proved useful for pretreatment counselling for HCV-1 patients. However, PR is no longer standard-of-care for HCV-1 in many parts of the world. In 2011, the first direct-acting antivirals (DAAs) for HCV were approved for the treatment of HCV-1, increasing overall SVR rates almost twofold. 2011 also saw proof-of-concept that HCV could be cured using IFN-free regimens. DAA therapy clearly attenuates the association between IL28B genotype and HCV treatment response, but emerging data suggest that IL28B genotype will remain relevant to emerging treatment paradigms, including IFN-free therapy. In this article, we will discuss the clinical utility of IL28B genotyping for pretreatment counselling in the rapidly evolving era of DAA therapies for HCV.

IL28B Genotype and Response to Dual Therapy With peg-Interferon-A and Ribavirin

The first-generation DAAs are not yet universally available, and it is pertinent to briefly review the literature describing the association between IL28B polymorphism and response to peg-IFN and RBV therapy. IL28B genotype is the most important pretreatment predictor of response to peg-IFN and RBV therapy for HCV-1, where patients who carry the good response genotype (e.g. C/C at rs12979860) have reported SVR rates ≥70%, a two- to threefold increase over patients who carry one of the poor response genotypes (e.g. C/T, T/T at rs12979860).[4,5] The frequency of the good response IL28B genotype varies between individuals of different ethnic backgrounds, being >80% in certain Asian populations, 35–55% in Caucasians and <20% in patients of African ancestry. This variation explains much of the disparity in treatment response rates observed according to ethnicity. It is also relevant to discussion of the health economics of novel DAA therapies (see below). The mechanism explaining the association between IL28B genotype and IFN responsiveness is not known, but it manifests as profound differences in on-treatment viral kinetics. The good response IL28B genotype is associated with increased phase-1 and phase-2 viral kinetics,[5,6] resulting in increased rates of rapid virological response (RVR) and complete early virological response (cEVR) on-treatment (Table 1). In fact, most RVR patients carry the good response IL28B genotype.[5] It is important to note that all patients who achieve an RVR do well, and a high rate of SVR is observed even in the minority of patients who carry a poor response IL28B genotype. It is also important to note that the good response IL28B genotype is not sufficient to indicate short-duration PR therapy using response-guided protocols for HCV-1. Recent data have shown that short-duration therapy (24 weeks) is only sufficient for patients who carry the good response IL28B genotype and have a low baseline viral load (<400–800 000 IU/ml) and achieve an RVR.[7] Finally, the importance of IL28B genotype as a pretreatment predictor of IFN responsiveness should not discount other predictors of response, especially liver fibrosis stage. In the IDEAL study cohort, SVR rates in patients with advanced liver fibrosis were considerably lower (METAVIR F3-4, SVR in C/C = 41% vs C/T = 22% vs T/T = 11%).[5]

IL28B Genotyping in the Setting of Telaprevir and Boceprevir Therapy

In the phase-3 registration studies of treatment-naïve HCV-1 patients, the addition of the NS3 protease inhibitors telaprevir (TVR) or boceprevir (BOC) to a PR backbone increased overall SVR rates from 40–45% to 68–79%.[8, 9] In the setting of such high SVR rates, the association between IL28B genotype and treatment response is attenuated (Table 2). However, it remains clinically relevant.

A retrospective analysis of the relationship between IL28B polymorphism (rs12979860) and treatment outcomes from the SPRINT-2 study of BOC-PR therapy for treatment-naïve patients has recently been published.[10] The analysis included 62% (653/1048) of the SPRINT-2 cohort who consented to genetic testing. Very high SVR rates were observed in all patients with the C/C genotype; in fact, SVR rates were equivalent in the BOC treatment arms and the PR control arm (Table 2). However, the C/C patients were much more likely to be eligible for short-duration therapy than the non-C/C patients (89% vs 52% non-C/C patients achieved undetectable HCV RNA levels at week 8). It was also notable that 97% of treatment-naïve C/C patients achieved ≥1 log10 IU/mL reduction in HCV RNA at the end of the 4 week lead-in phase of PR treatment.[10,11] A ≥1 log10 reduction in HCV RNA identifies good IFN responders, with SVR rates >80% and low risk of selection of resistance-associated variants. BOC therapy was associated with much more benefit in non-C/C patients, with rates of SVR of 55–71% compared to 27–28% with PR therapy alone in SPRINT-2 (Table 2). The lead-in phase of PR was more useful for stratifying IFN responsiveness in the non-C/C naïve population, in which 27% C/T and 46% T/T patients were identified to have poor IFN responsiveness, predicting for low SVR rate and higher risk of selecting resistant variants. Patients with poor IFN responsiveness might be considered for deferral of DAA exposure to minimize risk of selection of resistant variants, awaiting future quadruple therapy or combination DAA regimens. This should be an individualized decision, according to the urgency for antiviral therapy. IL28B genotyping can therefore identify patients in whom the lead-in has greatest clinical utility for stratifying IFN responsiveness.

Logistic regression modelling found that IL28B genotype was independently associated with the outcome of BOC-based therapy, OR = 2.6 (1.3–5.1) for C/C vs T/T and OR = 2.1 (1.2–3.7) for C/C vs C/T.[10] The other pretreatment predictors of SVR were low baseline HCV RNA level (< = 800, 000 IU/mL), the absence of cirrhosis, HCV-1 sub-type (1b vs 1a) and race (non-black vs black). IL28B genotype was the strongest predictor of good IFN response (≥1 log10 decline at week 4), OR = 26.5 (7.6–92.6) for C/C vs T/T and 16.4 (5.0–55.6) for C/C vs C/T.[10] When week 4 response was included in the SVR model, IL28B genotype was no longer independently associated with SVR. This is consistent with the observation from the PR literature that IL28B genotype informs IFN responsiveness, but once IFN responsiveness is defined in real-time by a trial of treatment, IL28B genotype is no longer clinically informative.[12]

IL28B genotyping has also been shown to be informative in the context of TVR therapy for treatment-naïve patients. Retrospective analysis of the association between IL28B polymorphism and treatment outcome was performed in a subset of the ADVANCE study population (n = 454/1088 [42%]).[13] The strength of association between IL28B genotype and treatment outcome was attenuated in the TVR treatment arms compared to the PR control arm. Rates of SVR were higher in the TVR treatment arms compared to the PR control arm among both C/C and non-C/C patients (it should be noted that the response rate among C/C patients in the PR control arm was lower than that observed in SPRINT-2, Table 2). SVR rates increased relatively more in non-C/C patients than C/C patients (Table 2). Similar to SPRINT-2, C/C patients were more likely to be eligible for short-duration therapy by achieving an extended rapid virological response (eRVR), defined as HCV RNA undetectable at weeks 4 and 12) with 12 weeks of TVR (C/C 78% vs C/T 57% vs T/T 45%).[13] SVR rates were very high in all patients who achieved an eRVR regardless of IL28B genotype (97% in CC patients and 88% in CT/TT patients). In patients who did not attain an eRVR, patients carrying the CC IL28B genotype had higher SVR rates (67% vs 38% for CT/TT patients). No data have yet been presented linking IL28B polymorphism to risk of resistance during TVR therapy, but given the key role for IFN responsiveness in controlling the emergence of resistance-associated variants (RAVs), this can be assumed.

In patients who have previously failed PR therapy, IL28B genotype is less informative for the outcome of TVR or BOC-based therapy. This was evaluated in retrospective analyses of the RESPOND-2 study of BOC therapy for prior relapsers and partial responders to PR therapy,[10] and the REALIZE study of TVR therapy for prior relapsers, partial responders and null responders (Table 2).[14] There was no significant association between IL28B genotype and treatment response noted in either study. This reflects again that IL28B genotype is no longer informative for SVR once IFN responsiveness is known, here defined by the prior course of PR therapy. IL28B genotyping may have a clinical role in real world patients where the prior treatment history is not well defined.

Can IL28B Genotype Identify HCV-1 Patients for Whom Dual Therapy With peg-IFN and RBV Should Remain First-line Therapy in the DAA Era?

The introduction of TVR and BOC represents a significant advance for the treatment of HCV-1. However, both drugs are very expensive. Modelling studies suggest that it may be possible to develop treatment algorithms in which PR is more cost-effective first-line therapy for a subgroup of patients. Patients who carry the C/C IL28B genotype achieve high rates of SVR, and a number of groups have suggested that in this population, PR is more cost-effective than universal triple therapy.[15–17] These patients also avoid the added morbidity of triple therapy, although this must be weighed against the need for an extra 24 weeks of total treatment time (most C/C patients will require 48 weeks of PR, but would be eligible for 24 weeks of triple therapy). There are a number of caveats to these modelling studies. They may be strongly influenced by underlying assumptions, as well as the set price for drug, and therefore may not be universally applicable to all patients and regions. One particular issue pertains to efficacy assumptions for patients with advanced liver fibrosis. In the IDEAL study, the rate of SVR was only 41% in C/C patients with F3-4 fibrosis,[5] and although there are little data concerning outcomes of triple therapy in this sub-population, it seems reasonable that triple therapy will be more effective, and cost-effective, for these patients.

IL28B Genotyping in Other Clinical Scenarios

Telaprevir and boceprevir are approved for the treatment of HCV-1 mono-infection only at present. The standard-of-care treatment for chronic infection with other HCV genotypes remains PR dual therapy. IL28B genotype is associated with the outcome of PR treatment for HCV-4, with a similar effect size to that seen in HCV-1.[18–20] IL28B genotype is less relevant to the outcome of PR treatment for HCV-2 and HCV-3.[21–26] HCV-2/3 are more IFN sensitive, and the data are conflicting. IL28B genotype may be most relevant for HCV-2/3 patients who are slow responders to PR (e.g. non-RVR patients).[21] IL28B genotype is associated with the outcome of PR therapy for HCV-1 in the setting of HIV co-infection, where HIV does not seem to attenuate the association.[27] IL28B genotype has been associated with the outcome of PR treatment for HCV-1 after liver transplantation, where both donor and recipient IL28B genotype influence outcome.[28–31] IL28B genotype is strongly associated with the outcome of acute HCV infection, where patients with poor response IL28B genotypes, particularly if anicteric, are unlikely to spontaneously clear infection and should be considered for early antiviral therapy.[32,33]

IL28B Genotyping and Next-generation Therapies Involving peg-Interferon

Emerging data suggest that IL28B genotype will remain relevant to the outcomes of DAA therapy when used in combination with a PR backbone. This has been the case for the emerging protease inhibitors (PIs), NS5A inhibitors (NS5I) cyclophilin inhibitors and non-nucleos(t)ide inhibitors (NNI) of the NS5B polymerase.[34–39] In general, rates of on-treatment response as well as SVR have been higher in patients with the good response IL28B genotype, and the good response genotype has predicted for short-duration therapy using response-guided regimens. Very recent interim data from the ATOMIC study suggest that the nucleotide inhibitor (NI) sofosbuvir (GS-7977) may overcome the IL28B effect. 90% of patients treated for 12 weeks with sofosbuvir plus PR achieved an SVR12 (n = 52).[40] Quadruple therapy regimens are also being evaluated. These involve the combination of two DAAs with PR. A small cohort of prior null responders was treated using the combination of daclatasvir (NS5I) plus asunaprevir (PI) plus PR.[41] 9/10 patients carried a poor response IL28B genotype. 10/10 patients achieved an SVR12; and 9/10 had a SVR24. Larger phase-3 studies are required in larger cohorts to confirm these encouraging results. Therefore, it seems likely that it will be possible to overcome the effect of IL28B polymorphism with the combination of PR plus either a high potency, high genetic barrier to resistance drug (sofosbuvir), or the combination of 2 DAAs. Even so, it may be that IL28B genotype might be used to individualize treatment strategies, such that patients who carry the good response IL28B genotype might be eligible for shorter, simpler or cheaper regimens, and conversely poor responder patients might require longer therapy with multiple DAAs. Such individualized treatment algorithms are yet to be explored in detail.

Finally, a brief note about IFN-lambda. IFN-lambda (IL29) is a type-3 IFN and member of the same family of IFNs as IL28B. The type-3 IFN receptor has a limited distribution of expression, and peg-IFN-lambda is being developed as a less toxic alternative to peg-IFNα. In a small phase-II dose escalation study, investigating the efficacy and safety of peg-IFN-lambda plus RBV, compared to peg-IFNα plus RBV, virological responses were similar, and similar associations between IL28B genotype and treatment response were observed comparing the two IFN preparations.[42]

IL28B Genotyping and IFN-free Therapy

Interferon-free therapy for HCV-1 is likely to be approved in the next 3–5 years. Recent data suggest that the good response IL28B genotype may represent an 'easy-to-cure' characteristic for certain IFN-free regimens also. The INFORM-1 study was the first study to demonstrate that IFN-free therapy could have a potent antiviral effect. Patients were treated with a combination of mericitabine (NI) and the danoprevir (PI) for 14 days, before follow-on PR therapy to 48 weeks. Analysis of the on-treatment viral kinetics in 15 patients during the 2 weeks of oral therapy revealed a significant difference in phase-II viral kinetics according to IL28B genotype,[43] suggesting that IL28B genotype influences the rate of clearance of infected hepatocytes during IFN-free therapy. This might be consistent with the association between IL28B genotype and spontaneous clearance of HCV.[44] SOUND-C2 is the largest study of IFN-free therapy to date (n = 362).[45] SOUND-C2 evaluated the combination of BI 201335 (PI), BI 207127 (NNI) ± RBV (Fig. 1a). Interim results demonstrated a clear difference in SVR12 according to IL28B genotype in HCV-1a patients (Fig. 1b,c). The low SVR rates observed in HCV-1a non-C/C patients resulted from virological breakthrough in most patients, suggesting that IL28B genotype influenced the emergence of RAVs. Future studies of this regimen plan to enrol only HCV-1a patients who carry the good response IL28B genotype. This IL28B effect may be overcome as more potent agents and combination regimens emerge. Analysis of the ELECTRON study observed SVR4 in 22/25 (88%) treatment-naïve HCV-1 patients treated with sofosbuvir plus RBV for 12 weeks.[46] 22 of the patients were infected with HCV-1a, and only 11/25 carried the good response IL28B genotype. Response rates with 'optimized' DAA combinations may be higher still. A recent study of the combination of sofosbuvir plus the daclatasvir reported SVR4 of 100% in 44 HCV-1 naive patients, with or without ribavirin.[47] Such optimized regimens are likely to be very expensive, however, and may not be necessary for all patients. IL28B genotype may continue to be useful to identify those patients for whom such regimens are most appropriate as first-line therapy.

771436-fig1

Figure 1. Interim results from the SOUND-C2 study 42. (a) Patients were randomized to one of five arms, involving variable durations of treatment with the protease inhibitor BI 201335 once daily, the NS5B non-nucleoside inhibitor BI 207127 BID or TID, plus or minus ribavirin. Interim analysis of SVR12 results was recently presented (with SVR4 results for the 40-week treatment arm). Overall results according to treatment arm: A – SVR12 = 59%, B – SVR12 = 61%, C – SVR4 = 56%, D – SVR12 = 68% and E – SVR 12 = 39% (treatment arm E was halted early because of concerns about RBV-free treatment); (b) SVR12 results in treatment arm D, according to HCV-1 subtype and IL28B genotype (rs12979860); (c) SVR results in treatment arms A–D, comparing non-C/C patients infected with HCV-1a (grey columns), with a composite group including C/C patients infected with HCV-1a and all HCV-1b patients (white columns).

Conclusion

IL28B genotype is the strongest pretreatment predictor of response to dual PR therapy for patients chronically infected with HCV-1. The approval of the first generation of NS3 protease inhibitors represented a significant advance for the field. The association between IL28B polymorphism and treatment outcome is attenuated in the setting of triple therapy, but IL28B genotyping continues to be useful for pretreatment counselling, with the good response IL28B genotype identifying the likelihood of an individual being eligible for short-duration therapy. IL28B genotype may also be relevant to strategies for maximizing cost-effectiveness. IL28B genotype is also associated with the response to IFN-free regimens, and C/C patients remain easier to cure, particularly in the setting of HCV-1a. Future regimens involving potent NI plus PR, quadruple therapy or combinations of best-in-class DAAs are likely to achieve very high SVR rates, and IL28B polymorphism will no longer predict treatment outcome. However, IL28B genotyping may remain useful if it can be used to individualize treatment strategies, identifying patients who can be successfully treated with shorter, simpler or cheaper regimens.

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  21. Mangia A, Thompson AJ, Santoro R et al. An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response. Gastroenterology 2010;139:821–827, 827 e1.
  22. Stattermayer AF, Stauber R, Hofer H, et al. Impact of IL28B genotype on the early and sustained virologic response in treatment-naive patients with chronic hepatitis C. Clin Gastroenterol Hepatol2011; 9: 344–350.
  23. Sarrazin C, Susser S, Doehring A, et al. Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients. J Hepatol 2011; 54: 415–421.
  24. Yu ML, Huang CF, Huang JF, et al. Role of interleukin-28B polymorphisms in the treatment of hepatitis C virus genotype 2 infection in Asian patients. Hepatology 2011; 53: 7–13.
  25. Moghaddam A, Melum E, Reinton N, et al. IL28B genetic variation and treatment response in patients with hepatitis C virus genotype 3 infection. Hepatology 2011; 53: 746–754.
  26. Kawaoka T, Hayes CN, Ohishi W, et al. Predictive value of the IL28B polymorphism on the effect of interferon therapy in chronic hepatitis C patients with genotypes 2a and 2b. J Hepatol 2011; 54: 408–414.
  27. Rallon NI, Naggie S, Benito JM et al. Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients. Aids 2010; 24: F23–F29.
  28. Charlton MR, Thompson A, Veldt BJ et al. Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection. Hepatology 2011; 53: 317–324.
  29. Fukuhara T, Taketomi A, Motomura T et al. Variants in IL28B in liver recipients and donors correlate with response to peg-interferon and ribavirin therapy for recurrent hepatitis C. Gastroenterology 2010; 139: 1577–1585e1–3.
  30. Eurich D, Boas-Knoop S, Ruehl M et al. Relationship between the interleukin-28b gene polymorphism and the histological severity of hepatitis C virus-induced graft inflammation and the response to antiviral therapy after liver transplantation. Liver Transpl 2011; 17: 289–298.
  31. Coto-Llerena M, Perez-Del-Pulgar S, Crespo G et al. Donor and recipient IL28B polymorphisms in HCV-infected patients undergoing antiviral therapy before and after liver transplantation. Am J Transplant 2011; 11: 1051–1057.
  32. Tillmann HL, Thompson AJ, Patel K et al. A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice. Gastroenterology 2010; 139: 1586–1592, 1592 e1.
  33. Grebely J, Petoumenos K, Hellard M et al. Potential role for interleukin-28B genotype in treatment decision-making in recent hepatitis C virus infection. Hepatology 2010; 52: 1216–1224.
  34. Zeuzem S, Foster GR, Fried MW et al. The ASPIRE trial: TMC435 in treatment-experienced patients with genotype-1 HCV infection who have failed previous pegIFN/RBV treatment. J Hepatol 2011; 54: A1376.
  35. Lok AS, Gardiner DF, Lawitz E et al. Combination therapy with BMS-790052 and BMS-650032 alone or with pegIFN/RBV results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders. J Hepatol 2011; 54. (LB-8).
  36. Pol S, Aerssens J, Zeuzem S, et al. Similar SVR rates in IL28B CC, CT or TT prior relapser, partial- or null-responder patients treated with telaprevir/peginterferon/ribavirin: retrospective analysis of the REALIZE study. Journal of Hepatology 2011;54. S6 (A13).
  37. Pockros P, Jensen D, Tsai N et al. First SVR data with the nucleoside analogue polymerase inhibitor mericitabine (RG7128) combined with peginterferon/ribavirin in treatment-naive HCV G1/4 patients: interim analysis from the JUMP-C trial. J Hepatol 2011; 54: A1359.
  38. Muir AJ, Lawitz E, Rodriguez-Torres M et al. IL28B polymorphism and kinetics of antiviral activity for ANA598 in combination with pegylated interferon alpha-2a plus ribavirin in treatment-naive genotype-1 chronic HCV patients Hepatology 2010;52(S1):abstract 1852.
  39. Flisiak R, Pawlotsky JM, Crabbé R, al. e. Once daily alisporivir (DEB025) plus pegIFNalfa2a/ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment naive patients. J Hepatol 2011; 54: A4.
  40. Kowdley KV, Lawitz E, Crespo I et al. ATOMIC: 97% RVR for PSI-7977+ PEG/RBV x 12 week regimen in HCV GT1: an end to response-guided therapy? J Hepatol 2012; 56: S1–A1.
  41. Lok AS, Gardiner DF, Lawitz E, Martorell C, al. e. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366: 216–224.
  42. Muir AJ, Lawitz E, Ghalib RH et al. Pegylated interferon lambda (PEG-IFN-λ) phase 2 dose-ranging, active controlled study in combination with ribavirin (RBV) for treatment naive HCV patients (genotype 1,2,3 or4): safety, viral response and impact of IL28B host genotype through week 12. Hepatology 2010;52:821 (abs).
  43. Chu TW, Kulkarni R, Gane EJ et al. Effect of IL28B genotype on early viral kinetics during interferon-free treatment of patients with chronic hepatitis C. Gastroenterology 2012; 142: 790–795.
  44. Thomas DL, Thio CL, Martin MP et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461: 798–801.
  45. Zeuzem S, Soriano V, Asselah T et al. SVR4 and SVR12 with an interferon-free regimen of BI 201335 AND BI 207127, +/− ribavirin, in treatment-naïve patients with chronic genotype-1 HCV infection: interim results of SOUND-C2. J Hepatol 2012;56:Abstract 101.
  46. Gane EJ, Stedman C, Hyland RH et al. ELECTRON: once daily PSI-7977 plus RBV in HCV Gt 1/2/3. J Hepatol 2012;56:S438 (abstract 1113).
  47. Sulkowski M, Gardiner DF, Lawitz E et al. Potent viral suppression with all-oral combination of daclatasvir (NS5A inhibitor) and GS-7977 (NS5b inhibitor), +/− ribavirin, in treatment-naive patients with chornic HCV GT 1, 2, or 3. J Hepatol 2012;56:Abstract 1422.
  48. Bacon BR, Gordon SC, Lawitz E et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1207–1217.
  49. Zeuzem S, Andreone P, Pol S et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364: 2417–2428.

Source

jiapac_article_level

From Journal of the International Association of Physicians in AIDS Care

Glenn Wagner, PhD; Karen Chan Osilla, PhD; Jeffrey Garnett, MPP; Bonnie Ghosh-Dastidar, PhD; Laveeza Bhatti, PhD, MD; Mallory Witt, MD; Matthew Bidwell Goetz, MD

Posted: 09/28/2012; J Int Assoc Physicians AIDS Care. 2012;11(4):245-251. © 2012 Sage Publications, Inc

Abstract and Introduction
Abstract

Despite low uptake of HCV treatment among HIV co-infected patients, few studies have examined the factors that contribute to provider decisions to recommend treatment. Surveys of 173 co-infected patients and their primary care providers, as well as patient chart data, were collected at three HIV clinics in Los Angeles; 73% of the patients had any history of being recommended HCV treatment. Multivariate predictors of being offered treatment included being Caucasian, greater HCV knowledge, receiving depression treatment if depressed, and one's provider having a lower weekly patient load and more years working at the study site. These findings suggest that provider decisions to recommend HCV treatment are influenced by patient factors including race and psychosocial treatment readiness, as well as characteristics of their own practice and treatment philosophy. With changes to HCV treatment soon to emerge, further evaluation of factors influencing treatment decisions is needed to improve HCV treatment uptake.

Introduction

Nearly 30% of HIV-positive Americans are co-infected with the hepatitis C virus (HCV). Hepatitis C virus is a leading cause of death among HIV co-infected patients,[1–3] with annual HCV-related mortality expected to peak at 13 000 in 2030 in this population.[4] However, despite a majority of co-infected patients having signs of liver disease progression,[5,6] only a minority (~30%) are deemed eligible for treatment and less than 10% actually receive treatment.[7–10] Low treatment uptake is often attributed to the limited efficacy (20%-50% response rate among co-infected patients) and high toxicity of pegylated interferon (PEG-IFN) and ribavirin (RBV),[11–16] the current standard of care for HCV treatment, and yet treatment can essentially cure the disease.

Whether a patient starts treatment depends first on the provider's decision to recommend treatment. Despite the disparity between the need for aggressive HCV treatment and low treatment uptake, few studies have examined the factors that contribute to provider decisions to offer treatment. Nonetheless, we expect provider decisions to offer treatment are likely influenced by the following: severity and stage of liver disease; stability of the patient's HIV disease and presence of other medical comorbidities; perception of the patient's readiness to tolerate and adhere to treatment; and the provider's beliefs and attitudes related to the urgency and expected outcomes of treatment.

CD4 counts temporarily decrease during the course of HCV treatment;[17] therefore, to limit the risk of developing opportunistic infections, the treatment is preferably started when the patient has a high CD4 count, low HIV viral load, and on a HIV antiretroviral therapy (ART).[18] Treatment is typically recommended for patients with moderate liver disease,[18,19] while patients with minimal disease progression are monitored and treatment are deferred.[20] However, some view the latter as optimal for treatment,[19] given the more rapid disease progression among co-infected patients[21] and the greater likelihood of treatment success with milder disease.[22,23] These conditions hold for the predominant genotype 1 patients for whom treatment is considerably less successful, while patients with genotype 2 or 3 are generally considered good treatment candidates because they respond to treatment much more favorably.[18,19]

Patients must also be ready to adhere to and tolerate treatment. Drug abuse and mental illness are among the most common reasons for patients being ineligible for HCV treatment,[8–10,24–26] as clinicians are concerned that treatment side effects (eg, depression, fatigue, flu-like symptoms) may lead to psychiatric deterioration, relapse into substance abuse, and treatment nonadherence and discontinuation. However, there is some evidence that treatment can be equally effective when patients have active psychiatric illness and are using drugs.[27–31]

Provider training and characteristics of their clinical practice may influence HCV treatment decisions, including experience and perceived skills and comfort in managing HCV care and treatment with HIV co-infected patients, and attitudes related to HCV treatment efficacy and patient readiness.[32,33]

We surveyed primary care providers at 3 HIV clinics in Los Angeles, along with the HCV co-infected patients who attended these clinics over 4 months to examine patient and provider characteristics associated with provider decisions to offer or defer HCV treatment.

Methods
Setting

Cross-sectional surveys were administered to primary care providers and HCV co-infected patients at 3 HIV clinics in Los Angeles: the Greater Los Angeles Veterans Administration (VA) Medical Center, Harbor-UCLA Medical Center, and AIDS Healthcare Foundation (AHF). The sites differ on a number of characteristics including the number of HIV patients (400–1700) and HCV co-infected patients (100–650), involvement of a liver specialist (at only 1 site), and HCV treatment rates (10%-40% of co-infected patients have received treatment). The clients at all 3 clinics are mostly racial/ethnic minorities and of lower socioeconomic status.

All 3 clinics provide comprehensive primary and subspecialty care, and thus patients receive their HCV care at the HIV clinic. At Harbor-UCLA, HIV and HCV primary care are provided predominantly by 4 nurse practitioners (NPs) who are supervised by 2 attending physicians, and treatment decisions are made jointly between the NPs and physicians. At the VA, HIV primary care is provided by 4 physicians, but HCV care and treatment for the co-infected patients are managed by one of the hospitals' gastroenterologists (with the assistance of a physician's assistant from the clinic) who comes to the clinic to conduct biweekly HCV care clinic sessions; the primary care physicians are consulted regarding HCV treatment decisions when warranted. The AHF clinic serves as the central HCV care site for the full system of AHF clinics in Los Angeles County; HCV care is provided mostly by 2 providers (1 physician and 1 NP), although the HCV care for some patients at the clinic are managed by their primary care provider. Support staff at the sites includes pharmacists, nurses, case managers, and social workers; 1 clinic has a mental health professional onsite, the others refer out for psychiatric consultation and treatment.

Sample

All clinic patients who were HCV co-infected, aged 18 or older, and speak English were considered eligible for the study. During the 4-month study enrollment period, the study coordinator at each site performed a chart review of all patients attending the clinic for a routine visit to identify those who were eligible. Patients were informed of the study while they were waiting to be seen by their provider; those who were interested in participating provided signed informed consent for completing a self-report questionnaire prior to leaving the clinic and allowing the study to abstract data from their clinic chart. All primary care providers were asked to participate and complete a self-report survey. Patients ($40) and providers ($50) were compensated for their participation, except at the VA where providers were not compensated due to institutional policy. The study protocol was approved by the Institutional Review Boards at RAND Corporation and the individual clinics.

Measures

For patients who had been offered HCV treatment, data were abstracted from the clinic visit closest and prior to the date at which HCV treatment was offered to the patient; for patients who had not been offered treatment, the most recent data prior to the date of survey were abstracted as these represent the latest indicators upon which a decision had been made to not recommend treatment. However, some variables, including all provider measures, could only be assessed at study enrollment with the study survey as indicated below.

Patient Variables

The HCV treatment status was abstracted from the clinic charts by first determining whether the patient had ever been treated. Among those who had not been treated, it was determined whether the provider had ever offered or recommended treatment. Dates were abstracted for time HCV treatment was offered and started, if applicable.

Demographic and background characteristics that were assessed by the study survey included age, gender, race/ethnicity, and education. The date the patient was diagnosed with HIV and HCV and the date the patient started receiving care at the study site were abstracted.

Stability of HIV was assessed with CD4 count, HIV viral load, and whether or not the patient was on ART. With regard to the stability of HCV and liver disease, measures included HCV viral load, genotype, and other laboratory markers related to liver functioning (aspartate aminotransferase [AST]/alanine aminotransferase [ALT], hemoglobin, absolute neutrophil count [ANC]). All of these variables were chart abstracted.

Psychosocial functioning was assessed with chart abstracted data related to whether the patient had a current diagnosis of depression or any other psychiatric disorder, and whether they were receiving any form of psychiatric treatment (eg, psychotropic medication, and counseling). We also abstracted data regarding alcohol and illicit drug use and history of injection drug use.

Adherence was assessed in the study survey by asking respondents to report whether or not they had missed any scheduled clinic appointments over the past 6 months, and those on ART were asked how many doses they had missed over the past 7 days (from study entry). Both measured were then converted into dichotomous variables based on whether or not they had missed any clinic appointments or missed any ART doses.

Knowledge of HCV was assessed at study entry with a scale adapted from that used by Doab et al.[34] The 4-item scale evaluates the patient's understanding of HCV (eg, whether a cure is possible, HCV always leads to sickness, and HIV worsens HCV, and genotypes 2 and 3 respond best to treatment); a yes/no response option was used and a score was calculated summing the correct responses.

Provider Variables

Demographic characteristics included age, gender, and race/ethnicity. Medical practice and training characteristics that were assessed included training discipline (eg, physician, NP, physician's assistant), number of years at the clinic, number of HIV/HCV co-infected patients cared for, number of patients treated with PEG-IFN/RBV, and average patient load per week.

Perceived challenges regarding HCV care were assessed with a measure adapted from that used by Meredith et al;[35] 11 items assess structural and patient factors that limit or challenge a provider's ability to provide optimal HCV care (eg, absence of a liver biopsy, mental health, or substance abuse counselors not readily available, patient reluctant to seek mental health or substance abuse treatment, patient's comorbid medical problems). Participants chose from 3 response options (ie, does not limit, limits somewhat, and limits a great deal). Mean item score was computed and higher scores indicate greater perceived challenges to providing optimal care. Internal reliability was high (α = .91).

Provider philosophy regarding patient psychosocial treatment readiness was assessed by asking the provider about their approach to treatment if a patient reported (1) current drug use or (2) moderate depression, ''but was otherwise a good HCV treatment candidate,'' in separate questions. Response options consisted of 5 scenarios that ranged from deferring treatment until the condition (drug use, depression) was treated and in remission, to counseling the patient about the risks of the condition for HCV treatment but letting the patient decide whether or not to start or defer treatment. Due to skewed response distributions, the responses were dichotomized into providers who believed that HCV treatment should only be offered after the patient was in remission versus more lenient views of readiness.

Provider's general threshold for patient treatment readiness was measured with a scale developed for the study, which assessed the likelihood that a provider would prescribe HCV treatment to a patient with various conditions that could affect the patient's readiness or appropriateness for treatment (eg, decompensated liver disease, genotype 2 or 3, active depression, smokes marijuana regularly, etc). Providers responded on a 5-point Likert-type scale ranging from very likely to very unlikely, with regard to 14 specific conditions; internal reliability was high (α = .86). The mean item score was calculated and higher scores represented a higher threshold for determining patient readiness for treatment.

Data Analysis

Descriptive statistics were used to examine the response distributions of variables and a number of variables were converted from continuous to dichotomous variables based on clinical significance (eg, CD4 count ≤200 cells/mm3; HIV viral load ≤400 copies/mL; genotype 1 or 4 versus 2 or 3) or the skewed distribution of responses (eg, none vs any missed ART doses). Bivariate statistics (independent 2-tailed t tests, chi-square tests) were used to examine the correlates of whether or not the patient was offered HCV treatment. Variables that were significant at P <.05 level in the bivariate analysis were then entered into a logistic regression model as independent variables, with the indicator of whether treatment was offered being the dependent variable. To account for potential correlations among outcomes of patients in the same clinic that share a provider, we computed robust standard errors for the regression models to account for intracluster correlations within provider.

Results
Sample Description

A total of 173 patients were surveyed: 97 from AHF, 41 from the VA, and 35 from Harbor-UCLA. Most (87%) participants were male, mean age was 49.0 (SD = 9.1), 60% had at least some college education, 69% were racial/ethnic minorities (including 41% who were black and 21% who were Hispanic), 38% identified as heterosexual, and 58% had a history of injection drug use. Most had been diagnosed with HIV for several years (mean = 13.5 years) and had been receiving care from the study site for an average of 7.8 years. Mean time since HCV diagnosis was 7.1 years, and 78% had an HCV genotype of 1 or 4.

Fourteen primary HCV care providers completed the survey, accounting for the HCV care providers of 155 (90%) of the patient participants. Among the 14 providers surveyed, half were male, 57% were Caucasian, and 69% were physicians. The mean number of years of practice at the clinic site was 11.1 (SD = 6.1; range: 2–19); each provider sees an average of 34 HIV patients (HCV and non-HCV) per week (SD = 21; range: 5–90), and the mean number of co-infected patients that each provider had treated with interferon was 21 (SD = 19; range: 4–60).

Factors Associated With Recommending HCV Treatment

Of the 173 patients, 127 (73%) had been offered or recommended HCV treatment; 79 (62%) accepted the recommendation and started treatment, and the factors associated with this patient decision are presented elsewhere.[36] For those who had been offered treatment, this event took place an average of 6.2 years (SD = 5.8 years; range: 1 week to 23.0 years) after HCV diagnosis and 2.3 years (SD = 2.7 years; range: 1 week to 10.9 years) prior to the study survey. The proportion of surveyed patients at each site who had been offered treatment was 85% at Harbor-UCLA, 71% at AHF, and 66% at the VA; these site differences were not statistically significant (p = .115).Table 1lists the characteristics of the subgroups that had been offered (N = 127) and not offered (N = 46) HCV treatment. Patients offered HCV treatment were more likely to have CD4 counts above 200 cells/mm3 and lower HIV viral loads; similarly, there were marginal trends (p <.10) for this group to have higher mean CD4 count and an undetectable HIV viral load. Other patient variables associated with being offered treatment included greater HCV knowledge, receiving depression treatment if depressed (compared to untreated depression), and not being black or Hispanic.

The providers of patients offered treatment were more likely to be female, to have worked longer at the clinic site, see fewer patients on a weekly basis, and to have a lower threshold for indicators of patient readiness for treatment (seeTable 1). Provider-related correlates that had marginal significance included fewer perceived challenges to providing optimal HCV care and the treatment philosophy that HCV treatment did not require that a drug using patient had entered a drug treatment program and been in remission.

In logistic regression analysis, significant independent predictors of being offered treatment included the patient not being black or Hispanic, having greater HCV knowledge, and receiving depression treatment if depressed, as well as the patient's provider having a lower weekly patient load and more years in practice at the clinic; the patient having a CD4 count >200 cells/mm3 was marginally significant as a predictor (seeTable 2).

Discussion

Findings from this study reveal that a majority of HIV/HCV co-infected patients are recommended PEG-IFN/RBV treatment by primary care providers over the course of receiving care, although like other studies,[7–10,37] only a minority of patients had actually received treatment. The data reveal that factors influencing provider decisions to offer or defer treatment are multifaceted. Provider HCV treatment decision making is influenced by patient factors including the patient's stability of HIV disease and psychosocial readiness for treatment. However, the provider's decision process is not only influenced by patient characteristics but also aspects of the provider's clinical practice, attitudes toward HCV treatment and philosophy about patient treatment readiness.

Having a CD4 count above 200 and low HIV viral load were bivariate correlates of having been offered treatment, as treatment response is positively correlated with CD4 count,[38] and PEG-IFN/RBV can temporarily deplete CD4 counts,[17] rendering clients vulnerable to opportunistic infections if they have severe immunosuppression. However, some patients with CD4 counts below even 100 had been offered treatment, which is consistent with some Hepatitis Research Network clinical trials, and this highlights how even patients whose immune systems are severely compromised can still be considered appropriate for treatment. Also, the vast majority of all participants were on ART when the treatment was offered, which can help limit the risks associated with treatment of patients with low CD4 counts. Provider decisions to offer treatment were not related to our measures of HCV disease, including HCV genotype and HCV RNA, which are correlates of treatment response;[11–13] however, we did not have measures of liver fibrosis.

Psychosocial indicators of patient treatment readiness, such as mental health, substance use, and adherence to clinical appointments and ART have been shown to be associated with HCV treatment eligibility in several other studies.[9,10] However, in this study, depression treatment status for current depression and patient knowledge of the goals and potential costs and benefits of treatment were the only psychosocial variables associated with whether the treatment was recommended. Past history of depression, or current depression that was being managed with treatment, was not the limiting factor to being recommended treatment, which is consistent with data suggesting that such factors are not necessarily impediments to HCV treatment response.[27–29] Greater HCV knowledge may be an indicator of patient self-advocacy or motivation for treatment,[32] at least in the perception of providers, and may explain in part its relationship to the offering of treatment; however, this relationship could also be bidirectional, with patients who are offered treatment consequently developing greater knowledge about the disease and treatment from their provider or through actively seeking out information.

The other patient characteristic associated with treatment being offered was race or ethnicity. African American and Hispanic patients, who together comprise the majority of the study sample, were less likely to be offered HCV treatment compared to the Caucasian patients, even after controlling for other significant correlates. This finding may reflect health disparities that are commonly seen among minority ethnic groups in the United States.[39] However, data show lower response rates to PEG-IFN/RBV among African American and Hispanic patients,[40–42] and this could tip the cost–benefit ratio in the favor of the potential burden on patients in the minds of providers.

Provider decisions of whether to recommend HCV treatment to an individual patient are not only predicted by characteristics of the patient but also by provider-related variables. Having a smaller weekly patient load was associated with a greater likelihood of recommending treatment, which may be a proxy for how availability of time for the provider to manage what is often complex treatment can influence provider treatment decisions. Years in practice at the study site was also associated with provider decisions to offer treatment, suggesting that greater experience in providing care may translate into greater comfort offering and managing HCV treatment. In bivariate analysis, treatment offers were more likely when the provider had a lower threshold for gauging patient readiness, which may also be an indicator of how urgent the provider considers the HCV treatment in general.[33]

The primary limitation of the study findings is the largely retrospective nature of the study design, and associated reliance on available chart abstracted data or current assessments that may not be reflective of the conditions present when the treatment was offered. While a prospective design that measured variables at the time the treatment decision was actually made would be optimal, such a design was not feasible in terms of time and resources. The findings cannot be considered generalizable to all co-infected patients, although nearly all coinfected patients who attended the clinic during the study enrollment period did participate. Also, we were unable to reliably abstract data regarding medical comorbidities from patient's charts and therefore cannot account for the role of this important factor in provider decision making. Furthermore, with newer, more efficacious (but perhaps even more burdensome) treatments soon to be available,[43] it is unknown how this will affect provider decisions about the balance of the costs and benefits of treatment.

With HCV treatment rates continuing to be steadily low among HIV co-infected patients, the results of this study highlight both patient and provider variables that influence provider decisions to recommend treatment. Program administrators and intervention developers with an intent to increase treatment uptake should focus not only on factors that improve patient readiness for treatment but also on provider attitudes and comfort level regarding treatment, as well as patient load and time availability. With changes to HCV treatment soon to emerge, and its uncertain effects on both the benefits and burden associated with treatment, further evaluation of factors influencing treatment decision making and treatment uptake will be needed to promote optimal HCV care management among HIV coinfected patients.

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