March 1, 2012

FDA: New Risks for Statins With HIV/HCV Protease Inhibitors

Robert Lowes

Posted: 03/01/2012

March 1, 2012 — The US Food and Drug Administration (FDA) today announced that it is revising the labels of certain statins as well as protease inhibitors for HIV and hepatitis C virus (HCV) to warn about interactions between the 2 sets of drugs that could increase the risk for myopathy and kidney failure.

When taken together with the affected statins, HIV and HCV protease inhibitors can boost the blood level of the statins, which in turn can lead to myopathy. One of the most serious forms of myopathy is rhabdomyolysis, which can damage the kidneys, possibly resulting in kidney failure and death.

On Tuesday, the FDA announced that it was revising the labels of all statins to warn that they can raise blood glucose and hemoglobin A1c levels. The agency added that it was also updating the label of lovastatin to warn that a number of interacting drugs, including protease inhibitors, can increase statin exposure up to 20-fold and trigger rhabdomyolysis. The revised label for lovastatin will include new contraindications and dose limitations.

Today's FDA announcement lists lovastatin, simvastatin, atorvastatin, and rosuvastatin as statins that will undergo label changes to reflect the risk for interactions with HIV and HCV protease inhibitors. These statins will be contraindicated, cautioned against, or subject to dose limitations, depending on the exact combination of statin and protease inhibitor.

More information about today's announcement is available on the FDA's Web site.

To report adverse events related to the combination of statins and protease inhibitors, contact MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm, or by mail to MedWatch, FDA, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

Source

Also See:

  1. FDA Hepatitis Update - Important info about interactions between certain hepatitis C drugs and cholesterol-lowering statin drugs
  2. Statins and HIV or Hepatitis C Drugs: Drug Safety Communication - Interaction Increases Risk of Muscle Injury

FDA Hepatitis Update - Important info about interactions between certain hepatitis C drugs and cholesterol-lowering statin drugs

You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.

Please do not reply to this message.

The U.S. Food and Drug Administration (FDA) is issuing updated recommendations concerning drug-drug interactions between drugs for human immunodeficiency virus (HIV) or hepatitis C virus (HCV) known as protease inhibitors and certain cholesterol-lowering drugs known as statins. Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal.

Facts about statins and protease inhibitors

  • Statins are a class of prescription drugs used together with diet and exercise to reduce blood levels of low-density lipoprotein (LDL) cholesterol (“bad cholesterol”).
  • HIV protease inhibitors are a class of prescription anti-viral drugs used to treat HIV.
  • HCV protease inhibitors are a class of prescription anti-viral drugs used to treat hepatitis C infection.
  • A side effect of taking HIV protease inhibitors is increased cholesterol and triglyceride (fat) levels. Therefore, some patients taking HIV protease inhibitors may need to take cholesterol-lowering medicines such as statins.

The labels for both the HIV protease inhibitors and the affected statins have been updated to contain consistent information about the drug-drug interactions. These labels also have been updated to include dosing recommendations for those statins that may safely be co-administered with HIV or HCV protease inhibitors (see Statin Dose Limitations below).

Healthcare professionals should refer to the current drug labels for protease inhibitors and statins for the latest recommendations on prescribing these drugs.

Patients should contact their healthcare professional if they have any questions or concerns about taking protease inhibitors and statins.

Additional Information for Patients

  • Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) protease inhibitors can interact with cholesterol-lowering statins to increase the risk of muscle injury.
  • Patients should inform their healthcare professional about all medicines that they are taking or plan to take prior to starting an HIV or HCV protease inhibitor or statin.
  • HIV and HCV protease inhibitors should never be taken (are contraindicated) with lovastatin (Mevacor) and simvastatin (Zocor) (see Statin Dose Limitations below).
  • Patients should contact their healthcare professional if they have any questions or concerns about HIV or HCV protease inhibitors or statins.
  • Patients should report side effects from the use of HIV or HCV protease inhibitors and/or statins to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of the page.

Additional Information for Healthcare Professionals

  • Co-administration of human immunodeficiency virus (HIV) or hepatitis C virus (HCV) protease inhibitors with certain statins can increase the risk of myopathy/rhabdomyolysis.
  • Healthcare professionals should follow the recommendations in the drug labels when prescribing HIV or HCV protease inhibitors with statins (also see Statin Dose Limitations below).
  • Healthcare professionals should report adverse events involving HIV or HCV protease inhibitors and/or statins to the FDA MedWatch program using the information in the "Contact FDA" box at the bottom of this page.

Data Summary

Atorvastatin

The results from a drug-drug interaction study with atorvastatin and lopinavir/ritonavir that were previously in the atorvastatin label have not yet been validated. Therefore, these results have been removed from the label and the dose cap of atorvastatin 20 mg when co-administered with lopinavir/ritonavir has also been removed. Pending validation of the study, healthcare professionals should use caution when co-administering atorvastatin with lopinavir/ritonavir and use the lowest necessary dose of atorvastatin.

Lovastatin and simvastatin

Lovastatin and simvastatin are sensitive in vivo cytochrome P450 3A4 (CYP3A4) substrates. Therefore, strong CYP3A4 inhibitors are predicted to significantly increase lovastatin and simvastatin exposures. A literature review indicates that itraconazole, a strong CYP3A4 inhibitor, increases lovastatin exposure up to 20-fold, and the drug interaction appears to result in rhabdomyolysis.1 Itraconazole increases simvastatin exposure up to 13-fold. Hence, other CYP3A4 inhibitors, including ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, nefazodone, human immunodeficiency virus (HIV) protease inhibitors, and the hepatitis C virus (HCV) protease inhibitors boceprevir and telaprevir, are also expected to significantly increase lovastatin and simvastatin exposures. Therefore, concomitant administration of lovastatin and simvastatin with HIV protease inhibitors or HCV protease inhibitors (boceprevir and telaprevir) is contraindicated.

Rosuvastatin

The HIV protease inhibitor combinations lopinavir/ritonavir and atazanavir/ritonavir increase rosuvastatin exposure up to 3-fold. For these combinations, the dose of rosuvastatin should be limited to 10 mg.

FDA_statins

Reference

  1. Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med. 1995;333:664-5.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Source: Email from FDA

Hypoferremia Predicts Treatment Response to IFN-α

hepatitis

Last Updated: March 01, 2012

THURSDAY, March 1 (HealthDay News) -- For patients with hepatitis C virus (HCV), hepcidin, a regulator of iron homeostasis, is induced following a single dose of pegylated interferon-α (PEG-IFNα), and may be a surrogate marker of immediate efficacy of IFN-α, according to a study published online Feb. 15 in Hepatology.

John D. Ryan, M.D., of the Mater Misericordiae University Hospital in Dublin, and associates analyzed blood samples of HCV patients to assess the clinical importance of the changes in iron homeostasis during the first 24 hours of treatment with PEG-IFNα.

The researchers found that a single dose of PEG-IFNα triggered a significant increase in serum hepcidin that peaked at 12 hours. This coincided with a 50 percent drop in serum iron and transferrin saturation over 24 hours. Significantly lower levels of serum iron and transferring saturation were seen at 12 and 24 hours in patients with a ≥2 log decrease in HCV viral load over the first 24 hours. Serum iron levels at 24 hours were an independent predictor of immediate HCV viral decline. Direct induction of hepcidin by IFN-α was seen in cell culture, and was controlled by the STAT3 transcription factor.

"Hepcidin induction occurs following the initiation of PEG-IFNα treatment for HCV, and is mediated via STAT3 signaling," the authors write. "The subsequent hypoferremia was greatest in those with the most significant decline in viral load, identifying systemic iron withdrawal as a marker of immediate IFN-α efficacy in HCV patients."

Abstract
Full Text (subscription or payment may be required)

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Statins and HIV or Hepatitis C Drugs: Drug Safety Communication - Interaction Increases Risk of Muscle Injury

ucm052224

AUDIENCE: Infectious Disease, Family Practice, Patients

ISSUE: FDA notified healthcare professionals of updates to the prescribing information concerning interactions between protease inhibitors and certain statin drugs. Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal.

BACKGROUND: Statins are a class of prescription drugs used together with diet and exercise to reduce blood levels of low-density lipoprotein (LDL) cholesterol (“bad cholesterol”). HIV protease inhibitors are a class of prescription anti-viral drugs used to treat HIV. HCV protease inhibitors are a class of prescription anti-viral drugs used to treat hepatitis C infection.

RECOMMENDATION: Healthcare professionals should follow the recommendations in the prescribing information ( drug labels ) when prescribing HIV or HCV protease inhibitors with statins. See the FDA Drug Safety Communication for additional information, including a data summary.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

  • Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
  • Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

Read the MedWatch safety alert, including a link to the FDA Drug Safety Communication, at:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm294294.htm

Source: Email Alert from the FDA

TMC435HPC2002 - Phase II Trial of TMC435 in Combination With PSI-7977 in Prior G1 Null Responders to Peg-IFN/RBV, Hepatitis C-Infected Patients

Provided by NATAP

This study is currently recruiting participants.

Verified February 2012 by Tibotec Pharmaceuticals, Ireland

http://clinicaltrials.gov/ct2/show/NCT01466790?term=hepatitis+C+AND+TMC+435&rank=1

TMC435+PSI-7977 with & without ribavirin for either 12 or 24 weeks total duration of therapy

This is a randomized (study drug assigned by chance), open-label ( patients and physicians know the names of the drugs they are taking), Phase IIa trial with TMC435 and PSI-7977 with or without ribavirin (RBV) in patients who are infected with chronic genotype 1 hepatitis C and who have failed standard treatment with pegylated interferon (PegIFN) and ribavirin (RBV).

The study will investigate the efficacy and safety of four different regimens: two arms will receive 12 weeks of treatment and two arms will receive 24 weeks of treatment. A target of 90 subjects will be randomly assigned to 4 treatment arms in the first study cohort (Cohort 1), which includes patients with lower stages of liver fibrosis (Metavir F0, F1, and F2). The trial will consist of a screening period of maximum 6 weeks, a 12-week or 24-week treatment period and a follow-up period.

Once treatment results are available on all patients in Cohort 1, the second cohort (Cohort 2) will begin enrollment in the study. A target of 90 patients will be enrolled in Cohort 2. Enrollment criteria will be the same as for Cohort 1, except that only patients with more advanced liver fibrosis (Metavir stage F3 or F4), will be enrolled. The treatment arms to be included in Cohort 2 will be determined by the results from the data analysis in Cohort 1.

Artificial liver cells win their creator prize for their potential to reduce animal experiments

artificialli

Top images diseased liver cells, bottom images healthy liver cells. Credit: Tamir-Rashid

February 29, 2012

Cambridge research that created liver cells from stem cells has today been recognised with a national prize by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs).

Producing liver cells that demonstrate inherited liver diseases from human skin cells has earned Dr. Ludovic Vallier from the University of Cambridge a major prize from the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). These cells, known as human induced pluripotent stem cells (hIPSCs), have already attracted attention for the possibilities they offer to regenerate damaged tissues and organs. But it is their potential to reduce the number of animals used for screening potential drug treatments that led to Dr. Vallier receiving the Centre’s 3Rs prize for 2011.

The prize, sponsored by GlaxoSmithKline, of a £2,000 personal award and a £18,000 research grant, is for the scientific paper published in the last three years that contributes most to the advancement of the 3Rs (Replacement, Reduction and Refinement). Dr Vallier’s winning paper was published in The Journal of Clinical Investigation in 2010. He received his prize from Professor Paul Matthews OBE of GlaxoSmithKline at the NC3Rs Annual Science Review Meeting in London on 28 February.

Human liver cells (hepatocytes) cannot be grown in the laboratory and differences between rodents and humans mean that it is rarely possible to recreate the human disease completely in mice or rats or to use cultures of rat or mouse liver cells. Dr Vallier’s team took skin cells (dermal fibroblasts) from seven patients with a variety of inherited liver diseases and three healthy individuals (the controls). They then reprogrammed cells from the skin samples back into stem cells. These stem cells were then used to generate liver cells which mimicked a broad range of liver diseases – and to create ‘healthy’ liver cells from the control group.

These hIPSC-generated liver cells can provide in vitro models for basic research and drug discovery. Their use has already reduced the use of animals needed for the production of liver cells in the laboratories that have adopted this technology. The cells could also transform the investigation of chemical/drug-induced liver injury, a major concern for the chemical and pharmaceutical industries, by reducing dependence on animal testing.

Sharmila Nebhrajani, chief executive of the Association of Medical Research Charities (AMRC) said: “Charities invest over £1bn in health research each year, money raised by patients, their families and carers to understand the causes of disease and search for possible cures. Using 3Rs techniques, these prize winning researchers are bringing real hope to people with liver disease. What’s more – they are developing new methods for medical research which should benefit patients with all kinds of conditions.”

On presenting Dr. Vallier with his prize, Professor Paul Matthews, Vice-President for Imaging at GlaxoSmithKline, commented: “Ludovic Vallier’s innovative study describes the development and validation of a method to produce cells similar to those in a human liver. Such cells could replace animals for some types of early drug testing and could also help us to predict adverse clinical reactions. Using these cells for drug testing could be transformative. Ludovic and his colleagues have well illustrated how addressing the 3Rs converges with improving the quality of science!”

Provided by University of Cambridge (news : web)

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Cirrhotic patients experience increased daytime sleepiness from higher ammonia levels

Public release date: 1-Mar-2012

Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell

Hyperammonaemia reduces restorative sleep for patients with cirrhosis

Italian and Swiss researchers confirm that induced hyperammonaemia significantly increases daytime sleepiness in patients with cirrhosis. The findings available in the March issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases, show that higher blood levels of ammonia reduced the ability of cirrhotic patients to produce restorative sleep.

Chronic liver disease can lead to cirrhosis—a condition where scar tissue replaces healthy tissue, resulting in decreased blood flow through the liver and reduced liver function. Viral hepatitis, heavy alcohol use and obesity are among the causes of cirrhosis according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

In patients with chronic liver failure neuropsychiatric abnormalities may arise—termed hepatic encephalopathy (HE)—which experts believe to be due to neurotoxic substances that originate in the gut and are not cleared by the liver, such as ammonia. HE is common following a gastrointestinal bleed, which can be simulated by the oral administration of a mixture of protein mimicking that contained in blood ('amino acid challenge'; AAC).

To investigate the effects of excess ammonia and HE on sleep-wake patterns in patients with cirrhosis, Dr. Sara Montagnese and colleagues from the Dipartimento di Medicina in Padova, Italy and the Institute of Pharmacology and Toxicology in Zurich, Switzerland, induced hyperammonaemia in participants by an AAC. Ten cirrhotic patients and ten healthy controls underwent eight days of sleep quality monitoring, neuropsychiatric/wake and sleep EEG assessment prior to and following the AAC, and hourly ammonia and sleepiness assessments for eight hours post-AAC.

"Our study found that induced hyperammonaemia led to a significant increase in daytime sleepiness in both patients and healthy volunteers," said Dr. Montagnese. The authors also report changes to the EEG architecture of a sleep episode (nap) in patients with cirrhosis, which they believe points to a reduced ability to produce restorative sleep.

Dr. Montagnese concludes, "Our findings have important clinical implications in that subjective sleepiness may be used as a surrogate marker for HE." The authors also suggest that strategies aimed at reducing daytime sleepiness may result in improved sleep at night.

###

This study is published in Hepatology. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.

Full Citation: "Induced Hyperammonaemia may Compromise the Ability to Generate Restful Sleep in Patients with Cirrhosis." A Bersagliere, ID Raduazzo, M Nardi, S Schiff, A Gatta, P Amodio, P Achermann and S Montagnese. Hepatology; January 19, 2012 (DOI: 10.1002/hep.24741); Print Issue Date: March 2012. http://onlinelibrary.wiley.com/doi/10.1002/hep.24741/abstract.

Author Contact: To arrange an interview with Dr. Montagnese, please contact her directly at sara.montagnese@unipd.it or +39 049 8218675 begin_of_the_skype_highlighting +39 049 8218675 end_of_the_skype_highlighting.

About the Journal

Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Hepatology's current impact factor is 10.885.Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350.

About Wiley-Blackwell

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit www.wileyblackwell.com or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

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Sequana Medical's ALFApump® System Receives Reimbursement in Germany for Breakthrough Technology in Ascites Management

ZÜRICH, March 1, 2012 /PRNewswire/ --

NUB Grants Approval for Fifteen Leading Hepatology Centres in Germany.

Sequana Medical announced today that its ALFApump® System has received German Neue Untersuchungs und Behandlungsmethode (NUB) approval which allows participating hospitals to receive reimbursement for innovative new products. Sequana Medical's ALFApump System is a fully implantable pump system designed to remove excess abdominal fluid, known as ascites, that collects in patients suffering from liver cirrhosis.

"This year only 16% of products submitted to the NUB received approval. Selection of the ALFApump System emphasizes the unmet medical need that exists in the management of refractory ascites and validates the ALFApump System as a breakthrough technology in ascites management" said Dr. Noel Johnson, President and CEO of Sequana Medical.

The ALFApump System consists of a subcutaneously implanted battery-powered pump connected to a catheter placed in the abdominal cavity which automatically and continually collects ascites as it forms and moves it into the bladder, where it is eliminated from the patient through normal urination. "This innovative development marks the beginning of a completely new treatment option for cirrhosis patients suffering with refractory ascites", says Professor Frank Lammert, Director, Department of Internal Medicine II, Saarland University Hospital, Homburg. Refractory ascites affects over 100,000 patients in Europe and the US every year and the number of patients is growing at an annual rate of 10% due to the accelerating incidence of hepatitis and obesity-related liver disease.

Ascites is a common complication among patients with late-stage liver disease and is the leading reason for hospitalization among patients with cirrhosis. Paracentesis, which involves inserting a large-bore needle into the abdomen to drain 5-10 liters of accumulated ascites, is the most common procedure for the treatment of ascites. However, paracentesis has to be repeated frequently, often every 7-10 days, as it doesn't prevent the re-accumulation of ascites. This repeated procedure is burdensome both to the patient and healthcare service provider.

"The economic benefits of the ALFApump System are substantial", says Dr. Johnson. "Use of the ALFApump System will provide considerable savings to payers by significantly reducing the requirement for paracentesis and avoiding repeated hospitalization." The NHS National Innovation Centre in the UK recently estimated that the ALFApump System could save the NHS £50 million per year. "Furthermore, the availability of this breakthrough technology to German hospitals will help to significantly improve the Quality of Life of patients suffering from refractory ascites. The successful NUB application for the ALFApump is a major milestone for Sequana Medical," concludes Johnson.

The ALFApump System was granted CE Mark in July 2011 and is currently being introduced into leading hepatology centres across Europe by Sequana Medical.

About Sequana Medical:

Founded in 2006, Sequana Medical is a Swiss medical device company backed by NeoMed Managment, VI Partners, Biomed Invest, Capricorn and Entrepreneurs Fund, dedicated to improving patient lives through innovative technologies to manage fluid overload in patients suffering from liver disease, cancer and congestive heart failure.

Sequana Medical
Emily Woodward, Product Marketing Manager
E-Mail: Emily.Woodward@sequanamedical.com
Tel: +41-44-446-50-74
Internet: http://www.sequanamedical.com

SOURCE Sequana Medical AG

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Old Drug Reveals New Tricks: How Interferon Works to Suppress Virus in Patients With HIV, Hepatitis

ScienceDaily (Feb. 29, 2012) — A drug once taken by people with HIV/AIDS but long ago shelved after newer, modern antiretroviral therapies became available has now shed light on how the human body uses its natural immunity to fight the virus -- work that could help uncover new targets for drugs.

In an article published online this month by the journal PNAS, a group of U.S. and Swiss researchers led by scientists at the University of California, San Francisco (UCSF) presented the first clinical assessment of how this drug fights infections in people. The drug, called interferon, is a biotechnology product based on a protein the body naturally produces to fight infections.

While purified interferon was given to people with HIV/AIDS in the early days of the epidemic because it alleviated many of the symptoms of the disease, its mode of action was always something of a black box.

"Nobody knew how it worked," said Satish K. Pillai, PhD, lead investigator and assistant professor of Medicine at UCSF and the San Francisco VA Medical Center.

Experiments in the laboratory in recent years have shown how interferon may work to suppress HIV in vitro, but there was no clinical evidence until now showing how the drug attacks HIV in treated patients. The problem is that so few people actually take interferon for HIV any more. However, interferon is still used in combination with other drugs to treat hepatitis C, which gave the team the possibility to assess its effect on HIV.

Interferon is commonly used to treat people with hepatitis C virus, and Pillai and his colleagues were able to identify 20 people enrolled in the Swiss HIV Cohort Study, which began in 1988, who have both HIV and hepatitis C. All 20 were taking interferon to treat their hepatitis C, but none were receiving antiretroviral drugs to treat HIV. This allowed researchers to examine how interferon works to suppress the virus.

How Interferon Works

The new work sheds further light on somewhat mysterious components of the immune system known as restriction factors, which are chemicals the human body produces to keep viruses like HIV in check and prevent them from infecting other cells.

These are just two fronts in the overall battle between HIV and the immune system -- a battle in which the immune system seeks to destroy the virus while the virus constantly counters by undermining the immune system.

Unlike other parts of the immune system, where whole cells gobble up invading pathogens or attack other cells, the action of these restriction factors is more subtle and localized within the infected cell itself -- one of the reasons scientists didn't appreciate what they do until just a few years ago.

One of them, called APOBEC3, fights viruses by stealthily jumping onto new virus particles as they form. Therein, the APOBEC3 protein fouls up HIV's genetic material by mutating it. When the virus tries to infect another cell, it no longer has the potency to replicate.

Another factor, called tetherin, takes an even more direct approach. It attaches to virus particles as they emerge from infected cells in the body and literally tethers them in place, preventing them from moving elsewhere in the body where they could infect new cells.

HIV has its own countermeasures to thwart these defenses. It produces a protein known as Vpu that neutralizes tetherin. Another HIV protein, called Vif, subverts APOBEC.

In the new study, Pillai and his colleagues showed that interferon combats HIV by mediating the action of both of these restriction factors. They collected samples from the 20 patients and measured the levels of APOBEC3 and tetherin before, during and after they took the drug interferon. The levels increased in response to interferon when the drug was in the bloodstream, and patients with the highest restriction factor levels showed the most precipitous drop in HIV viral load during interferon treatment.

While this insight does not immediately suggest new drugs or new ways of treating people with HIV, Pillai said scientists armed with this knowledge may one day figure out how to enhance this defense mechanism and specifically enhance the expression of restriction factors like tetherin and APOBEC3 in HIV-1-infected individuals.

If these factors can be induced to higher levels, their attack on the virus may become more potent -- perhaps even overriding HIV's countermeasures and helping flush the virus from infected cells.

The article, "Role of retroviral restriction factors in the interferon-α-mediated suppression of HIV-1 in vivo," was written by Satish K. Pillai, Mohamed Abdel-Mohsen, John Guatelli, Mark Skasko, Alexander Monto, Katsuya Fujimoto, Steven Yukl, Warner C. Greene, Helen Kovari, Andri Rauch, Jacques Fellay, Manuel Battegay, Bernard Hirschel, Andrea Witteck, Enos Bernasconi, Bruno Ledergerber, Huldrych F. Günthard, Joseph K. Wong, and the Swiss HIV Cohort Study.

In addition to UCSF, the authors of this study are affiliated with the San Francisco VA Medical Center, the Veterans Affairs San Diego Healthcare System at the University of California at San Diego, the Gladstone Institute of Virology and Immunology, and the Swiss university hospitals of Zurich, Berne, Lausanne, Basel, Geneva, St. Gallen and Lugano.

This work was funded by the National Institutes of Health and through the American Recovery and Reinvestment Act (ARRA). Additional support was provided by Swiss HIV Cohort Study Project 594; the Veterans Affairs Merit Review; and several Swiss National Science Foundation Grants. The Swiss HIV Cohort Study is supported by the Swiss National Science Foundation and the Swiss HIV Cohort Study Research Foundation.

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Differences in virological response to peginterferon-[alpha] plus ribavirin in HIV-positive patients coinfected with HCV subtypes 1a or 1b

JAIDS Journal of Acquired Immune Deficiency Syndromes:

POST ACCEPTANCE, 22 February 2012

doi: 10.1097/QAI.0b013e31824f5506

Original Article: PDF Only

Rallón, Norma I.; Pineda, Juan A.; Soriano, Vincent; Neukam, Karin; Vispo, Eugenia; Rivero, Antonio; Labarga, Pablo; Caruz, Antonio; Restrepo, Clara; Camacho, Angela; Barreiro, Pablo; Benito, Jose M.
Abstract

Background: Both viral and host factors influence response to peginterferon-[alpha] plus ribavirin (pegIFN[alpha]/RBV) in patients with chronic hepatitis C. The impact of these variables is more pronounced in HIV/HCV-coinfected individuals, in whom treatment response rates are lower.

Methods: Virological responses at multiple time points were assessed in all HIV/HCV-coinfected patients that completed a first course of pegIFN[alpha]/RBV. Viral responses were stratified by HCV geno/subtypes and IL28B rs12979860 variants.

Results: A total of 331 HIV/HCV-coinfected patients were analyzed. HCV geno/subtype distribution was as follows: HCV-1a in 97, HCV-1b in 62, HCV-3 in 122 and HCV-4 in 50. Age, gender, CD4 counts, plasma HIV-RNA and liver fibrosis stage did not differ significantly across HCV geno/subtypes. In contrast, mean serum HCV-RNA was greater in HCV-1a compared to the rest (p<0.0001). The proportion of IL28B CC variants was higher in HCV-3 compared to the rest (p=0.001).

Virological responses were better in HCV-1b than HCV-1a at any given time point during therapy. IL28B variants significantly influenced virological responses across all HCV-1 subtypes, with the strongest effect seen in HCV-1a. In a multivariate linear regression analysis, both HCV-1b and IL28B CC variants were significantly associated with greater HCV-RNA drops at weeks 4 (R=0.52, p<0.0001) and 12 (R=0.49, p<0.0001) of therapy.

Conclusion: The response to pegIFN[alpha]/RBV therapy is lower in HCV-1a than HCV-1b in HIV/HCV-coinfected patients. The strongest influence of IL28B variants is seen in HCV-1a. This information may be relevant when using most directly acting antivirals in coinfected patients along with pegIFN[alpha]/RBV, given that selection of drug resistance occurs more frequently in HCV-1a than HCV-1b.

Source