Early Metabolic and Hepatic Lipid Gene Expression Changes in Chronic Hepatitis C Patients Treated with an Interferon-free Regimen

Infectious Disease Week (IDWeek)
October 2-6, 2013
San Francisco, Ca

1830. Early Metabolic and Hepatic Lipid Gene Expression Changes in Chronic Hepatitis C Patients Treated with an Interferon-free Regimen

Session: Oral Abstract Session: Hepatitis C

Saturday, October 5, 2013: 3:15 PM

Room: The Moscone Center: 250-262

Background: Hepatitis C (HCV) modulates the intrahepatic VLDL synthetic pathway as part of its natural life cycle. Chronic HCV (CHC) infection is associated with an altered metabolic state including dyslipidemia and insulin resistance, contributing to disease progression and reduced response to therapy. The interactions between HCV replication and host lipid pathways are incompletely understood.

Methods: Sixty CHC genotype-1, treatment-naive patients were treated with 24 weeks of the HCV NS5B inhibitor sofosbuvir in combination with low or full dose ribavirin. Serum lipids and hemoglobin A1C (HbA1c) were measured at various time points. Targeted quantitative RT-PCR for lipid and glucose metabolism related genes was performed on paired liver biopsy specimens obtained from 7 patients before and at end-of treatment (EOT). 

Results: Of 55 patients who completed the study, 38 patients achieved a sustained virologic response (SVR₂₄) and 17 patients relapsed after EOT.  Between baseline and week 4 of therapy, LDL significantly increased (91 ± 4 to 104 ± 5 mg/dl, p=.0027) and triglycerides decreased (137 ± 10 to 98 ± 8 mg/dl, p<.0001) which persisted through EOT. Compared to patients who achieved SVR₂₄, LDL was significantly lower in patients who eventually relapsed both at baseline (97 ± 5 vs 78 ± 7 mg/dl; p=0.031) and at week 48 (109 ± 6 vs 82 ± 7mg/dl; p=0.005), while there was no difference during or at EOT (Fig 1A). Triglycerides differed by treatment outcome only after EOT (Fig 1B). No changes in HDL were observed. HbA1C decreased significantly (5.58 to 5.45) in the 39 patients with paired values obtained at baseline and 24 weeks after EOT (p=0.0033) and this was independent of treatment outcome (Figure 1C). Intrahepatic gene expression of lipid transport genes (APOB, APOC3, APOL3) was significantly up-regulated, while lipid assembly and signaling genes (LEPR, MTTP) were down-regulated at EOT in 7 patients with paired liver biopsies (all achieved SVR₂₄).    

Conclusion: Our data demonstrate changes in lipid metabolism pathways and glucose homeostasis in CHC genotype-1 infection following interferon-free antiviral therapy.  The early changes in LDL and triglycerides associated with treatment implicate a direct effect of viral clearance on lipid homeostasis.    

Eric Meissner, MD, PhD¹, Anu Osinusi, MD, MPH^1,2, Jing Qin, PhD³, Yu-Jin Lee, BA³, Susanna Naggie, MD⁴, Keyur Patel, MD⁴, John Mchutchison, MD⁵, Henry Masur, MD, FIDSA⁶ and Shyam Kottilil, MD, PhD¹, (1)NIAID/NIH, Bethesda, MD, (2)Clinical Research Directorate/Cmrp, Saic-Frederick, Inc., Frederick, MD, (3)Niaid/NIH, Bethesda, MD, (4)Duke University Medical Center, Durham, NC, (5)Gilead Sciences, Foster City, CA, (6)National Institutes of Health - Dept of Critical Care, Bethesda, MD

Disclosures:

E. Meissner, None

A. Osinusi, None

J. Qin, None

Y. J. Lee, None

S. Naggie, Gilead Sciences: Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient

K. Patel, Gilead Sciences: Consultant and Scientific Advisor, Consulting fee

J. Mchutchison, Gilead Sciences: Employee and Shareholder, Salary

H. Masur, None

S. Kottilil, None

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Hepatitis C education crucial to cut high infection rate in Middle East and North Africa

Jennifer Bell

October 6, 2013 Updated: October 6, 2013 21:13:00

DUBAI // The Middle East and North Africa region has one of the highest rates of hepatitis C in the world, experts have revealed.

About nine million people in the region are believed to be infected with the potentially lethal virus, which can lead to cirrhosis of the liver or liver cancer.

In the UAE alone, about 14 in every 100,000 people will become infected at some point in their lives.

The figures were revealed during a conference in Dubai that brought together more than 200 doctors to discuss the virus, the best ways to manage it and the medical breakthroughs that may help to reduce its growing prevalence.

According to the World Health Organisation, about 150 million people globally are chronically infected with hepatitis C, and more than 350,000 people die from related liver diseases each year.

“Despite the progress and medical breakthroughs that have taken place over the last decade, hepatitis C transmission rates in the Mena region are still among the highest in the world,” said Ramsey Morad from the healthcare company MSD, which organised the conference.

“Education is crucial if we are truly to start addressing this epidemic.”

In the UAE, the virus is most prevalent in Abu Dhabi, according to MSD, and least common in Ajman.

Mazen Altaruti, the managing director of MSD Gulf, described the virus, which is mainly transmitted through blood-to-blood contact, as a “silent killer” as most patients show no symptoms until it has caused irreversible liver damage.

jbell@thenational.ae

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Also See: Media academy held to support prevention and treatment of hepatitis C in Middle East

Rates and Causes of Mortality among People in Care with Hepatitis C Virus Infection — Chronic Hepatitis Cohort Study (CHeCS), 2006–2010

Infectious Disease Week (IDWeek)
October 2-6, 2013
San Francisco, Ca

1774. Rates and Causes of Mortality among People in Care with Hepatitis C Virus Infection — Chronic Hepatitis Cohort Study (CHeCS), 2006–2010

Session: Poster Abstract Session: Viral Infections; Pathogenesis and Epidemiology

Saturday, October 5, 2013

Room: The Moscone Center: Poster Hall C

Posters Mahajan- IDSA- 9-2013.pdf (397.6 kB)

Background: To examine the association of hepatitis C virus (HCV) infection with all-cause and liver-related mortality, we analyzed data from a prospective observational cohort study in four health care systems in the United States.

Methods: We examined electronic health records of adults with at least one health system encounter from January 2006 through December 2010 from four integrated health care systems, and created a cohort of confirmed HCV-infected patients [Chronic Hepatitis Cohort Study (CHeCS)]. Cohort patients who died during 2006-2010 were analyzed.   All-cause and disease-specific death rates were calculated based upon US census data from 2006-2010.  Total number of deaths came from Multiple Cause of Death (MCOD) data based on 12 million death certificates for U.S. residents for the same time period.

Results: Of 2,143,369 adult patients with an encounter with the four CHeCS sites during 2006-2010, 11,703 (0.5%) had diagnosed chronic HCV infection. Of these, 1,590 (14%) died during 2006–2010; 75% of whom were born between 1945-1965, 50% were white, and 68% were men. Primary cause of death (498 of 1590) was liver disease unrelated to alcohol. Despite confirmed chronic HCV infection in those who died, only 19%had HCV infection listed as an underlying cause of death, and only 32% among those who died of primary liver cancer.   Mean age of death for HCV patients (59 years) was 15 years younger than in those without HCV infection from national data.  The age-adjusted mortality rate for liver disease in CHeCS was twelve times higher than the MCOD rate. 

Conclusion:    HCV infection was not listed as a cause of mortality in approximately 80% of confirmed HCV-infected persons; currently only 15,000 deaths have HCV infection listed on the death certificate.  Our data suggests that the national mortality rate of those with HCV could be as high as 75,000 persons per year, with over 60% of current deaths in our HCV-infected cohort directly attributable to liver disease.  Whether ascribed to liver-related causes or not, mortality in HCV-infected persons was 15 years younger compared with the national average in non-HCV infected persons.

Reena Mahajan, MD, MHS¹, Jian Xing, PhD¹, Stephen Liu, MPH¹, Kathleen Ly, MPH¹, Anne C. Moorman, BSN, MPH¹, Lora Rupp, MSE, MBA², Fujie Xu, MD, PhD¹, Scott Holmberg, MD, MPH¹ and for the Chronic Hepatitis Cohort Study (CHeCS) Investigators, (1)Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, (2)Center for Health Services Research, Henry Ford Health System, Detroit, MI 

Disclosures:

R. Mahajan, None

J. Xing, None

S. Liu, None

K. Ly, None

A. C. Moorman, None

L. Rupp, None

F. Xu, None

S. Holmberg, None

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Rapid Hepatitis C Virus Testing: An Innovative Pilot Study for Testing and Linking High Risk Populations from a Mobile Healthcare Clinic

Infectious Disease Week (IDWeek)
October 2-6, 2013
San Francisco, Ca

1756. Rapid Hepatitis C Virus Testing: An Innovative Pilot Study for Testing and Linking High Risk Populations from a Mobile Healthcare Clinic

Session: Poster Abstract Session: Viral Infections; Pathogenesis and Epidemiology

Saturday, October 5, 2013

Room: The Moscone Center: Poster Hall C

Posters IDSA.2013.#41989.Morano.pdf (1.4 MB)

Background: After recent release of effective HCV treatments, CDC guidelines aim to increase HCV testing and linkage to treatment for certain high-risk populations. This approach has not, however, been empirically tested using rapid HCV testing strategies.

Methods: An innovative rapid HCV testing campaign was deployed from a mobile medical clinic (MMC) in New Haven, CT using routine medical intake information. Clients could select rapid versus traditional phlebotomy testing.  Traditional testing included phlebotomy for other medical co-morbidities, including syphilis, hepatitis B, and chronic medical conditions.  Independent correlates of: 1) type of HCV testing strategy; and 2) reactive HCV antibody results were assessed. Linkage to HCV care was defined as completing one follow-up clinical visit in person with confirmatory HCV testing.

Results: All of 190 clients approached from March 2012 to March 2013 accepted HCV testing; 154 (81.1%) chose rapid HCV testing. Overall, 17 (8.9%) were HCV+, with 13 (8.4%) in the rapid and 4 (11.1%) in the traditional group.  Generally, participants were mean age 35.9 years, previously incarcerated (51.1%), had >15 lifetime sexual partners (81.6%), were US-born (84.7%), had used illicit drugs (75.3%), and previously tattooed (64.2%).  Of the 60 (31.6%) people who inject drugs (PWID), only 9 (15.0%) were within the “baby boomer” cohort.

Independent correlates of choosing rapid HCV testing over phlebotomy were non-PWID (AOR 25.0; p=0.027) and less than 15 lifetime sexual partners (marginal effect 0.17; p=0.003). Independent correlates of being HCV+ were being non-Hispanic White (AOR 15.2; p=0.002), reported sex with a known HCV+ partner (AOR 33.0; p<0.001), and increasing age (AOR 1.08; p=0.003). Among the 17 HCV+ patients, only 7 (53.8%) were within the “baby boomer” cohort, and 12 (70.6%) were successfully linked to HCV care.  

Conclusion: The majority of individuals prefer rapid HCV testing, yet higher risk individuals opted for traditional phlebotomy testing, perhaps to identify other comorbid conditions. Rapid testing, however, identified the majority of new HCV infections, using an innovative MMC model which successfully engaged individuals who might otherwise not have been tested in traditional healthcare settings. Risk-based testing thus necessarily augments the “baby boomer” HCV screening age category.

Jamie Morano, MD, MPH¹, Alexei Zelenev, PhD², Andrea Lombard, RN, BSN, MPH, CIC³, Britton Gibson, MPH², Ruthanne Marcus, MPH⁴ and Frederick Altice, MD⁵, (1)Department of Infectious Diseases, Yale University School of Medicine, Yale Clinical Research, Yale University AIDS Program, Center for Interdisciplinary Research on AIDS, New Haven, CT, (2)Yale University School of Medicine, Yale University AIDS Program, New Haven, CT, (3)Viral Hepatitis Section, Connecticut Department of Public Health, Hartford, CT, (4)Yale Clinical Research, Yale University AIDS Program, Yale School of Public Health, New Haven, CT, (5)Yale University School of Medicine, Yale School of Public Health, Director, Yale University AIDS Program, Yale Clinical and Community Research, Yale Center for Interdisciplinary Research on AIDS, New Haven, CT

Disclosures:

J. Morano, Vertex Pharmaceuticals Circle of Care Hepatitis C Grant: Grant Investigator, Research grant and Research support

A. Zelenev, None

A. Lombard, None

B. Gibson, Vertex Pharmaceuticals: Collaborator, Salary

R. Marcus, None

F. Altice, Vertex Pharmaceuticals Circle of Care Hepatitis C Grant: Investigator, Research grant and Supporting Mobile Clinic Work for HCV Testing; No Drug Support Given

Source

Daclatasvir + Sofosbuvir Effective in Prior Telaprevir or Boceprevir Failures

Infectious Disease Week (IDWeek)
October 2-6, 2013
San Francisco, Ca

1357. Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) In Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) Or Boceprevir (BOC)

Session: Poster Abstract Session: Clinical Trials

Saturday, October 5, 2013

Room: The Moscone Center: Poster Hall C

Background: Daclatasvir (DCV) plus sofosbuvir (SOF) ±RBV achieved high rates of sustained virologic response in HCV GT1-3-infected previously untreated patients (arms A-H). Additional arms (I, J) evaluated the efficacy of DCV+SOF ±RBV in patients who failed TVR or BOC.

Methods: A total of 41 GT1 non-cirrhotic patients with previous breakthrough (n=15), relapse (n=13), or nonresponse (n=14) to pegIFN/RBV+TVR (n=33) or BOC (n=9) (1 patient received both) were randomized 1:1 to DCV+SOF with or without RBV for 24 weeks. Patients who discontinued TVR or BOC due to adverse events were excluded. DCV and SOF were dosed orally at 60mg QD and 400mg QD, respectively. RBV was dosed BID at 1000-1200 mg/d. The primary end point was HCV RNA<25 IU/mL at 12 weeks post-treatment (SVR₁₂).

Results: Most patients had HCV GT1a (83%), were IL28B non-CC (98%), and had estimated METAVIR stage ≥F2 (83%). Mean HCV RNA was ≥6 log IU/mL. HCV RNA <25 IU/mL was achieved in 40/41 patients by week 4 and in all patients by end of treatment. None had breakthrough or relapse and all patients with available data (40/41) achieved SVR₁₂ (Table). The most common adverse events (>30% total) were fatigue and headache. There were no grade 3-4 hematologic or hepatic laboratory abnormalities. 

Conclusion : The all-oral, once-daily combination of DCV+SOF with or without RBV for 24 weeks achieved SVR₁₂ in 98% of non-cirrhotic GT1 prior TVR/BOC treatment failures. These data provide proof-of-concept that the combination of two potent direct-acting antivirals with different viral targets is effective in patients who failed pegIFN/RBV + a protease inhibitor.

HCV RNA < 25 IU/mL, mITT	I DCV + SOF x 24 weeks (n = 21)	J DCV + SOF  + RBV x 24 weeks (n = 20)
Week 4	21 (100)	19 (95)a
End Of Treatment  (Week 24)	21 (100)	20 (100)
SVR4	21 (100)	20 (100)
SVR12	21 (100)	19 (95)b
a 1 missing; b 1 missing—patient had HCV RNA undetectable at post-treatment  week4 and post-treatment week 24 (preliminary)

Mark Sulkowski, MD¹, David Gardiner², Maribel Rodriguez-Torres, MD³, K. Rajender Reddy, MD⁴, Tarek Hassanein, MD⁵, Ira Jacobson, MD⁶, Eric Lawitz⁷, Anna S.F. Lok, MD, FRCP⁸, Federico Hinestrosa⁹, Paul J. Thuluvath¹⁰, Howard Schwartz¹¹, David Nelson¹², Gregory T. Everson¹³, Timothy Eley, PhD¹⁴, Megan Wind-Rotolo¹⁵, Shu-Pang Huang¹⁵, Min Gao¹⁶, Fiona Mcphee¹⁶, Dennis Hernandez¹⁶, Diane Sherman², Robert Hindes¹⁷, William Symonds, PharmD¹⁸, Claudio Pasquinelli¹⁴, Dennis Grasela, PharmD, PhD¹⁹ and AI444040 Study Group, (1)John Hopkins University School of Medicine, Baltimore, MD, (2)Bristol-Myers Squibb, Pennington, NJ, (3)Gastroenterology, Fundacion de Investigacion, Rio Piedras, PR, (4)Univ. of Pennsylvania, Philadelphia, PA, (5)230 Prospect Place, Suite 220, Southern California Liver Centers, Coronado, CA, (6)Weill Medical College of Cornell University, New York, NY, (7)Texas Liver Insititute, University of Texas Health Science Center, San Antonio, TX, (8)Internal Medicine, University of Michigan, Ann Arbor, MI, (9)Orlando Immunology Center, Orlando, FL, (10)Mercy Medical Center, Baltimore, MD, (11)Miami Research Associates, South Miami, FL, (12)University of Florida, Gainesville, FL, (13)University of Colorado Denver, Aurora, CO, (14)Bristol-Myers Squibb, Hopewell, NJ, (15)Bristol-Myers Squibb, Princeton, NJ, (16)Bristol-Myers Squibb, Wallingford, CT, (17)Consultant, Foster City, CA, (18)Gilead Sciences, Foster City, CA, (19)Bristol Myers-Squibb, Hopewell, NJ

Disclosures:

M. Sulkowski, AbbVie: Investigator and Scientific Advisor, Consulting fee and Research grant
BIPI: Investigator, Research Contractor and Scientific Advisor, Consulting fee and Research grant
BMS: Investigator and Scientific Advisor, Consulting fee and Research grant
Gilead : Investigator and Scientific Advisor, Consulting fee and Research grant
Janssen: Consultant, Investigator and Scientific Advisor, Consulting fee and Research grant
Merck : Investigator and Scientific Advisor, Research grant
Pfizer: Steering Committe, Consulting fee
Vertex: Investigator and Scientific Advisor, Consulting fee and Research grant

D. Gardiner, Bristol-Myers Squibb: Employee, Salary

M. Rodriguez-Torres, Bristol-Myers Squibb: Investigator, Research support

K. R. Reddy, Bristol-Myers Squibb: Investigator, Research support

T. Hassanein, Bristol-Myers Squibb: Investigator, Research support

I. Jacobson, Bristol-Myers Squibb: Investigator, Research support

E. Lawitz, Bristol-Myers Squibb: Investigator, Research support

A. S. F. Lok, Bristol-Myers Squibb: Investigator, Research support

F. Hinestrosa, Bristol-Myers Squibb: Investigator, Research support

P. J. Thuluvath, Bristol-Myers Squibb: Investigator, Research support

H. Schwartz, Bristol-Myers Squibb: Investigator, Research support

D. Nelson, Bristol-Myers Squibb: Investigator, Research support

G. T. Everson, Bristol-Myers Squibb: Investigator, Research support

T. Eley, Bristol-Myers Squibb: Employee, Salary

M. Wind-Rotolo, Bristol-Myers Squibb: Employee, Salary

S. P. Huang, Shu-Pang Huang: Employee, Salary

M. Gao, Bristol-Myers Squibb: Employee, Salary

F. Mcphee, Bristol-Myers Squibb: Employee, Salary

D. Hernandez, Bristol-Myers Squibb: Employee, Salary

D. Sherman, Bristol-Myers Squibb: Employee, Salary

R. Hindes, Bristol-Myers Squibb: Research Contractor, Research support

W. Symonds, Gilead Sciences: Employee, Salary

C. Pasquinelli, Bristol-Myers Squibb: Employee, Salary

D. Grasela, Bristol-Myers Squibb: Employee, Salary

Source

Media academy held to support prevention and treatment of hepatitis C in Middle East

United Arab Emirates: 1 hour, 21 minutes ago

As part of their ongoing commitment to reducing the growing epidemic that hepatitis C (HCV) has become in the Middle East, MSD hosted the HCV Middle East summit, which brought together more than 200 doctors from across the region to discuss the virus, the best ways to manage it and the medical breakthroughs that may help to reduce the virus's growing prevalence.

Over the course of two days, MSD brought together both international and regional medical experts to present on a range of topics, highlighting the latest clinical trials and medical advances that may help save the lives of hepatitis C sufferers.

More than 9 million people across the MENA region are already believed to be infected with hepatitis C, additionally, whilst statistics remain scarce it is estimated that as much as 13.9 people out every 100,000 UAE citizens may suffer from the virus.

On the sidelines of this conference and as part of MSD's ongoing commitment to reducing the prevalence of life threatening illnesses through continuous, MSD also hosted a media academy for more than 25 journalists from countries across the Middle East. Hosted at the Grand Hyatt in Dubai, the Academy which brought together local and regional Gastroenterologists, as well as MSD experts, covered a wide range of topics including the prevalence and causes of hepatitis C, the various treatment options available as well as those in the pipeline and the integral role the media plays in helping to reduce the hepatitis epidemic.

Talking about their decision to host both the medical conference and media academy, Dr. Ramsey Morad, Managing Director of MSD in the Middle East, said, "At MSD we are committed to providing continuous education, whether to support physicians in providing their patients with the best care possible, or whether we are working with the media, to ensure that they have the tools they need to support in raising public awareness. Hepatitis C has already become an epidemic, with WHO estimating that 3% of the world's population, or around 170 million are already infected with the virus. As a region, the Middle East and North Africa, already ranks amongst the highest in the world in terms of both prevalence and incidence. Despite the progress and medical breakthroughs that have taken place over the last decade, hepatitis C transmission rates in the MENA region, are still amongst the highest in the world. Education is crucial if we are truly to start addressing this epidemic."

Adding to Dr. Morad's comments, Mr. Mazen Altaruti, Managing Director of MSD Gulf, said, "Hepatitis C is often known as the silent killer, because in many cases there are no specific symptoms until they have advanced or become chronic hepatitis. By raising awareness and providing physicians and the general public with a better understanding of the virus and the ways to prevent it we can save the lives of the UAE citizens."

The conference and media academy are just the latest in a long line of initiatives that MSD has undertaken in the region over the last few years to try to raise awareness of hepatitis C, just some of these initiatives including free screenings and continuous education programs for physicians and medical professionals, like the Middle East School of Hepatology, that MSD launched earlier this year.

Dr. Ramsey Morad, Managing Director of MSD in the Middle East.

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