Lange Christian Markus, Sarrazin Christoph, Zeuzem Stefan
European Gastroenterology & Hepatology Review, 2010;6(1):70–7
PDF download article
Abstract
Numerous directly acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection are currently under development. The final results of phase II clinical trials that evaluated the most advanced compounds – telaprevir and boceprevir – indicate that the addition of these NS3/4A protease inhibitors to pegylated interferon-alpha (pegIFN-α) and ribavirin strongly improves the chances of achieving a sustained virological response (SVR) in treatment-naïve HCV genotype 1 patients and in prior non-responders and relapsers. However, monotherapy with DAAs frequently results in the selection of resistant quasi-species and viral breakthrough and is therefore not suitable. Generally, NS5B polymerase inhibitors have a lower antiviral efficacy than protease inhibitors, and their ability to improve SVR rates remains to be established. Future research should elaborate on whether an SVR can be achieved with combination therapies of DAA agents without IFN-α; in addition, DAAs targeting genotypes other than HCV genotype 1 should be evaluated.
Keywords
Directly acting antiviral agents (DAAs), specifically targeted antiviral therapy for hepatitis c (STAT-C), protease inhibitor, polymerase inhibitor, hepatitis C, antiviral therapy, viral resistance, drug resistance
Disclosure: Christian Markus Lange has no conflicts of interest to declare. Christoph Sarrazin is a clinical investigator, consultant and/or a member of the speaker’s bureau of Abbott, BMS, Boehringer Ingelheim, Falk, Gilead, Merck, Novartis, Roche, Siemens, Tibotec and Vertex. Stefan Zeuzum is a clinical investigator, consultant and/or a member of the speaker’s bureau of Abbott, Anadys, BMS, Boehringer Ingelheim, Gilead, HGS, Merck, Novartis, Roche, Tibotec and Vertex.
Received: 7 May 2010 Accepted: 29 June 2010 Citation: European Gastroenterology & Hepatology Review, 2010;6(1):70–6
Correspondence: Stefan Zeuzem, Klinikum der JW Goethe-Universität Frankfurt am Main Medizinische Klinik I, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. E: zeuzem@em.uni-frankfurt.de
The odds of achieving a sustained virological response (SVR) in patients with chronic hepatitis C with a therapy of pegylated interferon-alpha (pegIFN-α) and ribavirin are still too low, particularly in patients infected with hepatitis C virus (HCV) genotypes 1 or 4.1–4 Therefore, intensive efforts have been made to develop directly acting antiviral agents (DAAs) against HCV.5–12 Many of these DAAs are currently in phase I–III development and will significantly change treatment options for HCV infection in the near future. The most advanced compounds are telaprevir and boceprevir, which are both inhibitors of the HCV NS3 protease and have been shown to significantly enhance SVR rates in HCV genotype 1 patients when applied in addition to pegIFN-α and ribavirin.13–15
NS3/4A Protease Inhibitors
NS3/4A protease inhibitors can be divided into two chemical classes: macrocyclic inhibitors and linear tetra-peptide α-ketoamid derivatives. Ciluprevir has a macrocyclic structure and was the first protease inhibitor evaluated in patients with chronic hepatitis C. Ciluprevir, as well as subsequently developed NS3/4A protease inhibitors of both molecular classes, strongly inhibited HCV replication during monotherapy, but also frequently caused the selection of resistant mutants, which may be followed by viral breakthrough.12,16–18 Although the development of ciluprevir was stopped because of serious cardiotoxicity observed in an animal model, the proof of principle was provided for successful suppression of HCV replication by NS3/4A inhibitors in patients with chronic hepatitis C. Subsequent studies have shown that the frequency of resistance development against protease inhibitors can be vastly reduced by the additional administration of pegIFN and ribavirin. Telaprevir and boceprevir are the most advanced NS3/4A protease inhibitors, and are currently in phase III evaluation.
To register to view full article click here
Keywords:
Directly acting antiviral agents (DAAs), specifically targeted antiviral therapy for hepatitis c (STAT-C), protease inhibitor, polymerase inhibitor, hepatitis C, antiviral therapy, viral resistance, drug resistance
Source
January 5, 2011
Hepatitis C: In 2011, a predictive marker for response to therapy
Public release date: 5-Jan-2011
Contact: Matthew Albert
albertm@pasteur.fr
33-670-010-396
INSERM (Institut national de la santé et de la recherche médicale)
Scientists at Inserm and Institut Pasteur have performed biomarker discovery on patients being treated for chronic hepatitis C infection. Their work, published in The Journal of Clinical Investigation, demonstrates that the plasma levels of the protein IP-10 predict, prior to treatment initiation, the efficacy of treatment with pegylated-interferon and ribavirin. Based on these results, the scientists have developed a prognostic test. Commercialization is anticipated in 2011, and will help inform physicians of the chances that patients will respond to standard treatment or if instead they will require new therapeutic cocktails (e.g., inclusion of protease inhibitors).
Importantly, hepatitis C is the leading cause of primary liver cancer (hepatocellular carcinoma) and it remains an important cause of liver failure due to fibrosis and cirrhosis. This infectious disease represents a major public health problem, with greater than 170 million cases worldwide. The World Health Organization estimates 3 to 4 million new cases per year and considers the virus a " viral time bomb" due to the long term sequella of infection.
Currently, there is no approved vaccine available and approximately 80% of individuals infected by the virus develop chronic disease, a risk factor for cirrhosis, liver failure, liver cancer as well as other medical complications (e.g., diabetes).
For the past ten years, treatment has been based on the use of type I interferon given in combination with the anti-viral ribavirin. While effective, it results in a cure for only 50% of patients. Moreover, treatment is long (24 – 48 weeks), and it results in severe side effects (e.g., depression, anemia).
It is in this context that the Inserm and Institut Pasteur sponsored research lab of Dr. Matthew Albert, in close collaboration with the Liver Disease Unit headed by Prof. Stanislas Pol, evaluated plasma biomarkers to define predictors for patients' response to treatment.
With the help of the Centre for Human Immunology at Institut Pasteur, the investigators involved have performed a prospective study. They identified the protein IP-10 as a prognostic biomarker – elevated in those patients for whom treatment was ineffective. This observation was paradoxical as IP-10 is considered a pro-inflammatory molecule, which should have facilitated migration of activated T cells to the liver, the exact cell types responsible for viral immunity. In fact, what was discovered is that the IP-10 had been catabolized and it was a truncated form present in the HCV patients. Strikingly, the short form of IP-10 is an antagonist and inhibits T cell recruitment. Thus, it is suggested that the antagonist form of IP-10 is responsible for the failure to respond to treatment in the 50% of patients who do not benefit from pegylated-interferon / ribavirin treatment.
The investigators worked in close collaboration with an American company, Rules Based Medicine, Inc., who will develop a diagnostic test to distinguish the different forms of IP-10 as a simple blood test. This test will be a significant step towards the improved management of patients with HCV as well as other chronic inflammatory diseases.
###
This scientific work was conducted under the direction of Matthew L. Albert, MD PhD, Mixed Institut Pasteur / Inserm Research Unit; and Stanislas Pol, MD PhD, Univerisity of Paris, Descartes and Institut Cochin. Financial support was provided by the ANRS and promotion of the study was taken by Inserm Medical.
To know more:
Source
Evidence for chemokine antagonisms in human infected chronically with Hepatitis C Virus.
Armanda Casrouge, Jérémie Decalf, Mina Ahloulay, Cyril Lababidi, Hala Mansour, Anaïs Vallet-Pichard, Vincent Mallet, Estelle Mottez, James Mapes, Arnaud Fontanet, Stanislas Pol and Matthew L. Albert.
Journal of Clinical Investigation.
and the related news article
Chemokine antagonism in chronic hepatitis C virus infection.
Edgar D. Charles and Lynn B. Dustin
Journal of Clinical Investigation.
Contact information
Matthew Albert
Unité mixte Institut Pasteur / Inserm
Email : albertm@pasteur.fr
Tel : +33 6 7001 0396
Stanislas Pol
Unité 1016 « Institut Cochin »
Service Hépatologie, Hôpital Cochin
Email : stanislas.pol@cch.aphp.fr
Source
Contact: Matthew Albert
albertm@pasteur.fr
33-670-010-396
INSERM (Institut national de la santé et de la recherche médicale)
Scientists at Inserm and Institut Pasteur have performed biomarker discovery on patients being treated for chronic hepatitis C infection. Their work, published in The Journal of Clinical Investigation, demonstrates that the plasma levels of the protein IP-10 predict, prior to treatment initiation, the efficacy of treatment with pegylated-interferon and ribavirin. Based on these results, the scientists have developed a prognostic test. Commercialization is anticipated in 2011, and will help inform physicians of the chances that patients will respond to standard treatment or if instead they will require new therapeutic cocktails (e.g., inclusion of protease inhibitors).
Importantly, hepatitis C is the leading cause of primary liver cancer (hepatocellular carcinoma) and it remains an important cause of liver failure due to fibrosis and cirrhosis. This infectious disease represents a major public health problem, with greater than 170 million cases worldwide. The World Health Organization estimates 3 to 4 million new cases per year and considers the virus a " viral time bomb" due to the long term sequella of infection.
Currently, there is no approved vaccine available and approximately 80% of individuals infected by the virus develop chronic disease, a risk factor for cirrhosis, liver failure, liver cancer as well as other medical complications (e.g., diabetes).
For the past ten years, treatment has been based on the use of type I interferon given in combination with the anti-viral ribavirin. While effective, it results in a cure for only 50% of patients. Moreover, treatment is long (24 – 48 weeks), and it results in severe side effects (e.g., depression, anemia).
It is in this context that the Inserm and Institut Pasteur sponsored research lab of Dr. Matthew Albert, in close collaboration with the Liver Disease Unit headed by Prof. Stanislas Pol, evaluated plasma biomarkers to define predictors for patients' response to treatment.
With the help of the Centre for Human Immunology at Institut Pasteur, the investigators involved have performed a prospective study. They identified the protein IP-10 as a prognostic biomarker – elevated in those patients for whom treatment was ineffective. This observation was paradoxical as IP-10 is considered a pro-inflammatory molecule, which should have facilitated migration of activated T cells to the liver, the exact cell types responsible for viral immunity. In fact, what was discovered is that the IP-10 had been catabolized and it was a truncated form present in the HCV patients. Strikingly, the short form of IP-10 is an antagonist and inhibits T cell recruitment. Thus, it is suggested that the antagonist form of IP-10 is responsible for the failure to respond to treatment in the 50% of patients who do not benefit from pegylated-interferon / ribavirin treatment.
The investigators worked in close collaboration with an American company, Rules Based Medicine, Inc., who will develop a diagnostic test to distinguish the different forms of IP-10 as a simple blood test. This test will be a significant step towards the improved management of patients with HCV as well as other chronic inflammatory diseases.
###
This scientific work was conducted under the direction of Matthew L. Albert, MD PhD, Mixed Institut Pasteur / Inserm Research Unit; and Stanislas Pol, MD PhD, Univerisity of Paris, Descartes and Institut Cochin. Financial support was provided by the ANRS and promotion of the study was taken by Inserm Medical.
To know more:
Source
Evidence for chemokine antagonisms in human infected chronically with Hepatitis C Virus.
Armanda Casrouge, Jérémie Decalf, Mina Ahloulay, Cyril Lababidi, Hala Mansour, Anaïs Vallet-Pichard, Vincent Mallet, Estelle Mottez, James Mapes, Arnaud Fontanet, Stanislas Pol and Matthew L. Albert.
Journal of Clinical Investigation.
and the related news article
Chemokine antagonism in chronic hepatitis C virus infection.
Edgar D. Charles and Lynn B. Dustin
Journal of Clinical Investigation.
Contact information
Matthew Albert
Unité mixte Institut Pasteur / Inserm
Email : albertm@pasteur.fr
Tel : +33 6 7001 0396
Stanislas Pol
Unité 1016 « Institut Cochin »
Service Hépatologie, Hôpital Cochin
Email : stanislas.pol@cch.aphp.fr
Source
LSM detects undiagnosed chronic liver disease
Published date :24-Dec-2010
MedWire News: Study findings show that liver stiffness measurement (LSM) can detect undiagnosed chronic liver disease in apparently healthy individuals, with the added benefit of a 100% positive predictive value for cirrhosis screening.
"So far, liver biopsy has been the gold standard for the assessment of fibrosis in patients with chronic liver disease," say Dominique Roulot (Avicenne Hospital, Bobigny, France) and co-authors.
"However, in cases of suspicion of non-alcoholic fatty liver disease (NAFLD), liver biopsy is difficult to recommend for apparently healthy patients with normal liver tests, because of its possible complications," they add.
A total of 1190 individuals from the general population, aged 45 years or older, attending for a medical check-up participated in the current study. All patients received LSM, in addition to laboratory tests and medical examinations. Those who scored over 8 kPa on the LSM were referred to a liver unit for further investigations.
Overall, 94 (8.5%) patients had a LSM >8 kPa, including nine patients with a LSM >13 kPa. The researchers note that although LSM values were normal in 4% of patients with perturbed liver tests, these tests came back as normal in 43% of patients with LSM >8 kPa.
NAFLD and alcoholic liver disease (ALD) were diagnosed as the likely causes of chronic liver disease in 52 and 20 patients, respectively. Hepatitis B and C were diagnosed in nine patients, and primary biliary cirrhosis in one patient.
Liver biopsy results confirmed that all of the nine patients with LSM >13 kPa had liver cirrhosis due to ALD or chronic hepatitis B/C. The remaining 18 biopsies showed liver fibrosis in all patients except one who presented with isolated steatosis.
Factors significantly associated with a LSM >8 kPa included being aged 57 years or older, having a body mass index ≥30 kg/m2, elevated waist circumference, diabetes, alanine aminotransferase ≥40 UI/l, and γ-glutamyltranspeptidase ≥45 UI/l.
The researchers say the findings suggest that "a relatively high percentage of liver diseases remain undiagnosed in apparently healthy individuals, and that LSM might contribute to referring these patients to hepatologists."
They conclude in the journal Gut: "If future studies determine that the superior positive predictive value of LSM can be achieved at an acceptable cost, compared with common screening methods, LSM might represent a first-line procedure for the mass screening of liver disease in the general population."
MedWire (http://www.medwire-news.md/) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010
Source
MedWire News: Study findings show that liver stiffness measurement (LSM) can detect undiagnosed chronic liver disease in apparently healthy individuals, with the added benefit of a 100% positive predictive value for cirrhosis screening.
"So far, liver biopsy has been the gold standard for the assessment of fibrosis in patients with chronic liver disease," say Dominique Roulot (Avicenne Hospital, Bobigny, France) and co-authors.
"However, in cases of suspicion of non-alcoholic fatty liver disease (NAFLD), liver biopsy is difficult to recommend for apparently healthy patients with normal liver tests, because of its possible complications," they add.
A total of 1190 individuals from the general population, aged 45 years or older, attending for a medical check-up participated in the current study. All patients received LSM, in addition to laboratory tests and medical examinations. Those who scored over 8 kPa on the LSM were referred to a liver unit for further investigations.
Overall, 94 (8.5%) patients had a LSM >8 kPa, including nine patients with a LSM >13 kPa. The researchers note that although LSM values were normal in 4% of patients with perturbed liver tests, these tests came back as normal in 43% of patients with LSM >8 kPa.
NAFLD and alcoholic liver disease (ALD) were diagnosed as the likely causes of chronic liver disease in 52 and 20 patients, respectively. Hepatitis B and C were diagnosed in nine patients, and primary biliary cirrhosis in one patient.
Liver biopsy results confirmed that all of the nine patients with LSM >13 kPa had liver cirrhosis due to ALD or chronic hepatitis B/C. The remaining 18 biopsies showed liver fibrosis in all patients except one who presented with isolated steatosis.
Factors significantly associated with a LSM >8 kPa included being aged 57 years or older, having a body mass index ≥30 kg/m2, elevated waist circumference, diabetes, alanine aminotransferase ≥40 UI/l, and γ-glutamyltranspeptidase ≥45 UI/l.
The researchers say the findings suggest that "a relatively high percentage of liver diseases remain undiagnosed in apparently healthy individuals, and that LSM might contribute to referring these patients to hepatologists."
They conclude in the journal Gut: "If future studies determine that the superior positive predictive value of LSM can be achieved at an acceptable cost, compared with common screening methods, LSM might represent a first-line procedure for the mass screening of liver disease in the general population."
MedWire (http://www.medwire-news.md/) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010
Source
January 4, 2011
Study Finds That A Certain Type Of HIV Reduces Breast Cancer Risk Among HIV-Infected Women
By Meerat Oza and Courtney McQueen
Published: Jan 4, 2011 5:03 pm
Results of a recently published study have shown that women infected with a certain type of HIV may have a significantly lower risk of breast cancer compared to women with other strains of HIV, possibly because this type of HIV effectively targets and kills breast cancer cells.
The study authors stated that the results need to be confirmed by additional studies, but may explain results showing women with HIV are at lower risk for breast cancer than women without HIV.
HIV is often associated with increased rates of several types of malignant cancers, such as Kaposi’s sarcoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, cervical cancer, and anal cancer.
However, studies have shown that women with HIV may be at decreased risk of breast cancer. Between 1980 and 2002, the risk of breast cancer was found to be 31 percent lower in HIV-infected women as compared to uninfected women.
Researchers have speculated that this may be because a type of cell protein that HIV sometimes uses to infect immune system cells is also found on the surface of breast cancer cells.
In order to infect healthy white blood cells, HIV binds to certain proteins on their surface, called CCR5 or CXCR4. Most HIV, especially early in infection, uses CCR5 for infection. However, later in infection HIV will sometimes switch to using CXCR4 or a combination of the two proteins.
One hypothesis for why HIV-positive women may be at reduced risk for breast cancer is that the CXCR4 protein is also found on the surface of breast cancer cells. This protein is not found on normal breast cells and may be used by the cancer cells to grow and spread. Scientists have shown that in the laboratory, HIV that binds to breast cancer cells kills them.
If this hypothesis is correct, then women with HIV that uses the protein CXCR4 for infection should be at lower risk of developing breast cancer.
To test their hypothesis, the researchers in this study identified 23 HIV-infected women who had breast cancer and compared them to 69 HIV-positive women without breast cancer who were of similar age.
Results showed that only 9 percent of the women with breast cancer had CXCR4-dependent HIV, compared to 28 percent of the women without breast cancer.
Further analysis revealed that women with CXCR4-dependent HIV were only 10 percent as likely to have breast cancer as women infected with CCR5-dependent HIV.
Menopause was the only other factor that affected the risk of developing breast cancer. CD4 (white blood cell) count, viral load (amount of HIV in the blood), antiretroviral therapy regimen, ethnicity, and other lifestyle factors such as use of alcohol or contraceptives did not correlate with risk.
The researchers concluded that CXCR4-dependent HIV has a protective effect against breast cancer in women, and they speculated that CXCR4-dependent HIV may account for the lower risk of breast cancer in women with HIV.
They suggested that their findings could lead to new methods for trying to combat breast cancer.
Since the study was small, the researchers noted that their results will need to be confirmed by further studies with larger groups of women.
Also, while they presume the lower risk of breast cancer arises from CXCR4-dependent HIV infecting and killing breast cancer cells, they suggested further study on the exact mechanism by which CXCR4-dependent HIV protects against breast cancer.
For more information, please see the study in PLoS One.
Source
Published: Jan 4, 2011 5:03 pm
Results of a recently published study have shown that women infected with a certain type of HIV may have a significantly lower risk of breast cancer compared to women with other strains of HIV, possibly because this type of HIV effectively targets and kills breast cancer cells.
The study authors stated that the results need to be confirmed by additional studies, but may explain results showing women with HIV are at lower risk for breast cancer than women without HIV.
HIV is often associated with increased rates of several types of malignant cancers, such as Kaposi’s sarcoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, cervical cancer, and anal cancer.
However, studies have shown that women with HIV may be at decreased risk of breast cancer. Between 1980 and 2002, the risk of breast cancer was found to be 31 percent lower in HIV-infected women as compared to uninfected women.
Researchers have speculated that this may be because a type of cell protein that HIV sometimes uses to infect immune system cells is also found on the surface of breast cancer cells.
In order to infect healthy white blood cells, HIV binds to certain proteins on their surface, called CCR5 or CXCR4. Most HIV, especially early in infection, uses CCR5 for infection. However, later in infection HIV will sometimes switch to using CXCR4 or a combination of the two proteins.
One hypothesis for why HIV-positive women may be at reduced risk for breast cancer is that the CXCR4 protein is also found on the surface of breast cancer cells. This protein is not found on normal breast cells and may be used by the cancer cells to grow and spread. Scientists have shown that in the laboratory, HIV that binds to breast cancer cells kills them.
If this hypothesis is correct, then women with HIV that uses the protein CXCR4 for infection should be at lower risk of developing breast cancer.
To test their hypothesis, the researchers in this study identified 23 HIV-infected women who had breast cancer and compared them to 69 HIV-positive women without breast cancer who were of similar age.
Results showed that only 9 percent of the women with breast cancer had CXCR4-dependent HIV, compared to 28 percent of the women without breast cancer.
Further analysis revealed that women with CXCR4-dependent HIV were only 10 percent as likely to have breast cancer as women infected with CCR5-dependent HIV.
Menopause was the only other factor that affected the risk of developing breast cancer. CD4 (white blood cell) count, viral load (amount of HIV in the blood), antiretroviral therapy regimen, ethnicity, and other lifestyle factors such as use of alcohol or contraceptives did not correlate with risk.
The researchers concluded that CXCR4-dependent HIV has a protective effect against breast cancer in women, and they speculated that CXCR4-dependent HIV may account for the lower risk of breast cancer in women with HIV.
They suggested that their findings could lead to new methods for trying to combat breast cancer.
Since the study was small, the researchers noted that their results will need to be confirmed by further studies with larger groups of women.
Also, while they presume the lower risk of breast cancer arises from CXCR4-dependent HIV infecting and killing breast cancer cells, they suggested further study on the exact mechanism by which CXCR4-dependent HIV protects against breast cancer.
For more information, please see the study in PLoS One.
Source
Anadys Pharmaceuticals Initiates Phase IIb Study of ANA598 in HCV Patients
SAN DIEGO, Jan. 4, 2011 /PRNewswire/ -- Anadys Pharmaceuticals, Inc. (Nasdaq: ANDS) announced today that it has initiated the planned Phase IIb study of ANA598 in combination with pegylated interferon and ribavirin. The protocol for the study has been cleared by the United States Food and Drug Administration (FDA) and Health Canada. Patient screening has begun and patient dosing is expected to commence within the next several weeks. In the study ANA598 will be tested in both treatment-naive patients and treatment-experienced patients who failed a prior course of therapy with interferon and ribavirin. ANA598 is the Company's direct-acting antiviral, or DAA, being developed for the treatment of hepatitis C.
"We are excited to initiate this Phase IIb study of ANA598," said James L. Freddo, M.D., Anadys' Senior Vice President, Drug Development and Chief Medical Officer. "By establishing safety and efficacy in a greater number of patients, including those who have failed prior HCV treatment, we hope to position ANA598 as a highly attractive HCV agent ready for Phase III development."
Phase IIb Protocol Design
In the study, approximately 200 chronically infected genotype 1 hepatitis C patients are expected to receive ANA598 200 mg twice a day (bid) in combination with Pegasys® (peginterferon alfa-2a) and Copegus® (ribavirin, USP) (a current standard of care, or SOC) with a loading dose of 800 mg bid on day 1, while approximately 66 patients are to receive placebo and SOC. Enrollment is expected to include approximately equal numbers of treatment-naive patients and patients who have failed a prior course of SOC, including difficult to treat prior null-responders. The primary endpoint of the study is Sustained Virological Response 24 weeks after patients conclude all treatment, known as SVR24. Anadys is conducting the study at sites within and outside the United States.
Naive Arm
Approximately 100 treatment-naive HCV patients are expected to receive ANA598 in combination with SOC and 33 treatment-naive HCV patients are to receive placebo plus SOC. Treatment duration for naive patients will be response-guided; patients who achieve undetectable levels of virus at Week 8 and maintain undetectable levels of virus will be scheduled to conclude all treatment at Week 28. For naive patients with detectable virus at Week 8 dosing with ANA598, or placebo, and SOC is planned to continue through Week 48. The Company expects to receive Week 8 antiviral response data by the end of the second quarter of 2011, Week 12 antiviral response data in the third quarter of 2011 and Week 24 antiviral response data in the fourth quarter of 2011.
Treatment-Experienced Arm, Including Prior Null Responders
Approximately 80 patients who were partial responders during, or relapsers after, a prior course of therapy with SOC alone are expected to receive ANA598 in combination with SOC, and 33 corresponding patients are to receive placebo plus SOC. Additionally, approximately 28 prior null responder patients are to receive ANA598 in combination with SOC. All treatment-experienced patients who receive ANA598 are scheduled to receive triple combination therapy for 48 weeks. For the treatment-experienced patients, the Company expects to receive Week 12 antiviral response data in the third quarter of 2011 and Week 24 antiviral response data in the fourth quarter of 2011.
About Anadys
Anadys Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to improving patient care by developing novel medicines for the treatment of hepatitis C. The Company believes hepatitis C represents a large unmet medical need in which meaningful improvements in treatment outcomes may be attainable with the introduction of new medicines. Anadys has initiated a Phase IIb study of ANA598, the Company's DAA, added to current standard of care for the treatment of hepatitis C. The Company is also preparing to resume clinical development of ANA773, the Company's oral, small-molecule inducer of endogenous interferons that acts via the Toll like receptor 7, or TLR7, pathway in hepatitis C.
Safe Harbor Statement
Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to (i) expectations regarding the timing for commencing patient dosing in the ANA598 Phase IIb study; (ii) the goal of establishing safety and efficacy in a greater number of patients, including those who have failed prior HCV treatment; (iii) the hope to position ANA598 as a highly attractive HCV agent ready for Phase III development; (iv) the scheduled trial design for the Phase IIb study; and (v) Anadys' expectations regarding the timing of receipt of data from the study. Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause Anadys' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements. For example, the results of preclinical and early clinical studies may not be predictive of future results, and Anadys cannot provide any assurances that ANA598 will not have unforeseen safety issues, will have favorable results in ongoing or future clinical trials or will receive regulatory approval. In addition, Anadys' results may be affected by competition from other biotechnology and pharmaceutical companies, its effectiveness at managing its financial resources, its ability to enter into transactions around its product candidates, its ability to successfully develop and market products, difficulties or delays in its non-clinical studies or clinical trials, difficulties or delays in manufacturing its clinical trials materials, the scope and validity of patent protection for its products, regulatory developments and its ability to obtain additional funding to support its operations. Risk factors that may cause actual results to differ are more fully discussed in Anadys' SEC filings, including Anadys' Form 10-Q for the quarter ended September 30, 2010. All forward-looking statements are qualified in their entirety by this cautionary statement. Anadys is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.
Pegasys® and Copegus® are registered trademarks of Hoffman-La Roche Inc.
SOURCE Anadys Pharmaceuticals, Inc.
Source
"We are excited to initiate this Phase IIb study of ANA598," said James L. Freddo, M.D., Anadys' Senior Vice President, Drug Development and Chief Medical Officer. "By establishing safety and efficacy in a greater number of patients, including those who have failed prior HCV treatment, we hope to position ANA598 as a highly attractive HCV agent ready for Phase III development."
Phase IIb Protocol Design
In the study, approximately 200 chronically infected genotype 1 hepatitis C patients are expected to receive ANA598 200 mg twice a day (bid) in combination with Pegasys® (peginterferon alfa-2a) and Copegus® (ribavirin, USP) (a current standard of care, or SOC) with a loading dose of 800 mg bid on day 1, while approximately 66 patients are to receive placebo and SOC. Enrollment is expected to include approximately equal numbers of treatment-naive patients and patients who have failed a prior course of SOC, including difficult to treat prior null-responders. The primary endpoint of the study is Sustained Virological Response 24 weeks after patients conclude all treatment, known as SVR24. Anadys is conducting the study at sites within and outside the United States.
Naive Arm
Approximately 100 treatment-naive HCV patients are expected to receive ANA598 in combination with SOC and 33 treatment-naive HCV patients are to receive placebo plus SOC. Treatment duration for naive patients will be response-guided; patients who achieve undetectable levels of virus at Week 8 and maintain undetectable levels of virus will be scheduled to conclude all treatment at Week 28. For naive patients with detectable virus at Week 8 dosing with ANA598, or placebo, and SOC is planned to continue through Week 48. The Company expects to receive Week 8 antiviral response data by the end of the second quarter of 2011, Week 12 antiviral response data in the third quarter of 2011 and Week 24 antiviral response data in the fourth quarter of 2011.
Treatment-Experienced Arm, Including Prior Null Responders
Approximately 80 patients who were partial responders during, or relapsers after, a prior course of therapy with SOC alone are expected to receive ANA598 in combination with SOC, and 33 corresponding patients are to receive placebo plus SOC. Additionally, approximately 28 prior null responder patients are to receive ANA598 in combination with SOC. All treatment-experienced patients who receive ANA598 are scheduled to receive triple combination therapy for 48 weeks. For the treatment-experienced patients, the Company expects to receive Week 12 antiviral response data in the third quarter of 2011 and Week 24 antiviral response data in the fourth quarter of 2011.
About Anadys
Anadys Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to improving patient care by developing novel medicines for the treatment of hepatitis C. The Company believes hepatitis C represents a large unmet medical need in which meaningful improvements in treatment outcomes may be attainable with the introduction of new medicines. Anadys has initiated a Phase IIb study of ANA598, the Company's DAA, added to current standard of care for the treatment of hepatitis C. The Company is also preparing to resume clinical development of ANA773, the Company's oral, small-molecule inducer of endogenous interferons that acts via the Toll like receptor 7, or TLR7, pathway in hepatitis C.
Safe Harbor Statement
Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to (i) expectations regarding the timing for commencing patient dosing in the ANA598 Phase IIb study; (ii) the goal of establishing safety and efficacy in a greater number of patients, including those who have failed prior HCV treatment; (iii) the hope to position ANA598 as a highly attractive HCV agent ready for Phase III development; (iv) the scheduled trial design for the Phase IIb study; and (v) Anadys' expectations regarding the timing of receipt of data from the study. Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause Anadys' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements. For example, the results of preclinical and early clinical studies may not be predictive of future results, and Anadys cannot provide any assurances that ANA598 will not have unforeseen safety issues, will have favorable results in ongoing or future clinical trials or will receive regulatory approval. In addition, Anadys' results may be affected by competition from other biotechnology and pharmaceutical companies, its effectiveness at managing its financial resources, its ability to enter into transactions around its product candidates, its ability to successfully develop and market products, difficulties or delays in its non-clinical studies or clinical trials, difficulties or delays in manufacturing its clinical trials materials, the scope and validity of patent protection for its products, regulatory developments and its ability to obtain additional funding to support its operations. Risk factors that may cause actual results to differ are more fully discussed in Anadys' SEC filings, including Anadys' Form 10-Q for the quarter ended September 30, 2010. All forward-looking statements are qualified in their entirety by this cautionary statement. Anadys is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.
Pegasys® and Copegus® are registered trademarks of Hoffman-La Roche Inc.
SOURCE Anadys Pharmaceuticals, Inc.
Source
NYC Department Of Health Releases H.I.V. PSA (GRAPHIC VIDEO)
First Posted: 01- 4-11 10:34 AM
Updated: 01- 4-11 10:34 AM
The NYC Department of Health, which recently has made a name for itself by publicizing startlingly graphic public service announcements, has release a new ad about H.I.V.
The tag is "it's never just H.I.V." and the video, which resembles an NBC drama promo, goes on to explain how the virus can lead to other terrible diseases like osteoporosis or dementia.
But the video, which shows only men and flashes graphic illustrations of broken bones, and even documentation of anal cancer, is striking some as far too aggressive a campaign.
The New York Times reports that the ad is dividing health experts and gay activists alike. Those like Larry Kramer, the founder of the AIDS activist group Act Up, think the commercials are effective. "This ad is honest and true and scary, all of which it should be," he told the Times. "H.I.V. is scary, and all attempts to curtail it via lily-livered nicey-nicey 'prevention' tactics have failed."
Others think the message is exploitative and unnecessarily graphic.
"We know from our longstanding H.I.V. prevention work that portraying gay and bisexual men as dispensing diseases is counterproductive," said Marjorie Hill, chief executive ofGay Men's Health Crisis. "Studies have shown that scare tactics are not effective."
Source
Exhausted by Illness, and Doubts
By DAVID TULLER
Published: January 3, 2011
Chronic fatigue syndrome causes a host of debilitating symptoms: profound exhaustion, disordered sleep, muscle and joint pain and severe cognitive problems, among others. But what causes the syndrome itself
Since the first cases in the United States were identified in the 1980s, scientists have been divided over that question. Some have suspected that one or more viral infections are likely to play a central role.
But many other researchers — not to mention relatives, friends, employers, doctors and insurers of the million or more Americans estimated to suffer from the illness — have dismissed it as stress-related, psychosomatic or simply imaginary.
Now recent back-to-back announcements have highlighted both the volatility of the issue and the ambiguity of the science, and have alternately heartened and dismayed patients.
On Dec. 14, an advisory panel suggested that the Food and Drug Administration ban blood donations by people with a history of C.F.S., as the illness is often called. The goal was to prevent the possible spread of viruses that two high-profile studies had linked to the condition.
But then, on Dec. 20, the journal Retrovirology published four papers suggesting that key findings in those studies could have resulted from laboratory contamination.
The F.D.A. is not required to accept the opinion of its advisory panel. Yet patients still hailed the recommendation as a sign that their illness was being taken seriously.
“When an F.D.A. panel suggests that patients with C.F.S. not donate blood, that’s going to impact the way doctors think about it,” said Mary Schweitzer, a former history professor at Villanova, who has frequently written about living with the illness. Dr. Schweitzer said she has been unable to work for 16 years because of the syndrome, which was diagnosed after she suffered from a series of flulike illnesses.
The studies that concerned the F.D.A. had reported that people with the syndrome, which is also called myalgic encephalomyelitis or myalgic encephalopathy in Europe, showed higher rates of infection with the virus XMRV or others from the same category, known as MLV-related viruses. (These viruses are all relatives of mouse leukemia viruses, some of which can infect species other than mice; their role in human disease, if any, remains poorly understood.)
But several other research teams in the last year have found no connection between chronic fatigue syndrome and these viruses, although none tried to replicate the exact methods used by researchers who reported an association.
The new papers in Retrovirology reported that contamination of tissue samples or other laboratory items with mouse DNA or viral genetic material could lead to false positive results for XMRV, and by extension other MLV-related viruses, specifically when using polymerase chain reaction technology. The technique rapidly produces millions of copies of genetic segments, so even minute traces of genetic contamination can skew results.
“Our conclusion is quite simple: XMRV is not the cause of chronic fatigue syndrome,” said the senior author of one of the studies, Greg Towers, a professor of virology at University College London, in a statement released by Wellcome Trust Sanger Institute, the British research center that co-sponsored it.
Other scientists and advocates for patients have sharply criticized such certainty as unwarranted, noting that the Retrovirology papers themselves expressed their findings in more cautious terms. The critics agree that contamination can be a serious issue when using polymerase chain reaction technology. But the new papers, said Eric Gordon, a doctor in Santa Rosa, Calif., who treats many patients with the illness, do not evaluate other strategies besides P.C.R., as the technique is known, for detecting the MLV-related viruses, like testing for an immune response and culturing the viruses in cell lines.
“The articles make the point that P.C.R. doesn’t work that well for these viruses, and then they act like that disproves the whole idea,” said Dr. Gordon.
XMRV was first identified in 2006 and has been detected in prostate cancer patients in some studies. It was linked to chronic fatigue syndrome in October 2009 in a paper in the journal Science by researchers from the Whittemore Peterson Institute for Neuro-Immune Disease at the University of Nevada, Reno, the National Cancer Institute and the Cleveland Clinic.
The researchers relied on P.C.R. technology to show that about two-thirds of patients but less than 4 percent of control subjects harbored XMRV. Using other technologies, however, they also documented an antibody response in some chronic fatigue syndrome patients, and reported that XMRV in human blood could infect other human cell lines.
In a statement responding to the new papers in Retrovirology, Judy A. Mikovits, director of research at Whittemore Peterson and the senior author of the Science study, said her team took extensive steps to rule out P.C.R. contamination and also focused on other approaches to finding XMRV. “Nothing that has been published to date refutes our data,” she said.
Even some specialists stumbled over the meaning of the new findings. Vincent Racaniello, a professor of microbiology at Columbia not involved in the research, apologized on his Virology Blog for having stated that it was likely to spell “the beginning of the end” for the proposed connection between the viruses and chronic fatigue syndrome.
After reviewing the issue more thoroughly, he wrote, he realized that the new studies “show that identification of XMRV can be fraught with contamination problems, but they do not imply that previously published studies are compromised.” He added, “If I had difficulties interpreting these papers, how would nonscientists fare?”
Federal agencies have come down on different sides of the issue. In a paper published in The Proceedings of the National Academy of Sciences in August, researchers from the National Institutes of Health and the F.D.A. found a link between the fatigue syndrome and MLV-related viruses (although not specifically XMRV). In contrast, a study from the Centers for Disease Control and Prevention was among those not reporting a link.
Federal health officials have organized two research efforts to resolve the inconsistencies, determine whether XMRV and MLV-related viruses are possible human pathogens, and identify reliable ways to detect them. Patients hope the increased attention will quickly lead to research on treatments, including clinical trials of H.I.V. drugs, some of which have been shown in lab studies to inhibit the replication of XMRV.
The unsettled situation has created a quandary for patients with chronic fatigue syndrome and the doctors who treat them. Some patients are seeking to be treated with H.I.V. drugs, which doctors can legally prescribe even though the F.D.A. has not approved them for that purpose.
Many doctors and researchers say it is too early to prescribe the drugs for chronic fatigue because of possible side effects, like bone marrow suppression, gastrointestinal problems and liver or kidney dysfunction, among others. But Michael Allen, a writer and a former psychologist in San Francisco who has been disabled for more than 15 years, said he wouldn’t hesitate to try the medications if he found out he was positive for an MLV-related virus.
“It feels patronizing when the medical establishment says the side effects are too risky and we should keep waiting,” he said. “What that says to me is they have no idea whatsoever how sick people like me have been with this disease.”
Source
Related: The Lingering Mystery of Chronic Fatigue Syndrome
Published: January 3, 2011
Chronic fatigue syndrome causes a host of debilitating symptoms: profound exhaustion, disordered sleep, muscle and joint pain and severe cognitive problems, among others. But what causes the syndrome itself
Since the first cases in the United States were identified in the 1980s, scientists have been divided over that question. Some have suspected that one or more viral infections are likely to play a central role.
But many other researchers — not to mention relatives, friends, employers, doctors and insurers of the million or more Americans estimated to suffer from the illness — have dismissed it as stress-related, psychosomatic or simply imaginary.
Now recent back-to-back announcements have highlighted both the volatility of the issue and the ambiguity of the science, and have alternately heartened and dismayed patients.
On Dec. 14, an advisory panel suggested that the Food and Drug Administration ban blood donations by people with a history of C.F.S., as the illness is often called. The goal was to prevent the possible spread of viruses that two high-profile studies had linked to the condition.
But then, on Dec. 20, the journal Retrovirology published four papers suggesting that key findings in those studies could have resulted from laboratory contamination.
The F.D.A. is not required to accept the opinion of its advisory panel. Yet patients still hailed the recommendation as a sign that their illness was being taken seriously.
“When an F.D.A. panel suggests that patients with C.F.S. not donate blood, that’s going to impact the way doctors think about it,” said Mary Schweitzer, a former history professor at Villanova, who has frequently written about living with the illness. Dr. Schweitzer said she has been unable to work for 16 years because of the syndrome, which was diagnosed after she suffered from a series of flulike illnesses.
The studies that concerned the F.D.A. had reported that people with the syndrome, which is also called myalgic encephalomyelitis or myalgic encephalopathy in Europe, showed higher rates of infection with the virus XMRV or others from the same category, known as MLV-related viruses. (These viruses are all relatives of mouse leukemia viruses, some of which can infect species other than mice; their role in human disease, if any, remains poorly understood.)
But several other research teams in the last year have found no connection between chronic fatigue syndrome and these viruses, although none tried to replicate the exact methods used by researchers who reported an association.
The new papers in Retrovirology reported that contamination of tissue samples or other laboratory items with mouse DNA or viral genetic material could lead to false positive results for XMRV, and by extension other MLV-related viruses, specifically when using polymerase chain reaction technology. The technique rapidly produces millions of copies of genetic segments, so even minute traces of genetic contamination can skew results.
“Our conclusion is quite simple: XMRV is not the cause of chronic fatigue syndrome,” said the senior author of one of the studies, Greg Towers, a professor of virology at University College London, in a statement released by Wellcome Trust Sanger Institute, the British research center that co-sponsored it.
Other scientists and advocates for patients have sharply criticized such certainty as unwarranted, noting that the Retrovirology papers themselves expressed their findings in more cautious terms. The critics agree that contamination can be a serious issue when using polymerase chain reaction technology. But the new papers, said Eric Gordon, a doctor in Santa Rosa, Calif., who treats many patients with the illness, do not evaluate other strategies besides P.C.R., as the technique is known, for detecting the MLV-related viruses, like testing for an immune response and culturing the viruses in cell lines.
“The articles make the point that P.C.R. doesn’t work that well for these viruses, and then they act like that disproves the whole idea,” said Dr. Gordon.
XMRV was first identified in 2006 and has been detected in prostate cancer patients in some studies. It was linked to chronic fatigue syndrome in October 2009 in a paper in the journal Science by researchers from the Whittemore Peterson Institute for Neuro-Immune Disease at the University of Nevada, Reno, the National Cancer Institute and the Cleveland Clinic.
The researchers relied on P.C.R. technology to show that about two-thirds of patients but less than 4 percent of control subjects harbored XMRV. Using other technologies, however, they also documented an antibody response in some chronic fatigue syndrome patients, and reported that XMRV in human blood could infect other human cell lines.
In a statement responding to the new papers in Retrovirology, Judy A. Mikovits, director of research at Whittemore Peterson and the senior author of the Science study, said her team took extensive steps to rule out P.C.R. contamination and also focused on other approaches to finding XMRV. “Nothing that has been published to date refutes our data,” she said.
Even some specialists stumbled over the meaning of the new findings. Vincent Racaniello, a professor of microbiology at Columbia not involved in the research, apologized on his Virology Blog for having stated that it was likely to spell “the beginning of the end” for the proposed connection between the viruses and chronic fatigue syndrome.
After reviewing the issue more thoroughly, he wrote, he realized that the new studies “show that identification of XMRV can be fraught with contamination problems, but they do not imply that previously published studies are compromised.” He added, “If I had difficulties interpreting these papers, how would nonscientists fare?”
Federal agencies have come down on different sides of the issue. In a paper published in The Proceedings of the National Academy of Sciences in August, researchers from the National Institutes of Health and the F.D.A. found a link between the fatigue syndrome and MLV-related viruses (although not specifically XMRV). In contrast, a study from the Centers for Disease Control and Prevention was among those not reporting a link.
Federal health officials have organized two research efforts to resolve the inconsistencies, determine whether XMRV and MLV-related viruses are possible human pathogens, and identify reliable ways to detect them. Patients hope the increased attention will quickly lead to research on treatments, including clinical trials of H.I.V. drugs, some of which have been shown in lab studies to inhibit the replication of XMRV.
The unsettled situation has created a quandary for patients with chronic fatigue syndrome and the doctors who treat them. Some patients are seeking to be treated with H.I.V. drugs, which doctors can legally prescribe even though the F.D.A. has not approved them for that purpose.
Many doctors and researchers say it is too early to prescribe the drugs for chronic fatigue because of possible side effects, like bone marrow suppression, gastrointestinal problems and liver or kidney dysfunction, among others. But Michael Allen, a writer and a former psychologist in San Francisco who has been disabled for more than 15 years, said he wouldn’t hesitate to try the medications if he found out he was positive for an MLV-related virus.
“It feels patronizing when the medical establishment says the side effects are too risky and we should keep waiting,” he said. “What that says to me is they have no idea whatsoever how sick people like me have been with this disease.”
Source
Related: The Lingering Mystery of Chronic Fatigue Syndrome
Hepatitis A warning issued for those who received Communion on Christmas at N.Y. church
By Mary Forgione
Tribune Health
January 4, 2011, 12:21 p.m.
Communion and hepatitis A are rarely mentioned in the same sentence. But health officials in New York are concerned that parishioners at a Long Island church who took Communion on Christmas Day may have been exposed to hepatitis A. Church-goers in attendance that day are being urged to get a hepatitis A vaccine shot.
A statement issued Monday by the Nassau County Health Department to Our Lady of Lourdes Church in Massapequa Park said: "Individuals may be at risk if they received Communion during the 10:30 a.m. and 12 noon masses on December 25, 2010."
Hepatitis A is a virus transmitted by eating or drinking something that has been contaminated with the feces of an infected person. It’s rarely fatal, unlike other forms -- Hepatitis C in particular -- of the liver disease.
Here are symptoms to look for from the Centers for Disease Control and Prevention: fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, clay-colored bowel movements, joint pain and jaundice.
And the treatment? There really isn't any, though some who become dehydrated from nausea or vomiting may require hospitalization. Read more from the CDC about hepatitis A. And the Foundation for Digestive Health and Nutrition explains the different forms of hepatitis here.
Now, don't let any of this be an excuse to skip church.
Source
Tribune Health
January 4, 2011, 12:21 p.m.
Communion and hepatitis A are rarely mentioned in the same sentence. But health officials in New York are concerned that parishioners at a Long Island church who took Communion on Christmas Day may have been exposed to hepatitis A. Church-goers in attendance that day are being urged to get a hepatitis A vaccine shot.
A statement issued Monday by the Nassau County Health Department to Our Lady of Lourdes Church in Massapequa Park said: "Individuals may be at risk if they received Communion during the 10:30 a.m. and 12 noon masses on December 25, 2010."
Hepatitis A is a virus transmitted by eating or drinking something that has been contaminated with the feces of an infected person. It’s rarely fatal, unlike other forms -- Hepatitis C in particular -- of the liver disease.
Here are symptoms to look for from the Centers for Disease Control and Prevention: fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, clay-colored bowel movements, joint pain and jaundice.
And the treatment? There really isn't any, though some who become dehydrated from nausea or vomiting may require hospitalization. Read more from the CDC about hepatitis A. And the Foundation for Digestive Health and Nutrition explains the different forms of hepatitis here.
Now, don't let any of this be an excuse to skip church.
Source
EU drugs agency launches new guidelines for HIV testing in injecting drug users
Download the PDF here
Guidelines for testing HIV, viral hepatitis and other infections in injecting drug users
A manual for provider-initiated medical examination,
testing and counselling
EMCDDA, Lisbon, November/December 2010, Source: European Monitoring Centre for Drugs and Drug Addiction
EMCDDA: European Monitoring Centre for Drugs and Drug Addiction ...
Aims to provide reliable information on drugs and drug addiction in the EU. Provides online reports databases about drug usage and anti-drug programs. www.emcdda.europa.eu/
EMCDDA, your reference point on drugs in Europe
The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) was established in 1993. Inaugurated in Lisbon in 1995, it is one of the EU's decentralised agencies.
The EMCDDA exists to provide the EU and its Member States with a factual overview of European drug problems and a solid evidence base to support the drugs debate. Today it offers policymakers the data they need for drawing up informed drug laws and strategies. It also helps professionals and practitioners working in the field pinpoint best practice and new areas of research.
"The EMCDDA estimates that 30Ð50% of HIV positive IDUs in Europe are unaware of being infected. It also estimates that around 50% of IDUs (varying between countries from 10% to 90%) are infected with viral hepatitis (notably hepatitis C), which can lead to severe liver disease and premature death."
More injecting drug users should undergo tests for HIV, viral hepatitis and other infections such as tuberculosis, says the EU drugs agency (EMCDDA). In new guidelines published today on the eve of World AIDS Day, the agency describes how, in this group, the uptake of testing is still low in many European countries (1).
Infectious diseases are among the most serious health consequences of injecting drug use and can lead to significant healthcare costs. The new guidelines recommend a strategy to increase testing uptake, both in Europe and beyond, that would ensure earlier treatment for injecting drug users (IDUs) and would lower the risk of infection spreading to the wider population.
IDUs are vulnerable to a range of infectious diseases due to a variety of risk behaviours and underlying conditions, such as poor hygiene, homelessness and poverty. The EMCDDA estimates that 30Ð50% of HIV positive IDUs in Europe are unaware of being infected. It also estimates that around 50% of IDUs (varying between countries from 10% to 90%) are infected with viral hepatitis (notably hepatitis C), which can lead to severe liver disease and premature death.
Commenting today, EMCDDA Director Wolfgang Gštz said: 'It is crucial that those infected are aware of their condition so that they can protect their partners and access the appropriate care and treatment. We encourage service providers and healthcare professionals to take a more proactive approach and ensure that clients at the highest risk of contracting drug-related infections are offered testing on a regular basis. Until now, timely diagnosis and treatment of infectious diseases has often been too low a priority among professionals in contact with drug users'.
Today's manual provides guidance at a practical level, proposing a series of standard tests to be undertaken regularly on a voluntary and informed basis. Among these are serology tests for HIV, hepatitis (A, B, C, D) and other sexually transmitted infections; general blood tests; and tests for tuberculosis. For high-risk IDUs, these tests should be considered annually, or even bi-annually. The guidelines also offer a package of prevention, primary care and referral routines in relation to IDUs and infections.
The guidelines recommend that health providers initiate examination, testing and counselling in IDUs in a variety of healthcare settings (e.g. primary healthcare; special health services for IDUs; low-threshold service centres visited by IDUs; rehabilitation centres; dedicated sexually transmitted infections clinics and prison healthcare facilities). Developed in collaboration with European experts on drug-related infectious diseases, the guidelines are now being distributed across the European Union and globally. They are intended to be of use to thousands of service providers, and may potentially benefit hundreds of thousands of IDUs.
Summary:
Infectious diseases are among the most serious health consequences of injecting drug use and can lead to significant healthcare costs. Injecting drug users are vulnerable to a range of infectious and communicable diseases through a variety of risk behaviours, and because of underlying conditions such as poor hygiene, homelessness and poverty. There is a recognised need for guidance on providing IDUs with a medical examination and testing for HIV, viral hepatitis and several other infections on a regular basis. In addition, improving testing uptake in this group would benefit epidemiological surveillance and monitoring as carried out at the national and international level.
These guidelines are accompanied by a recommended package of prevention and primary care in relation to injecting drug users and infections. Treatment and other specialist care are not discussed in detail but are dealt with by indicating referral to appropriate services.
A thorough medical examination, testing and counselling of IDUs should include:
testing for infections;
post-test counselling;
prevention counselling;
Basic recommended tests
The tests that should be included in a standard offer to all IDUs in provider-initiated routine
medical examinations are-
Serology testing for:
· HIV
· hepatitis A
· hepatitis B
· hepatitis C
· hepatitis D (if evidence of chronic or recent hepatitis B);
· syphilis.
Hepatitis C
When to refer: All IDUs with a positive antibody test and a positive PCR should be followed up by a repeated test after three to six months, and if the test is still positive, should be considered for eradication therapy. Liver function status is important in the evaluation of the need for medication therapy.
Specific guidelines exist for the treatment of hepatitis C at national and European level (Hepatol, 1999). It is important to note that although some guidelines still exclude active IDUs or IDUs on opioid substitution treatment from viral treatment, study results indicate that IDUs can be successfully treated and may avoid reinfection (Hepatol, 1999; Reimer et al., 2005).
Training and ongoing supervision and monitoring of healthcare providers carrying out routine medical examination, testing and counselling with IDUs is required for the successful implementation of the service. Training programmes for personnel should be developed
Source
Guidelines for testing HIV, viral hepatitis and other infections in injecting drug users
A manual for provider-initiated medical examination,
testing and counselling
EMCDDA, Lisbon, November/December 2010, Source: European Monitoring Centre for Drugs and Drug Addiction
EMCDDA: European Monitoring Centre for Drugs and Drug Addiction ...
Aims to provide reliable information on drugs and drug addiction in the EU. Provides online reports databases about drug usage and anti-drug programs. www.emcdda.europa.eu/
EMCDDA, your reference point on drugs in Europe
The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) was established in 1993. Inaugurated in Lisbon in 1995, it is one of the EU's decentralised agencies.
The EMCDDA exists to provide the EU and its Member States with a factual overview of European drug problems and a solid evidence base to support the drugs debate. Today it offers policymakers the data they need for drawing up informed drug laws and strategies. It also helps professionals and practitioners working in the field pinpoint best practice and new areas of research.
"The EMCDDA estimates that 30Ð50% of HIV positive IDUs in Europe are unaware of being infected. It also estimates that around 50% of IDUs (varying between countries from 10% to 90%) are infected with viral hepatitis (notably hepatitis C), which can lead to severe liver disease and premature death."
More injecting drug users should undergo tests for HIV, viral hepatitis and other infections such as tuberculosis, says the EU drugs agency (EMCDDA). In new guidelines published today on the eve of World AIDS Day, the agency describes how, in this group, the uptake of testing is still low in many European countries (1).
Infectious diseases are among the most serious health consequences of injecting drug use and can lead to significant healthcare costs. The new guidelines recommend a strategy to increase testing uptake, both in Europe and beyond, that would ensure earlier treatment for injecting drug users (IDUs) and would lower the risk of infection spreading to the wider population.
IDUs are vulnerable to a range of infectious diseases due to a variety of risk behaviours and underlying conditions, such as poor hygiene, homelessness and poverty. The EMCDDA estimates that 30Ð50% of HIV positive IDUs in Europe are unaware of being infected. It also estimates that around 50% of IDUs (varying between countries from 10% to 90%) are infected with viral hepatitis (notably hepatitis C), which can lead to severe liver disease and premature death.
Commenting today, EMCDDA Director Wolfgang Gštz said: 'It is crucial that those infected are aware of their condition so that they can protect their partners and access the appropriate care and treatment. We encourage service providers and healthcare professionals to take a more proactive approach and ensure that clients at the highest risk of contracting drug-related infections are offered testing on a regular basis. Until now, timely diagnosis and treatment of infectious diseases has often been too low a priority among professionals in contact with drug users'.
Today's manual provides guidance at a practical level, proposing a series of standard tests to be undertaken regularly on a voluntary and informed basis. Among these are serology tests for HIV, hepatitis (A, B, C, D) and other sexually transmitted infections; general blood tests; and tests for tuberculosis. For high-risk IDUs, these tests should be considered annually, or even bi-annually. The guidelines also offer a package of prevention, primary care and referral routines in relation to IDUs and infections.
The guidelines recommend that health providers initiate examination, testing and counselling in IDUs in a variety of healthcare settings (e.g. primary healthcare; special health services for IDUs; low-threshold service centres visited by IDUs; rehabilitation centres; dedicated sexually transmitted infections clinics and prison healthcare facilities). Developed in collaboration with European experts on drug-related infectious diseases, the guidelines are now being distributed across the European Union and globally. They are intended to be of use to thousands of service providers, and may potentially benefit hundreds of thousands of IDUs.
Summary:
Infectious diseases are among the most serious health consequences of injecting drug use and can lead to significant healthcare costs. Injecting drug users are vulnerable to a range of infectious and communicable diseases through a variety of risk behaviours, and because of underlying conditions such as poor hygiene, homelessness and poverty. There is a recognised need for guidance on providing IDUs with a medical examination and testing for HIV, viral hepatitis and several other infections on a regular basis. In addition, improving testing uptake in this group would benefit epidemiological surveillance and monitoring as carried out at the national and international level.
These guidelines are accompanied by a recommended package of prevention and primary care in relation to injecting drug users and infections. Treatment and other specialist care are not discussed in detail but are dealt with by indicating referral to appropriate services.
A thorough medical examination, testing and counselling of IDUs should include:
testing for infections;
post-test counselling;
prevention counselling;
Basic recommended tests
The tests that should be included in a standard offer to all IDUs in provider-initiated routine
medical examinations are-
Serology testing for:
· HIV
· hepatitis A
· hepatitis B
· hepatitis C
· hepatitis D (if evidence of chronic or recent hepatitis B);
· syphilis.
Hepatitis C
When to refer: All IDUs with a positive antibody test and a positive PCR should be followed up by a repeated test after three to six months, and if the test is still positive, should be considered for eradication therapy. Liver function status is important in the evaluation of the need for medication therapy.
Specific guidelines exist for the treatment of hepatitis C at national and European level (Hepatol, 1999). It is important to note that although some guidelines still exclude active IDUs or IDUs on opioid substitution treatment from viral treatment, study results indicate that IDUs can be successfully treated and may avoid reinfection (Hepatol, 1999; Reimer et al., 2005).
Training and ongoing supervision and monitoring of healthcare providers carrying out routine medical examination, testing and counselling with IDUs is required for the successful implementation of the service. Training programmes for personnel should be developed
Source
Insulin resistance predicts re-treatment failure in an efficacy study of peginterferon-α-2a and ribavirin in HIV/HCV co-infected patients
Download the PDF here
Jnl of Hepatology Dec 2010
"Baseline IR (insulin resistance) was strongly associated with virological response. This study demonstrates that a proportion of HIV/HCV co-infected patients respond to HCV re-treatment. The best outcome is achieved in patients with baseline HOMA-IRφ2. Calculating baseline HOMA-IR may be a useful tool when considering re-treatment. Future studies are needed to confirm these findings and determine if improvement of HOMA-IR prior to starting HCV therapy increases SVR rates. The impact of IR on SVR requires further study in patients receiving direct-acting antiviral agents as they are soon to become part of standard HCV treatment......This is the largest prospective study of HCV re-treatment in the population of HIV/HCV co-infected patients conducted so far. In this study, re-treatment with pegIFN-α-2a plus weight-based RBV led to a SVR rate of 15%. The strongest predictor of failure to achieve SVR was IR and the highest SVR rate of 35% was in patients with HOMA-IR<2. This is the first study to examine IR as a possible predictor of SVR during re-treatment of HIV/HCV co-infected patients. IR appears to predict SVR better than steatosis or cirrhosis. As such, these data provide important insight into the management of hepatitis C in co-infected persons who failed to respond to prior therapy."
From Jules of NATAP: At AASLD Vertex reported insulin resistance did not impact SVR, I would feel more comfortable with this finding in monoinfection after a study in coinfection:
No Impact of Insulin Resistance on Antiviral Efficacy of ...
Nov 3, 2010 ... No Impact of Insulin Resistance on Antiviral Efficacy of Telaprevir-based Regimen in HCV Genotype 1 Treatment-naïve Patients: Subanalysis of ...
www.natap.org/2010/AASLD/AASLD_76.htm
Marie-Louise C. Vachon 1 Corresponding Author Information email address, Stephanie H. Factor 2, Andrea D. Branch 1, Maria-Isabel Fiel 3, Maribel Rodriguez-Torres 4, Norbert BrŠu 5 6, Richard K. Sterling 7, Jihad Slim 8, Andrew H. Talal 9, Douglas T. Dieterich 1, Mark S. Sulkowski 10
1 Division of Liver Diseases, Mount Sinai School of Medicine, NY, USA
2 Division of Infectious Diseases, Mount Sinai School of Medicine, NY, USA
3 Department of Pathology, Mount Sinai School of Medicine, NY, USA
4 Fundacion de Investigacion de Diego, San Juan, PR, USA
5 Divisions of Infectious Diseases and Liver Diseases, Mount Sinai School of Medicine, NY, USA
6 Veterans Affairs Medical Center, Bronx, NY, USA
7 Division of Liver Diseases, Virginia Commonwealth University Health Systems, Richmond, VA, USA
8 Division of Infectious Diseases, St-Michael's Medical Center, NY, USA
9 Division of Gastroenterology and Hepatology and Center for the Study of Hepatitis C, Weill Cornell Medical College, NY, USA
10 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MA, USA
Background & Aims
Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology.
Methods
This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48weeks. Serum HCV RNA was measured 24weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR>2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined.
Results
Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR<2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA-IR between 2-4, and 7% (3/41) of those with HOMA-IR>4 (p=0.01). In multivariable analysis, insulin resistance and log10 HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05-0.64, p=0.009, and AOR 0.36; 95% CI 0.14-0.93, p=0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p=0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes.
Conclusions
In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response.
Abbreviations: HIV, human immunodeficiency virus, HCV, hepatitis C virus, HRN, hepatitis Resource Network, HCV RNA, hepatitis C virus ribonucleic acid, HOMA-IR, homeostasis model of assessment of insulin resistance, AOR, adjusted odds ratio, CI, confidence interval, HCC, hepatocellular carcinoma, SVR, sustained virological response, PegIFN, pegylated interferon, RBV, ribavirin, IR, insulin resistance, IFN, interferon, HIV RNA, human immunodeficiency virus ribonucleic acid, ART, antiretroviral therapy, ULN, upper limit of normal, Hb, hemoglobin, HbA1c, hemoglobin A1c, TSH, thyroid-stimulating hormone, pEVR, partial early virological response, cEVR, complete early virological response, EOT, end of treatment, IRB, institutional review board, HAI, histology activity index, BMI, body mass index, IQR, interquartile range, OR, odds ratio, SAE, severe adverse event, RVR, rapid virological response, ACTG, AIDS Clinical Trials Group, SOCS3, suppressor of cytokine signaling 3, IRS-1, insulin receptor substrate 1, STAT-1, signal transducers and activators of transcription 1
Introduction
Co-infection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) affects an estimated 10 million people worldwide. HCV-related liver disease is now a leading cause of death among HIV-infected patients [1], [2]. Successful treatment of HCV is associated with reduced liver-related complications, including liver decompensation, hepatocellular carcinoma (HCC), and liver-related mortality [3], [4].
The goal of HCV treatment is to achieve sustained virological response (SVR), defined as undetectable serum HCV RNA 24weeks after the end of treatment. The current standard of care is 48weeks of peginterferon-α (pegIFN) and ribavirin (RBV; fixed dose for HCV genotypes 2 and 3, and weight-based for HCV genotypes 1 and 4). However, SVR is achieved in less than half of HIV/HCV co-infected patients in both initial and re-treatment of HCV. In initial HCV treatment, the combination of pegIFN and weight-based RBV has lead to SVR in 22-35% of patients with HCV genotypes 1 and 4 [5], [6] and 53-72% of patients with HCV genotypes 2 and 3 [6], [7]. Despite the high rate of failure of initial HCV treatment regimens, few studies have been done on re-treatment of HCV in co-infected non-responders. The studies that have been published were small and reported overall SVR rates of 16-31% [8], [9], [10], [11]. In addition, predictors of SVR in re-treatment have not been well studied.
HIV/HCV co-infected patients, who had failed to respond to a previous course of HCV treatment, were enrolled in an open-label, phase IIIb study (Hepatitis Resource Network (HRN)-004) to evaluate safety, tolerability, and efficacy of pegIFN-α-2a and RBV in re-treatment. In addition, we prospectively evaluated predictors of SVR including baseline insulin resistance (IR). Finally, we examined the relationship between baseline IR and liver histology (steatosis and cirrhosis).
Discussion
This is the largest prospective study of HCV re-treatment in the population of HIV/HCV co-infected patients conducted so far. In this study, re-treatment with pegIFN-α-2a plus weight-based RBV led to a SVR rate of 15%. The strongest predictor of failure to achieve SVR was IR and the highest SVR rate of 35% was in patients with HOMA-IR<2. This is the first study to examine IR as a possible predictor of SVR during re-treatment of HIV/HCV co-infected patients. IR appears to predict SVR better than steatosis or cirrhosis. As such, these data provide important insight into the management of hepatitis C in co-infected persons who failed to respond to prior therapy.
Non-response to HCV treatment is common in HIV/HCV co-infected patients treated with pegIFN and RBV. Our population had a high prevalence of factors known to predict non-response to HCV treatment. Specifically, there was a high prevalence of men, African American race, Latino ethnicity, prior treatment non-responders as opposed to relapsers, HCV genotype 1 infection, high HCV RNA levels, steatosis, cirrhosis, and IR.
Baseline IR was strongly associated with virological response. These data are consistent with prior retrospective studies at the initial course of HCV treatment in co-infected patients. Among 238 co-infected patients treated with pegIFN-α-2b and RBV, Cacoub and colleagues reported that a HOMA-IR score>2.5 was a negative predictor of SVR [17]. In a cohort of 134 co-infected patients, Ryan et al. similarly reported that a HOMA-IR score >3.8 was a negative predictor of SVR [18]. A third retrospective study of 74 HIV/HCV co-infected patients reported that a HOMA-IR >3.0 was a negative predictor of rapid virological response (RVR) [19]. RVR is achieved when serum HCV RNA is below the limit of detection at week 4 and is a known correlate of SVR [20]. One study found that IR was not associated with response to pegIFN (α-2a and α-2b) and RBV in treatment-naive HIV/HCV co-infected patients [21]. However the results appeared to show a negative dose-response relationship between baseline HOMA-IR score and SVR rate. These results may be explained by differences in patient samples, in terms of both sample size and patient characteristics. The patients in the study by Merchante et al. were younger (median age 40 vs 48years), had lower BMI scores (median 22.9 vs 25.8), and were all Caucasians (100% vs 28% of our patients). Furthermore, they were HCV treatment naïve, had less advanced liver disease (15% cirrhosis vs 27% of our patients), and a lower prevalence of IR. Twenty-nine percent had HOMA-IR scores>4, compared to 44% in our population.
In our study, co-infected patients with HOMA-IR<2 had a SVR rate of 35% compared to 7-14% in those with higher scores. The 35% SVR rate in patients with HOMA-IR<2 is equivalent to SVR rates achieved in the HIV/HCV co-infected patients undergoing initial treatment. This suggests that calculation of HOMA-IR prior to treatment may improve the estimate of treatment response.
In HCV mono-infected patients, recent studies evaluated the impact of insulin sensitizing agents on SVR at the time of starting pegIFN and RBV treatment in patients with IR. Two showed positive results in defined populations [22], [23], one did not [24]. An ongoing study using pioglitazone prior to pegIFN and RBV therapy is being conducted in HIV/HCV co-infected patients with IR who were non-responders to prior HCV treatment (ACTG 5239).
There is biological data supporting the association between IR and treatment response. Insulin diminishes the ability of IFN to inhibit HCV replication in a replicon model at insulin levels similar to those seen in patients with IR [25]. Elevated levels of suppressor of cytokine signaling 3 (SOCS3) in liver biopsies predict IFN treatment failure [26], [27], [28]. Some evidence suggests that SOCS3 down-regulates both insulin receptor substrate 1 (IRS-1), a key component of the insulin signaling pathway [29], and signal transducers and activators of transcription 1 (STAT1), a key component of IFN signaling [30]. This literature suggests that induction of SOCS3, which is reported to occur in cells carrying the HCV core gene [29], [30], might contribute to both IR and IFN treatment failure in patients.
Our statistical models suggest that IR is more significantly associated with response to HCV re-treatment in HIV-infected patients than is steatosis or cirrhosis. Similar to previous studies, this study demonstrates a correlation between IR and both steatosis and cirrhosis [31], [32]. Previous studies have found steatosis and cirrhosis to be negative predictors of response to HCV treatment in some patient populations [32], [33], [34], [35], [36]. The correlation between IR and steatosis/cirrhosis and their ability to negatively predict treatment response suggest all three may be markers of pathologic changes along a common pathway. With our current technology, IR is the only measure which does not require an invasive procedure and is therefore feasible for widespread use.
While we found baseline HCV RNA to be statistically associated with SVR, we did not find HCV genotype to be associated with SVR. This is not consistent with prior studies [10], [11]. In the study by Labarga et al., HCV genotypes 2 and 3 infection was significantly associated with SVR compared to HCV genotypes 1 and 4, as was RBV plasma trough concentrations at week 4 [11]. The high prevalence of HCV genotype 1 compared to HCV genotypes 2 and 3 in this study may have prevented our ability to find associations. It is also possible that HCV genotype, while a significant predictor of treatment success for initial treatment of HIV/HCV co-infected patients, may not be as significant of a predictor during re-treatment. The low prevalence of patients with prior HCV relapse compared to HCV non-responders is also likely responsible for the lack of association with SVR in this study. However, prior small studies of re-treatment in the population of HIV/HCV co-infected patients have not found prior relapse vs non-response to be significantly associated with SVR [8], [10], [11].
Previous studies on predictors of SVR have often included EVR and total dose of pegIFN and/or RBV as predictors in their univariable and multivariable analyses; we did not. Because EVR almost always (98-100%) predicts SVR, EVR is likely along the causal pathway to SVR and therefore a measure of outcome not exposure. PegIFN-α-2a and weight-based RBV were given to all participants up to week 20 and virological status at week 20 determined further treatment. Thus, the total dose of pegIFN-α-2a and RBV was, in part, determined by the risk factors at baseline. Similar to EVR, medication dose in this study is a measure of outcome.
This study, with numerous strengths, expands the current literature but has some limitations. The most important strength is the prospective collection of data using standardized tools. Our study is limited by its sample size and the homogeneity of the patients in sex, age, and HCV genotype. The homogeneity of the population, especially the high prevalence of patients with HCV genotype 1 infection and HOMA-IR above 2, may have contributed to the strong relationship we found between baseline IR and SVR in this study. At the time the study was conducted, IL28B polymorphisms analyses were not performed. This information may have influenced our study results.
This study demonstrates that a proportion of HIV/HCV co-infected patients respond to HCV re-treatment. The best outcome is achieved in patients with baseline HOMA-IRφ2. Calculating baseline HOMA-IR may be a useful tool when considering re-treatment. Future studies are needed to confirm these findings and determine if improvement of HOMA-IR prior to starting HCV therapy increases SVR rates. The impact of IR on SVR requires further study in patients receiving direct-acting antiviral agents as they are soon to become part of standard HCV treatment.
Patients and methods
Patients
Patients were recruited at 10 centers in the United States from August 2002 to June 2005. Eligible patients were co-infected with HIV and HCV and had either relapsed or not responded to prior IFN-based treatment. Chronic HCV infection was defined as a positive HCV antibody test for at least 6months and detectable serum HCV RNA. HIV-related criteria included patients with either (i) CD4+ T-cell count<100 cells/mm3 and HIV RNA level<25,000IU/ml, or (ii) CD4+ T count100 cells/mm3 and any HIV viral load. Patients were required to be on stable antiretroviral therapy (ART) or off ART for at least 4weeks prior to the screening visit. Prior IFN-based treatment was defined as IFN-α monotherapy or IFN-α and RBV combination therapy administered for at least 12weeks and discontinued for at least 4weeks before the screening visit. Prior non-response was defined as a <2-log10 decrease in HCV RNA at week 12 or detectable HCV RNA at week 24 during HCV treatment. Prior relapse was defined as detectable HCV RNA after cessation of treatment in a patient who had undetectable HCV RNA at the end of treatment. A liver biopsy showing features consistent with chronic HCV infection was required within 18months prior to study entry.
Exclusion criteria were decompensated liver disease (ascites, bleeding varices, or encephalopathy), other causes of liver disease (steatosis and steatohepatitis were not excluded), prothrombin time3 s, bilirubin>20% above the ULN, albumin<3.0g/dl, hemoglobin (Hb)φ11g/dl, white blood cell countφ3000/mm3, absolute neutrophil countφ1250/mm3, platelet countφ70,000/mm3, fasting blood glucose>115mg/dl in non-diabetic patients, HbA1c>8.5% in diabetic patients, serum creatinine1.5mg/dl, abnormal TSH value, alpha-fetoprotein100ng/ml, hemoglobinopathies, alcohol and/or drug abuse within 1year of entry (active intravenous drug users were excluded), severe psychiatric disease, hypersensitivity to IFN or RBV, pregnancy or breastfeeding, and persons unwilling to use contraception during the study period.
Results
Baseline characteristics
Of the 102 patients enrolled, 6 did not receive study medication and 96 were included in the study (Table 1). Median age was 48years (Interquartile range (IQR)=44-53). The group was 84% male, 42% Latino, 29% African American, and 28% Caucasian. Of the 96 patients, 81 (85%) were infected with HCV genotype 1. Twenty-one (22%) patients had a past history of intravenous drug use and none were active users.
Of the 94 patients with available baseline fasting insulin and glucose levels, 77 (82%) had a HOMA-IR>2; 36 (38%) had a HOMA-IR between 2 and 4; and 41 (44%) had a HOMA-IR>4. Steatosis was present in 53 (55%) of the liver biopsies and cirrhosis was present in 26 (27%). Of the 96 patients, 92 (96%) had a CD4+ T-cell count >200, 81 (84%) were on ART and 67 (70%) had undetectable HIV RNA.
Efficacy outcomes
Of the 96 patients who received at least one dose of the study drug, 37 (39%) experienced EVR. Twelve (13%) had pEVR and 25 (26%) had cEVR. An EOT response was achieved in 30 (31%) patients and SVR was achieved in 14 (15%) (Fig. 1). The negative predictive value of EVR to achieve SVR was 100%. The positive predictive value of EVR (partial and complete) to achieve SVR was 38%.
In the univariable analyses of possible predictors of SVR, IR was negatively associated with SVR [odds ratio (OR) 0.21; 95% CI 0.06-0.73, p=0.02] (Table 1). In multivariable logistic regression, IR and baseline log10 HCV RNA were negatively associated with SVR [adjusted odds ratio (AOR) 0.17; 95% CI 0.05-0.64, p=0.009, and AOR 0.36; 95% CI 0.14-0.93, p=0.04, respectively]. The interaction between IR and HCV RNA was not significant.
A sub-analysis including only patients with HCV genotype 1 infection (n=81) was performed. Out of 81 patients, 10 (12%) achieved SVR. In multivariable analysis, HOMA-IR>2 was the only independent negative predictor of SVR (AOR 0.16; 95% CI 0.04-0.67, p=0.01). The African American race and Latino ethnicity were correlated with the presence of IR, but were not significant predictors of SVR when analyzed in the multivariable model.
Role of baseline IR and SVR
The matched, nested case-control analysis included 81 patients, with 14 cases matched to between 1 and 6 controls. In both univariable and multivariable analyses, IR was negatively associated with SVR (AOR 0.13; 95% CI 0.03-0.55, p=0.006).
When looking at SVR in relation to the HOMA-IR score divided into 3 categories,<2, 2-4, and >4, there was a significant negative dose-response relationship between percent SVR and HOMA-IR: 35% (6/17) in HOMA-IR<2, 14% (5/36) in HOMA-IR between 2 and 4, and 7% (3/41) in HOMA-IR>4 (p=0.01, chi-square test for trend) (Fig. 2).
Relationship between baseline IR and liver histology
IR was correlated with steatosis (r=0.22, p=0.02) and cirrhosis (r=0.23, p=0.03). Steatosis was present in 47/77 (61%) patients with IR, compared to 5/17 (29%) patients without IR (p=0.02). Cirrhosis was present in 25/77 (32%) patients with IR, compared to 1/17 (6%) patients without IR (p=0.03). When looking at the HOMA-IR score divided into 3 categories, <2, 2-4, and >4, there was a positive dose-response relationship between both percent steatosis and HOMA-IR (p=0.02, chi-square test for trend), and percent cirrhosis and HOMA-IR (p=0.03, chi-square test for trend) (Fig. 3).
Using the multivariable logistic regression models with SVR as the outcome, log10 HCV RNA as a covariate, and steatosis or cirrhosis substituted in for IR, the models for steatosis and cirrhosis had larger -2log likelihood values indicating that these models were less precise in predicting SVR (Table 2).
A sub-analysis including only patients without cirrhosis (n=70) was performed. Out of 70 patients without cirrhosis, 13 (19%) achieved SVR. In multivariable analysis, HOMA-IR>2 was negatively associated with SVR (AOR 0.22; 95% CI 0.06-0.89, p=0.03). Baseline log10 HCV RNA was also significantly associated with SVR (AOR 0.37; 95% CI 0.14-0.98, p=0.046) in this analysis.
Safety and tolerability
The most common adverse events were cytopenias. Anemia with Hb<10g/dl occurred in 13 (14%) patients and severe anemia (Hb<8.5) occurred in 3 (3%). A neutrophil count<750/mm3 occurred in 74 (77%) and a neutrophil count<500/mm3 occurred in 48 (50%). A platelet count<50,000cells/mm3 occurred in 5 (5%) patients. RBV dose reduction was required in 18 (19%) patients during treatment, most frequently due to anemia. PegIFN-α-2a dose reduction was required in 25 patients (26%) during treatment, most frequently due to neutropenia. There were no incidents of opportunistic infections, episodes of hepatic decompensation, or development of HCC. There were two deaths in the study patients both of which were unrelated to study medications.
Overall, 23 (24%) patients discontinued treatment. Thirteen discontinuations were due to adverse events. There were 8 discontinuations due to severe adverse events (SAEs), all within the first 24weeks (3 severe anemia, 2 suicidal ideation, 1 hyperglycemia, 1 diarrhea and fever, and 1 rhabdomyolysis).
Study design
Patients received 180μg pegIFN-α-2a subcutaneously every week plus weight-based RBV (Pegasys® and Copegus®, Roche Laboratory, Nutley, NJ, USA), regardless of HCV genotype (800mg/day for <65kg; 1000mg/day for 65kg and φ85kg; 1200mg/day for>85kg). A complete medical history, physical examination, and laboratory tests were taken at the baseline visit. Additional data were collected at weeks 2, 4, 8, 12, 16, 20, 24, 36, and 48 during treatment and 24weeks after the end of treatment. Unlike traditional treatment, patients who did not achieve a 2-log10 drop in HCV RNA at week 12 did not discontinue treatment. The decision to discontinue treatment was made at week 24 based on the week 20 HCV RNA result. Patients with a detectable HCV RNA level at week 20 were considered treatment failures and were diverted to a maintenance study arm to be discussed elsewhere. Patients with undetectable HCV RNA at week 20 were continued on treatment for a total of 48weeks.
Partial early virological response (pEVR) was defined as a decrease of at least 2-log10 HCV RNA from baseline but with detectable HCV RNA at week 12. Complete EVR (cEVR) was defined as undetectable HCV RNA at week 12. End of treatment (EOT) response was defined as undetectable serum HCV RNA at week 48. Successful treatment was defined as sustained virological response (SVR) (an undetectable HCV RNA at 24weeks after the end of treatment).
Safety and tolerability were assessed by the evaluation of adverse events, adherence, and discontinuation of study drugs at weeks 2, 4 and every 4weeks through week 48 then at weeks 4, 12, and 24 after the end of treatment. For the management of side effects due to RBV, the initial dose was reduced to 600mg daily until the event responsible for the dosage adjustment was resolved. For management of side effects due to pegIFN-α-2a, the initial dose was reduced by half until the event responsible for the dosage adjustment was resolved. Growth factors for anemia and neutropenia were used at the individual investigator's discretion.
The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. The protocol and consent form were approved by a central institutional review board (IRB) and IRBs of participating sites. Informed consent was obtained from each patient included in the study.
Laboratory tests
Quantification of serum HCV RNA was performed using the AMPLICOR HCV MONITOR® Test, version 2.0 (Roche Molecular Diagnostics, Branford, CT, USA). The detection limit was 600IU/ml. Quantification of serum HIV RNA was performed using the AMPLICOR® HIV-1 MONITOR UltraSensitive Test (Roche Molecular Diagnostics, Branford, CT, USA). The limit of detection was 48 copies/ml. To determine fasting serum levels of glucose and insulin, patients fasted overnight for at least 12h prior to blood collection. Serum samples were let to stand for 15min to allow clotting, centrifuged at full speed for 15min, frozen in cryovials, and shipped the same day for analysis. Serum glucose was determined using the VITROS® 950 test (Ortho Clinical Diagnostics, Rochester, NY, USA) and insulin level was determined using the Immulite® 1000 assay (Siemens Healthcare Diagnostics Deerfield, IL, USA). All laboratory tests were performed at a central laboratory (Consolidated Laboratory Services Van Nuys, CA, USA).
The homeostasis model of assessment of insulin resistance (HOMA-IR) was calculated using the equation described by Matthews et al.: HOMA-IR=fasting insulin (mU/ml)xfasting glucose (mmol/l)/22.5 [12]. Fasting glucose was measured in mg/dl and thus every value was multiplied by a factor of 0.055 before being used in the formula. A person with a HOMA-IR value above 2 was defined as having IR consistent with previous studies [13], [14].
Liver pathology
Liver specimens, which were obtained 18months prior to study entry, were fixed in formalin and embedded in paraffin before they were stained with hematoxylin-eosin and Masson Trichrome. Each was reviewed by a single pathologist at the central site (M-I F) who was unaware of the patient's clinical and biological data. The Ishak-modified histology activity index (HAI) classification scale was used to analyze the biopsy specimens for necroinflammation (range 0-12), and fibrosis (range 0-6). Cirrhosis was defined as a fibrosis score of 5-6 [15]. Steatosis was graded by percentage of liver parenchyma with fat-containing hepatocytes (0 for none; 1 for 1-32%; 2 for 33-67%; and 3 for >67% [16].
Statistical analysis
To determine the efficacy of the treatment, the percentage of patients achieving SVR was calculated. Consistent with previous studies on the efficacy of pegIFN and RBV, the denominator included all patients who received at least one dose of the study drug. Treatment failures included patients who were lost to follow up, discontinued treatment per study protocol at week 24, discontinued treatment due to adverse events, did not achieve SVR, withdrew from the study, or died.
To evaluate predictors of SVR, host characteristics (age, sex, race, body mass index (BMI), baseline HOMA-IR), HCV-related characteristics (HCV genotype, log10 HCV RNA, and non-response versus relapse to prior HCV therapy), HIV-related characteristics (CD4+ T-cell count, HIV RNA, and current use of ART), and liver pathology (steatosis and cirrhosis) were evaluated. First, univariable analyses were done using Chi-square, Fisher's Exact test, Student's t-test or Mann-Whitney, as appropriate, with SVR as the outcome. Second, variables with p-valueφ0.20 in univariable analysis were evaluated using forward and backward multivariable logistic regression to identify variables significantly associated with SVR.
To further study the relationship between IR and SVR, we conducted a post hoc matched, nested case-control analysis. Cases were those who achieved SVR and controls were those who did not. Cases and controls were placed into strata based on baseline HCV RNA and were matched on HCV genotype within each strata. McNemar's test was used for univariable analysis to identify significant associations between SVR and possible predictors. Conditional logistic regression with SVR as the outcome was used to determine whether IR was a statistically significant predictor of SVR.
To determine if IR was correlated with steatosis and/or cirrhosis, Spearman's rank correlation was used. To determine the best predictor of SVR among these three, we used the multivariable logistic regression model obtained above with SVR as the outcome, all variables found to be statistically associated with SVR as covariates, and we substituted IR, steatosis, and cirrhosis as the main predictor. We compared the -2log likelihood values for each model to identify which model had the best fit.
All analyses were done using SPSS Statistics 17.0 (Chicago, IL, USA) or Epi Info Version 6 (CDC, Atlanta, GA, USA). The Cox regression function was used for the conditional regression analysis. A p-value<0.05 (two-sided) was considered significant in all analyses.
Source
Jnl of Hepatology Dec 2010
"Baseline IR (insulin resistance) was strongly associated with virological response. This study demonstrates that a proportion of HIV/HCV co-infected patients respond to HCV re-treatment. The best outcome is achieved in patients with baseline HOMA-IRφ2. Calculating baseline HOMA-IR may be a useful tool when considering re-treatment. Future studies are needed to confirm these findings and determine if improvement of HOMA-IR prior to starting HCV therapy increases SVR rates. The impact of IR on SVR requires further study in patients receiving direct-acting antiviral agents as they are soon to become part of standard HCV treatment......This is the largest prospective study of HCV re-treatment in the population of HIV/HCV co-infected patients conducted so far. In this study, re-treatment with pegIFN-α-2a plus weight-based RBV led to a SVR rate of 15%. The strongest predictor of failure to achieve SVR was IR and the highest SVR rate of 35% was in patients with HOMA-IR<2. This is the first study to examine IR as a possible predictor of SVR during re-treatment of HIV/HCV co-infected patients. IR appears to predict SVR better than steatosis or cirrhosis. As such, these data provide important insight into the management of hepatitis C in co-infected persons who failed to respond to prior therapy."
From Jules of NATAP: At AASLD Vertex reported insulin resistance did not impact SVR, I would feel more comfortable with this finding in monoinfection after a study in coinfection:
No Impact of Insulin Resistance on Antiviral Efficacy of ...
Nov 3, 2010 ... No Impact of Insulin Resistance on Antiviral Efficacy of Telaprevir-based Regimen in HCV Genotype 1 Treatment-naïve Patients: Subanalysis of ...
www.natap.org/2010/AASLD/AASLD_76.htm
Marie-Louise C. Vachon 1 Corresponding Author Information email address, Stephanie H. Factor 2, Andrea D. Branch 1, Maria-Isabel Fiel 3, Maribel Rodriguez-Torres 4, Norbert BrŠu 5 6, Richard K. Sterling 7, Jihad Slim 8, Andrew H. Talal 9, Douglas T. Dieterich 1, Mark S. Sulkowski 10
1 Division of Liver Diseases, Mount Sinai School of Medicine, NY, USA
2 Division of Infectious Diseases, Mount Sinai School of Medicine, NY, USA
3 Department of Pathology, Mount Sinai School of Medicine, NY, USA
4 Fundacion de Investigacion de Diego, San Juan, PR, USA
5 Divisions of Infectious Diseases and Liver Diseases, Mount Sinai School of Medicine, NY, USA
6 Veterans Affairs Medical Center, Bronx, NY, USA
7 Division of Liver Diseases, Virginia Commonwealth University Health Systems, Richmond, VA, USA
8 Division of Infectious Diseases, St-Michael's Medical Center, NY, USA
9 Division of Gastroenterology and Hepatology and Center for the Study of Hepatitis C, Weill Cornell Medical College, NY, USA
10 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MA, USA
Background & Aims
Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology.
Methods
This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48weeks. Serum HCV RNA was measured 24weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR>2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined.
Results
Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR<2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA-IR between 2-4, and 7% (3/41) of those with HOMA-IR>4 (p=0.01). In multivariable analysis, insulin resistance and log10 HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05-0.64, p=0.009, and AOR 0.36; 95% CI 0.14-0.93, p=0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p=0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes.
Conclusions
In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response.
Abbreviations: HIV, human immunodeficiency virus, HCV, hepatitis C virus, HRN, hepatitis Resource Network, HCV RNA, hepatitis C virus ribonucleic acid, HOMA-IR, homeostasis model of assessment of insulin resistance, AOR, adjusted odds ratio, CI, confidence interval, HCC, hepatocellular carcinoma, SVR, sustained virological response, PegIFN, pegylated interferon, RBV, ribavirin, IR, insulin resistance, IFN, interferon, HIV RNA, human immunodeficiency virus ribonucleic acid, ART, antiretroviral therapy, ULN, upper limit of normal, Hb, hemoglobin, HbA1c, hemoglobin A1c, TSH, thyroid-stimulating hormone, pEVR, partial early virological response, cEVR, complete early virological response, EOT, end of treatment, IRB, institutional review board, HAI, histology activity index, BMI, body mass index, IQR, interquartile range, OR, odds ratio, SAE, severe adverse event, RVR, rapid virological response, ACTG, AIDS Clinical Trials Group, SOCS3, suppressor of cytokine signaling 3, IRS-1, insulin receptor substrate 1, STAT-1, signal transducers and activators of transcription 1
Introduction
Co-infection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) affects an estimated 10 million people worldwide. HCV-related liver disease is now a leading cause of death among HIV-infected patients [1], [2]. Successful treatment of HCV is associated with reduced liver-related complications, including liver decompensation, hepatocellular carcinoma (HCC), and liver-related mortality [3], [4].
The goal of HCV treatment is to achieve sustained virological response (SVR), defined as undetectable serum HCV RNA 24weeks after the end of treatment. The current standard of care is 48weeks of peginterferon-α (pegIFN) and ribavirin (RBV; fixed dose for HCV genotypes 2 and 3, and weight-based for HCV genotypes 1 and 4). However, SVR is achieved in less than half of HIV/HCV co-infected patients in both initial and re-treatment of HCV. In initial HCV treatment, the combination of pegIFN and weight-based RBV has lead to SVR in 22-35% of patients with HCV genotypes 1 and 4 [5], [6] and 53-72% of patients with HCV genotypes 2 and 3 [6], [7]. Despite the high rate of failure of initial HCV treatment regimens, few studies have been done on re-treatment of HCV in co-infected non-responders. The studies that have been published were small and reported overall SVR rates of 16-31% [8], [9], [10], [11]. In addition, predictors of SVR in re-treatment have not been well studied.
HIV/HCV co-infected patients, who had failed to respond to a previous course of HCV treatment, were enrolled in an open-label, phase IIIb study (Hepatitis Resource Network (HRN)-004) to evaluate safety, tolerability, and efficacy of pegIFN-α-2a and RBV in re-treatment. In addition, we prospectively evaluated predictors of SVR including baseline insulin resistance (IR). Finally, we examined the relationship between baseline IR and liver histology (steatosis and cirrhosis).
Discussion
This is the largest prospective study of HCV re-treatment in the population of HIV/HCV co-infected patients conducted so far. In this study, re-treatment with pegIFN-α-2a plus weight-based RBV led to a SVR rate of 15%. The strongest predictor of failure to achieve SVR was IR and the highest SVR rate of 35% was in patients with HOMA-IR<2. This is the first study to examine IR as a possible predictor of SVR during re-treatment of HIV/HCV co-infected patients. IR appears to predict SVR better than steatosis or cirrhosis. As such, these data provide important insight into the management of hepatitis C in co-infected persons who failed to respond to prior therapy.
Non-response to HCV treatment is common in HIV/HCV co-infected patients treated with pegIFN and RBV. Our population had a high prevalence of factors known to predict non-response to HCV treatment. Specifically, there was a high prevalence of men, African American race, Latino ethnicity, prior treatment non-responders as opposed to relapsers, HCV genotype 1 infection, high HCV RNA levels, steatosis, cirrhosis, and IR.
Baseline IR was strongly associated with virological response. These data are consistent with prior retrospective studies at the initial course of HCV treatment in co-infected patients. Among 238 co-infected patients treated with pegIFN-α-2b and RBV, Cacoub and colleagues reported that a HOMA-IR score>2.5 was a negative predictor of SVR [17]. In a cohort of 134 co-infected patients, Ryan et al. similarly reported that a HOMA-IR score >3.8 was a negative predictor of SVR [18]. A third retrospective study of 74 HIV/HCV co-infected patients reported that a HOMA-IR >3.0 was a negative predictor of rapid virological response (RVR) [19]. RVR is achieved when serum HCV RNA is below the limit of detection at week 4 and is a known correlate of SVR [20]. One study found that IR was not associated with response to pegIFN (α-2a and α-2b) and RBV in treatment-naive HIV/HCV co-infected patients [21]. However the results appeared to show a negative dose-response relationship between baseline HOMA-IR score and SVR rate. These results may be explained by differences in patient samples, in terms of both sample size and patient characteristics. The patients in the study by Merchante et al. were younger (median age 40 vs 48years), had lower BMI scores (median 22.9 vs 25.8), and were all Caucasians (100% vs 28% of our patients). Furthermore, they were HCV treatment naïve, had less advanced liver disease (15% cirrhosis vs 27% of our patients), and a lower prevalence of IR. Twenty-nine percent had HOMA-IR scores>4, compared to 44% in our population.
In our study, co-infected patients with HOMA-IR<2 had a SVR rate of 35% compared to 7-14% in those with higher scores. The 35% SVR rate in patients with HOMA-IR<2 is equivalent to SVR rates achieved in the HIV/HCV co-infected patients undergoing initial treatment. This suggests that calculation of HOMA-IR prior to treatment may improve the estimate of treatment response.
In HCV mono-infected patients, recent studies evaluated the impact of insulin sensitizing agents on SVR at the time of starting pegIFN and RBV treatment in patients with IR. Two showed positive results in defined populations [22], [23], one did not [24]. An ongoing study using pioglitazone prior to pegIFN and RBV therapy is being conducted in HIV/HCV co-infected patients with IR who were non-responders to prior HCV treatment (ACTG 5239).
There is biological data supporting the association between IR and treatment response. Insulin diminishes the ability of IFN to inhibit HCV replication in a replicon model at insulin levels similar to those seen in patients with IR [25]. Elevated levels of suppressor of cytokine signaling 3 (SOCS3) in liver biopsies predict IFN treatment failure [26], [27], [28]. Some evidence suggests that SOCS3 down-regulates both insulin receptor substrate 1 (IRS-1), a key component of the insulin signaling pathway [29], and signal transducers and activators of transcription 1 (STAT1), a key component of IFN signaling [30]. This literature suggests that induction of SOCS3, which is reported to occur in cells carrying the HCV core gene [29], [30], might contribute to both IR and IFN treatment failure in patients.
Our statistical models suggest that IR is more significantly associated with response to HCV re-treatment in HIV-infected patients than is steatosis or cirrhosis. Similar to previous studies, this study demonstrates a correlation between IR and both steatosis and cirrhosis [31], [32]. Previous studies have found steatosis and cirrhosis to be negative predictors of response to HCV treatment in some patient populations [32], [33], [34], [35], [36]. The correlation between IR and steatosis/cirrhosis and their ability to negatively predict treatment response suggest all three may be markers of pathologic changes along a common pathway. With our current technology, IR is the only measure which does not require an invasive procedure and is therefore feasible for widespread use.
While we found baseline HCV RNA to be statistically associated with SVR, we did not find HCV genotype to be associated with SVR. This is not consistent with prior studies [10], [11]. In the study by Labarga et al., HCV genotypes 2 and 3 infection was significantly associated with SVR compared to HCV genotypes 1 and 4, as was RBV plasma trough concentrations at week 4 [11]. The high prevalence of HCV genotype 1 compared to HCV genotypes 2 and 3 in this study may have prevented our ability to find associations. It is also possible that HCV genotype, while a significant predictor of treatment success for initial treatment of HIV/HCV co-infected patients, may not be as significant of a predictor during re-treatment. The low prevalence of patients with prior HCV relapse compared to HCV non-responders is also likely responsible for the lack of association with SVR in this study. However, prior small studies of re-treatment in the population of HIV/HCV co-infected patients have not found prior relapse vs non-response to be significantly associated with SVR [8], [10], [11].
Previous studies on predictors of SVR have often included EVR and total dose of pegIFN and/or RBV as predictors in their univariable and multivariable analyses; we did not. Because EVR almost always (98-100%) predicts SVR, EVR is likely along the causal pathway to SVR and therefore a measure of outcome not exposure. PegIFN-α-2a and weight-based RBV were given to all participants up to week 20 and virological status at week 20 determined further treatment. Thus, the total dose of pegIFN-α-2a and RBV was, in part, determined by the risk factors at baseline. Similar to EVR, medication dose in this study is a measure of outcome.
This study, with numerous strengths, expands the current literature but has some limitations. The most important strength is the prospective collection of data using standardized tools. Our study is limited by its sample size and the homogeneity of the patients in sex, age, and HCV genotype. The homogeneity of the population, especially the high prevalence of patients with HCV genotype 1 infection and HOMA-IR above 2, may have contributed to the strong relationship we found between baseline IR and SVR in this study. At the time the study was conducted, IL28B polymorphisms analyses were not performed. This information may have influenced our study results.
This study demonstrates that a proportion of HIV/HCV co-infected patients respond to HCV re-treatment. The best outcome is achieved in patients with baseline HOMA-IRφ2. Calculating baseline HOMA-IR may be a useful tool when considering re-treatment. Future studies are needed to confirm these findings and determine if improvement of HOMA-IR prior to starting HCV therapy increases SVR rates. The impact of IR on SVR requires further study in patients receiving direct-acting antiviral agents as they are soon to become part of standard HCV treatment.
Patients and methods
Patients
Patients were recruited at 10 centers in the United States from August 2002 to June 2005. Eligible patients were co-infected with HIV and HCV and had either relapsed or not responded to prior IFN-based treatment. Chronic HCV infection was defined as a positive HCV antibody test for at least 6months and detectable serum HCV RNA. HIV-related criteria included patients with either (i) CD4+ T-cell count<100 cells/mm3 and HIV RNA level<25,000IU/ml, or (ii) CD4+ T count100 cells/mm3 and any HIV viral load. Patients were required to be on stable antiretroviral therapy (ART) or off ART for at least 4weeks prior to the screening visit. Prior IFN-based treatment was defined as IFN-α monotherapy or IFN-α and RBV combination therapy administered for at least 12weeks and discontinued for at least 4weeks before the screening visit. Prior non-response was defined as a <2-log10 decrease in HCV RNA at week 12 or detectable HCV RNA at week 24 during HCV treatment. Prior relapse was defined as detectable HCV RNA after cessation of treatment in a patient who had undetectable HCV RNA at the end of treatment. A liver biopsy showing features consistent with chronic HCV infection was required within 18months prior to study entry.
Exclusion criteria were decompensated liver disease (ascites, bleeding varices, or encephalopathy), other causes of liver disease (steatosis and steatohepatitis were not excluded), prothrombin time3 s, bilirubin>20% above the ULN, albumin<3.0g/dl, hemoglobin (Hb)φ11g/dl, white blood cell countφ3000/mm3, absolute neutrophil countφ1250/mm3, platelet countφ70,000/mm3, fasting blood glucose>115mg/dl in non-diabetic patients, HbA1c>8.5% in diabetic patients, serum creatinine1.5mg/dl, abnormal TSH value, alpha-fetoprotein100ng/ml, hemoglobinopathies, alcohol and/or drug abuse within 1year of entry (active intravenous drug users were excluded), severe psychiatric disease, hypersensitivity to IFN or RBV, pregnancy or breastfeeding, and persons unwilling to use contraception during the study period.
Results
Baseline characteristics
Of the 102 patients enrolled, 6 did not receive study medication and 96 were included in the study (Table 1). Median age was 48years (Interquartile range (IQR)=44-53). The group was 84% male, 42% Latino, 29% African American, and 28% Caucasian. Of the 96 patients, 81 (85%) were infected with HCV genotype 1. Twenty-one (22%) patients had a past history of intravenous drug use and none were active users.
Of the 94 patients with available baseline fasting insulin and glucose levels, 77 (82%) had a HOMA-IR>2; 36 (38%) had a HOMA-IR between 2 and 4; and 41 (44%) had a HOMA-IR>4. Steatosis was present in 53 (55%) of the liver biopsies and cirrhosis was present in 26 (27%). Of the 96 patients, 92 (96%) had a CD4+ T-cell count >200, 81 (84%) were on ART and 67 (70%) had undetectable HIV RNA.
Efficacy outcomes
Of the 96 patients who received at least one dose of the study drug, 37 (39%) experienced EVR. Twelve (13%) had pEVR and 25 (26%) had cEVR. An EOT response was achieved in 30 (31%) patients and SVR was achieved in 14 (15%) (Fig. 1). The negative predictive value of EVR to achieve SVR was 100%. The positive predictive value of EVR (partial and complete) to achieve SVR was 38%.
In the univariable analyses of possible predictors of SVR, IR was negatively associated with SVR [odds ratio (OR) 0.21; 95% CI 0.06-0.73, p=0.02] (Table 1). In multivariable logistic regression, IR and baseline log10 HCV RNA were negatively associated with SVR [adjusted odds ratio (AOR) 0.17; 95% CI 0.05-0.64, p=0.009, and AOR 0.36; 95% CI 0.14-0.93, p=0.04, respectively]. The interaction between IR and HCV RNA was not significant.
A sub-analysis including only patients with HCV genotype 1 infection (n=81) was performed. Out of 81 patients, 10 (12%) achieved SVR. In multivariable analysis, HOMA-IR>2 was the only independent negative predictor of SVR (AOR 0.16; 95% CI 0.04-0.67, p=0.01). The African American race and Latino ethnicity were correlated with the presence of IR, but were not significant predictors of SVR when analyzed in the multivariable model.
Role of baseline IR and SVR
The matched, nested case-control analysis included 81 patients, with 14 cases matched to between 1 and 6 controls. In both univariable and multivariable analyses, IR was negatively associated with SVR (AOR 0.13; 95% CI 0.03-0.55, p=0.006).
When looking at SVR in relation to the HOMA-IR score divided into 3 categories,<2, 2-4, and >4, there was a significant negative dose-response relationship between percent SVR and HOMA-IR: 35% (6/17) in HOMA-IR<2, 14% (5/36) in HOMA-IR between 2 and 4, and 7% (3/41) in HOMA-IR>4 (p=0.01, chi-square test for trend) (Fig. 2).
Relationship between baseline IR and liver histology
IR was correlated with steatosis (r=0.22, p=0.02) and cirrhosis (r=0.23, p=0.03). Steatosis was present in 47/77 (61%) patients with IR, compared to 5/17 (29%) patients without IR (p=0.02). Cirrhosis was present in 25/77 (32%) patients with IR, compared to 1/17 (6%) patients without IR (p=0.03). When looking at the HOMA-IR score divided into 3 categories, <2, 2-4, and >4, there was a positive dose-response relationship between both percent steatosis and HOMA-IR (p=0.02, chi-square test for trend), and percent cirrhosis and HOMA-IR (p=0.03, chi-square test for trend) (Fig. 3).
Using the multivariable logistic regression models with SVR as the outcome, log10 HCV RNA as a covariate, and steatosis or cirrhosis substituted in for IR, the models for steatosis and cirrhosis had larger -2log likelihood values indicating that these models were less precise in predicting SVR (Table 2).
A sub-analysis including only patients without cirrhosis (n=70) was performed. Out of 70 patients without cirrhosis, 13 (19%) achieved SVR. In multivariable analysis, HOMA-IR>2 was negatively associated with SVR (AOR 0.22; 95% CI 0.06-0.89, p=0.03). Baseline log10 HCV RNA was also significantly associated with SVR (AOR 0.37; 95% CI 0.14-0.98, p=0.046) in this analysis.
Safety and tolerability
The most common adverse events were cytopenias. Anemia with Hb<10g/dl occurred in 13 (14%) patients and severe anemia (Hb<8.5) occurred in 3 (3%). A neutrophil count<750/mm3 occurred in 74 (77%) and a neutrophil count<500/mm3 occurred in 48 (50%). A platelet count<50,000cells/mm3 occurred in 5 (5%) patients. RBV dose reduction was required in 18 (19%) patients during treatment, most frequently due to anemia. PegIFN-α-2a dose reduction was required in 25 patients (26%) during treatment, most frequently due to neutropenia. There were no incidents of opportunistic infections, episodes of hepatic decompensation, or development of HCC. There were two deaths in the study patients both of which were unrelated to study medications.
Overall, 23 (24%) patients discontinued treatment. Thirteen discontinuations were due to adverse events. There were 8 discontinuations due to severe adverse events (SAEs), all within the first 24weeks (3 severe anemia, 2 suicidal ideation, 1 hyperglycemia, 1 diarrhea and fever, and 1 rhabdomyolysis).
Study design
Patients received 180μg pegIFN-α-2a subcutaneously every week plus weight-based RBV (Pegasys® and Copegus®, Roche Laboratory, Nutley, NJ, USA), regardless of HCV genotype (800mg/day for <65kg; 1000mg/day for 65kg and φ85kg; 1200mg/day for>85kg). A complete medical history, physical examination, and laboratory tests were taken at the baseline visit. Additional data were collected at weeks 2, 4, 8, 12, 16, 20, 24, 36, and 48 during treatment and 24weeks after the end of treatment. Unlike traditional treatment, patients who did not achieve a 2-log10 drop in HCV RNA at week 12 did not discontinue treatment. The decision to discontinue treatment was made at week 24 based on the week 20 HCV RNA result. Patients with a detectable HCV RNA level at week 20 were considered treatment failures and were diverted to a maintenance study arm to be discussed elsewhere. Patients with undetectable HCV RNA at week 20 were continued on treatment for a total of 48weeks.
Partial early virological response (pEVR) was defined as a decrease of at least 2-log10 HCV RNA from baseline but with detectable HCV RNA at week 12. Complete EVR (cEVR) was defined as undetectable HCV RNA at week 12. End of treatment (EOT) response was defined as undetectable serum HCV RNA at week 48. Successful treatment was defined as sustained virological response (SVR) (an undetectable HCV RNA at 24weeks after the end of treatment).
Safety and tolerability were assessed by the evaluation of adverse events, adherence, and discontinuation of study drugs at weeks 2, 4 and every 4weeks through week 48 then at weeks 4, 12, and 24 after the end of treatment. For the management of side effects due to RBV, the initial dose was reduced to 600mg daily until the event responsible for the dosage adjustment was resolved. For management of side effects due to pegIFN-α-2a, the initial dose was reduced by half until the event responsible for the dosage adjustment was resolved. Growth factors for anemia and neutropenia were used at the individual investigator's discretion.
The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. The protocol and consent form were approved by a central institutional review board (IRB) and IRBs of participating sites. Informed consent was obtained from each patient included in the study.
Laboratory tests
Quantification of serum HCV RNA was performed using the AMPLICOR HCV MONITOR® Test, version 2.0 (Roche Molecular Diagnostics, Branford, CT, USA). The detection limit was 600IU/ml. Quantification of serum HIV RNA was performed using the AMPLICOR® HIV-1 MONITOR UltraSensitive Test (Roche Molecular Diagnostics, Branford, CT, USA). The limit of detection was 48 copies/ml. To determine fasting serum levels of glucose and insulin, patients fasted overnight for at least 12h prior to blood collection. Serum samples were let to stand for 15min to allow clotting, centrifuged at full speed for 15min, frozen in cryovials, and shipped the same day for analysis. Serum glucose was determined using the VITROS® 950 test (Ortho Clinical Diagnostics, Rochester, NY, USA) and insulin level was determined using the Immulite® 1000 assay (Siemens Healthcare Diagnostics Deerfield, IL, USA). All laboratory tests were performed at a central laboratory (Consolidated Laboratory Services Van Nuys, CA, USA).
The homeostasis model of assessment of insulin resistance (HOMA-IR) was calculated using the equation described by Matthews et al.: HOMA-IR=fasting insulin (mU/ml)xfasting glucose (mmol/l)/22.5 [12]. Fasting glucose was measured in mg/dl and thus every value was multiplied by a factor of 0.055 before being used in the formula. A person with a HOMA-IR value above 2 was defined as having IR consistent with previous studies [13], [14].
Liver pathology
Liver specimens, which were obtained 18months prior to study entry, were fixed in formalin and embedded in paraffin before they were stained with hematoxylin-eosin and Masson Trichrome. Each was reviewed by a single pathologist at the central site (M-I F) who was unaware of the patient's clinical and biological data. The Ishak-modified histology activity index (HAI) classification scale was used to analyze the biopsy specimens for necroinflammation (range 0-12), and fibrosis (range 0-6). Cirrhosis was defined as a fibrosis score of 5-6 [15]. Steatosis was graded by percentage of liver parenchyma with fat-containing hepatocytes (0 for none; 1 for 1-32%; 2 for 33-67%; and 3 for >67% [16].
Statistical analysis
To determine the efficacy of the treatment, the percentage of patients achieving SVR was calculated. Consistent with previous studies on the efficacy of pegIFN and RBV, the denominator included all patients who received at least one dose of the study drug. Treatment failures included patients who were lost to follow up, discontinued treatment per study protocol at week 24, discontinued treatment due to adverse events, did not achieve SVR, withdrew from the study, or died.
To evaluate predictors of SVR, host characteristics (age, sex, race, body mass index (BMI), baseline HOMA-IR), HCV-related characteristics (HCV genotype, log10 HCV RNA, and non-response versus relapse to prior HCV therapy), HIV-related characteristics (CD4+ T-cell count, HIV RNA, and current use of ART), and liver pathology (steatosis and cirrhosis) were evaluated. First, univariable analyses were done using Chi-square, Fisher's Exact test, Student's t-test or Mann-Whitney, as appropriate, with SVR as the outcome. Second, variables with p-valueφ0.20 in univariable analysis were evaluated using forward and backward multivariable logistic regression to identify variables significantly associated with SVR.
To further study the relationship between IR and SVR, we conducted a post hoc matched, nested case-control analysis. Cases were those who achieved SVR and controls were those who did not. Cases and controls were placed into strata based on baseline HCV RNA and were matched on HCV genotype within each strata. McNemar's test was used for univariable analysis to identify significant associations between SVR and possible predictors. Conditional logistic regression with SVR as the outcome was used to determine whether IR was a statistically significant predictor of SVR.
To determine if IR was correlated with steatosis and/or cirrhosis, Spearman's rank correlation was used. To determine the best predictor of SVR among these three, we used the multivariable logistic regression model obtained above with SVR as the outcome, all variables found to be statistically associated with SVR as covariates, and we substituted IR, steatosis, and cirrhosis as the main predictor. We compared the -2log likelihood values for each model to identify which model had the best fit.
All analyses were done using SPSS Statistics 17.0 (Chicago, IL, USA) or Epi Info Version 6 (CDC, Atlanta, GA, USA). The Cox regression function was used for the conditional regression analysis. A p-value<0.05 (two-sided) was considered significant in all analyses.
Source
January 3, 2011
Lower Recurrence Rate for HCC Treated With Resection Than Radiofrequency Ablation
By: DENISE NAPOLI, Internal Medicine News Digital Network
01/03/11
Although percutaneous radiofrequency ablation and surgical resection for small hepatocellular carcinomas have similar survival rates, ablation patients have a higher rate of cancer recurrence, compared with surgical resection patients, reported Dr. Hung-Hsu Hung and colleagues in the January issue of Clinical Gastroenterology and Hepatology.
Dr. Hung, of Taipei (Taiwan) Veterans General Hospital and the National Yang-Ming University, also in Taipei, looked at 419 consecutive patients who underwent radiofrequency ablation (RFA) or surgical resection (SR) at the hospital in 2002-2007. All patients had no more than three small (5 cm or less) liver tumors without extrahepatic metastasis (Clin. Gastroenterol. Hepatol. 2011 January [doi:10.1016/j.cgh.2010.08.018]).
In all, 190 patients underwent RFA and the remaining 229 underwent SR to treat their liver cancer. Patients who chose SR were on average slightly younger (60 years vs. 67 years; P less than .001). This was expected, given the invasive nature of the surgery.
Additionally, the authors found that there was a higher proportion of patients with chronic hepatitis B in the SR group than in the RFA group (59.8% vs. 46.3%; P = .004), whereas chronic hepatitis C was more common in the RFA group (44.7% vs. 26.6%; P less than .001).
This was also an expected finding, because in chronic HBV infection, hepatocellular carcinomas tend to occur at a younger age, the researchers wrote.
Regarding survival, 83 patients had died after a median follow-up of more than 42 months. "Among the 190 patients [who] underwent RFA, 41 (21.6%) died during the follow-up period; 97 (51.1%) were alive with regular visits" until Jan. 31, 2010, and the remaining 52 (27.4%) were lost to follow-up sometime before 2010.
In comparison, there were 42 deaths (18.3%) among the SR group, with 120 patients known to be alive through Jan. 31, 2010 (52.4%), and the remaining 67 patients (29.3%) lost to follow-up.
"The cumulative overall survival rates at 1, 2, 3, and 5 years were 97.3%, 92.2%, 88.2%, and 79.3% in the SR group and 96.6%, 86.7%, 77.3%, and 67.4% in the RFA group, respectively," a significant difference in univariate analysis (P less than 0.009), wrote the authors.
However, after controlling for the older age and comorbidities of the RFA group in multivariate analysis, the authors found that RFA was not an independent risk factor associated with poor survival.
Next, the authors looked at factors associated with cancer recurrence. Overall, 244 patients had experienced tumor recurrence at a median of 14.5 months following RFA or SR.
"The cumulative recurrence rates at 1, 2, 3, and 5 years were 17.4%, 30.5%, 43.9%, and 59.1% in the SR group and 37.4%, 54.1%, 71.0%, and 79.5% in the RFA group, respectively (P less than .001)," they reported.
As with survival, that translated to a significantly higher univariate risk of recurrence among RFA patients (hazard ratio, 2.05; 95% confidence interval, 1.58-2.65). When assessed in a multivariate analysis, RFA was still significantly associated with cancer recurrence (HR, 1.95; 95% CI, 1.48-2.57; P less than .001).
The finding of equal survival but greater recurrence among RFA patients persisted in a third propensity analysis, which employed nearest-neighbor one-to-one matching of 84 patients in each group in terms of age, sex, tumor size, tumor number, platelet counts, hepatitis status, and several other parameters.
The only subgroup for which RFA was equal to SR in terms of both survival and tumor recurrence was patients with solitary hepatocellular carcinoma less than 2 cm in size, known as "very early small HCC (Barcelona Clinic Liver Cancer stage 0)" tumors.
According to the authors, their study "highlights the importance of close surveillance after local ablation therapy." Additionally, the authors concluded that RFA may be a good alternative to surgical resection for BCLC stage 0 HCC, although prospective study is needed.
Dr. Hung and colleagues disclosed no conflicts of interest related to this study.
Source
01/03/11
Although percutaneous radiofrequency ablation and surgical resection for small hepatocellular carcinomas have similar survival rates, ablation patients have a higher rate of cancer recurrence, compared with surgical resection patients, reported Dr. Hung-Hsu Hung and colleagues in the January issue of Clinical Gastroenterology and Hepatology.
Dr. Hung, of Taipei (Taiwan) Veterans General Hospital and the National Yang-Ming University, also in Taipei, looked at 419 consecutive patients who underwent radiofrequency ablation (RFA) or surgical resection (SR) at the hospital in 2002-2007. All patients had no more than three small (5 cm or less) liver tumors without extrahepatic metastasis (Clin. Gastroenterol. Hepatol. 2011 January [doi:10.1016/j.cgh.2010.08.018]).
In all, 190 patients underwent RFA and the remaining 229 underwent SR to treat their liver cancer. Patients who chose SR were on average slightly younger (60 years vs. 67 years; P less than .001). This was expected, given the invasive nature of the surgery.
Additionally, the authors found that there was a higher proportion of patients with chronic hepatitis B in the SR group than in the RFA group (59.8% vs. 46.3%; P = .004), whereas chronic hepatitis C was more common in the RFA group (44.7% vs. 26.6%; P less than .001).
This was also an expected finding, because in chronic HBV infection, hepatocellular carcinomas tend to occur at a younger age, the researchers wrote.
Regarding survival, 83 patients had died after a median follow-up of more than 42 months. "Among the 190 patients [who] underwent RFA, 41 (21.6%) died during the follow-up period; 97 (51.1%) were alive with regular visits" until Jan. 31, 2010, and the remaining 52 (27.4%) were lost to follow-up sometime before 2010.
In comparison, there were 42 deaths (18.3%) among the SR group, with 120 patients known to be alive through Jan. 31, 2010 (52.4%), and the remaining 67 patients (29.3%) lost to follow-up.
"The cumulative overall survival rates at 1, 2, 3, and 5 years were 97.3%, 92.2%, 88.2%, and 79.3% in the SR group and 96.6%, 86.7%, 77.3%, and 67.4% in the RFA group, respectively," a significant difference in univariate analysis (P less than 0.009), wrote the authors.
However, after controlling for the older age and comorbidities of the RFA group in multivariate analysis, the authors found that RFA was not an independent risk factor associated with poor survival.
Next, the authors looked at factors associated with cancer recurrence. Overall, 244 patients had experienced tumor recurrence at a median of 14.5 months following RFA or SR.
"The cumulative recurrence rates at 1, 2, 3, and 5 years were 17.4%, 30.5%, 43.9%, and 59.1% in the SR group and 37.4%, 54.1%, 71.0%, and 79.5% in the RFA group, respectively (P less than .001)," they reported.
As with survival, that translated to a significantly higher univariate risk of recurrence among RFA patients (hazard ratio, 2.05; 95% confidence interval, 1.58-2.65). When assessed in a multivariate analysis, RFA was still significantly associated with cancer recurrence (HR, 1.95; 95% CI, 1.48-2.57; P less than .001).
The finding of equal survival but greater recurrence among RFA patients persisted in a third propensity analysis, which employed nearest-neighbor one-to-one matching of 84 patients in each group in terms of age, sex, tumor size, tumor number, platelet counts, hepatitis status, and several other parameters.
The only subgroup for which RFA was equal to SR in terms of both survival and tumor recurrence was patients with solitary hepatocellular carcinoma less than 2 cm in size, known as "very early small HCC (Barcelona Clinic Liver Cancer stage 0)" tumors.
According to the authors, their study "highlights the importance of close surveillance after local ablation therapy." Additionally, the authors concluded that RFA may be a good alternative to surgical resection for BCLC stage 0 HCC, although prospective study is needed.
Dr. Hung and colleagues disclosed no conflicts of interest related to this study.
Source
The CDC HIV/Hepatitis/STD/TB Prevention News Update
January 3, 2011
National News
International News - EGYPT: "No Sex Education, Please, We're Arab"
- PHILIPPINES: "HIV Infections Rising in Some Areas of Philippines, Warns UN Official"
- CANADA: "Methadone Use in Relation to Hepatitis C Virus Testing in British Columbia"
- THAILAND: "An Exploration of Factors Influencing Adherence to Highly Active Antiretroviral Therapy (HAART) Among People Living with HIV/AIDS in Northern Thailand"
- PENNSYLVANIA: "Philadelphia's Condom Contest"
- NEW YORK: "HIV Deaths Fall Below 1,000"
- CALIFORNIA: "Volunteers Sought to Lead HIV Support Groups"
Beacon NewsFlashes – January 3, 2011 (The AIDS Beacon)
By Courtney McQueen
Published: Jan 3, 2011 3:05 pm
ViiV Healthcare Opens Its Patient Assistance Program For People With HIV – On January 1, ViiV Healthcare, a joint venture by pharmaceutical companies Pfizer and GlaxoSmithKline, opened its patient assistance program to help low-income people with HIV obtain their medications. The program will cover the medications Combivir (zidovudine/lamivudine), Epivir (lamivudine), Epzicom (abacavir/lamivudine), Lexiva (fosamprenavir), Rescriptor (delavirdine), Retrovir (zidovudine), Selzentry (maraviroc), Trizivir (zidovudine/lamivudine/abacavir), Viracept (nelfinavir), and Ziagen (abacavir). Eligible participants must have an annual household income of no more than 500 percent of the federal poverty level ($72,850 for a family of two) and no prescription drug coverage for brand-name drugs. Patients on Medicaid are eligible if they meet income requirements and have spent $600 or more out of pocket for their HIV medications. For more information or to apply for the program, please see the ViiV Healthcare website.
AIDS Healthcare Foundation Offers Free HIV Drugs To People On Florida ADAP Waiting Lists – The AIDS Healthcare Foundation (AHF), a California-based treatment and advocacy group for people with HIV and AIDS, announced today that it will provide up to $1 million in free HIV drugs to people who have been placed on an AIDS Drug Assistance Program (ADAP) waiting list in Florida or have been removed from the program due to new, stricter eligibility requirements. ADAPs are programs that provide anti-HIV medications to low-income people with HIV. The offer from AHF is expected to benefit about 2,850 people and is intended to allow time for them to transition to private patient assistance programs without interrupting treatment. The HIV drugs will be distributed by AHF’s pharmacies throughout the state. For more information, please see the AHF press release.
Maine Now Requires Registration Cards For Medical Marijuana Use – A new state law that went into effect January 1 now requires registration for people in Maine who wish to use medical marijuana. Previously, the state only required a doctor’s permission for marijuana use. Applications for a registration card can be found on the Maine Department of Health and Human Services website; cards cost $100 ($75 for patients in the state’s Medicaid program, MaineCare). The new law also restricts the amount of marijuana a person can carry to 2.5 ounces and limits the number of marijuana plants a patient or their caregiver is allowed to grow. In addition, it provides for new medical marijuana dispensaries, which are expected to open in March or April. Medical marijuana has been legal in Maine since 1999 for treatment of symptoms related to specific conditions, including HIV and AIDS. For more information, please see the article at the Portland Press Herald.
Source
Published: Jan 3, 2011 3:05 pm
ViiV Healthcare Opens Its Patient Assistance Program For People With HIV – On January 1, ViiV Healthcare, a joint venture by pharmaceutical companies Pfizer and GlaxoSmithKline, opened its patient assistance program to help low-income people with HIV obtain their medications. The program will cover the medications Combivir (zidovudine/lamivudine), Epivir (lamivudine), Epzicom (abacavir/lamivudine), Lexiva (fosamprenavir), Rescriptor (delavirdine), Retrovir (zidovudine), Selzentry (maraviroc), Trizivir (zidovudine/lamivudine/abacavir), Viracept (nelfinavir), and Ziagen (abacavir). Eligible participants must have an annual household income of no more than 500 percent of the federal poverty level ($72,850 for a family of two) and no prescription drug coverage for brand-name drugs. Patients on Medicaid are eligible if they meet income requirements and have spent $600 or more out of pocket for their HIV medications. For more information or to apply for the program, please see the ViiV Healthcare website.
AIDS Healthcare Foundation Offers Free HIV Drugs To People On Florida ADAP Waiting Lists – The AIDS Healthcare Foundation (AHF), a California-based treatment and advocacy group for people with HIV and AIDS, announced today that it will provide up to $1 million in free HIV drugs to people who have been placed on an AIDS Drug Assistance Program (ADAP) waiting list in Florida or have been removed from the program due to new, stricter eligibility requirements. ADAPs are programs that provide anti-HIV medications to low-income people with HIV. The offer from AHF is expected to benefit about 2,850 people and is intended to allow time for them to transition to private patient assistance programs without interrupting treatment. The HIV drugs will be distributed by AHF’s pharmacies throughout the state. For more information, please see the AHF press release.
Maine Now Requires Registration Cards For Medical Marijuana Use – A new state law that went into effect January 1 now requires registration for people in Maine who wish to use medical marijuana. Previously, the state only required a doctor’s permission for marijuana use. Applications for a registration card can be found on the Maine Department of Health and Human Services website; cards cost $100 ($75 for patients in the state’s Medicaid program, MaineCare). The new law also restricts the amount of marijuana a person can carry to 2.5 ounces and limits the number of marijuana plants a patient or their caregiver is allowed to grow. In addition, it provides for new medical marijuana dispensaries, which are expected to open in March or April. Medical marijuana has been legal in Maine since 1999 for treatment of symptoms related to specific conditions, including HIV and AIDS. For more information, please see the article at the Portland Press Herald.
Source
Study Suggests Genetic Tests Could Predict HIV Drug Side Effects
January 3, 2011
A new study published in the January 15 issue of The Journal of Infectious Diseases suggests genetic testing might help predict whether a person will have side effects from some HIV drugs. This could allow people to avoid those drugs or at least take them with greater caution.
Previous studies have found that side effects can result in switching meds or discontinuing treatment in up to 45 percent of people starting HIV therapy for the first time. Thus far, however, researchers have found only one form of a gene (an allele) conclusively responsible for side effects: The HLA-B5701 allele, which causes people to have a hypersensitivity reaction to abacavir (found in Ziagen and Epzicom).
Other alleles have been linked to changes in drug blood levels or increased side effect risks for other HIV medications, but the influence of these alleles isn’t as predictable as that of the HLA-B5701 allele.
To determine whether other alleles might predict poor tolerability to drugs other than abacavir, Rubin Lubomirov, MD, PhD, from the University of Lausanne in Switzerland, and his colleagues analyzed data from 577 people enrolled in the Swiss HIV Cohort study. All of the people were starting HIV treatment for the first time.
The specific drugs they studied were abacavir, tenofovir (found in Viread, Truvada and Atripla), efavirenz (found in Sustiva and Atripla), Kaletra (which contains lopinavir and ritonavir) and Norvir (ritonavir)–boosted Reyataz (atazanavir).
Based on data linking alleles to side effects or drug level changes in previous studies, Lubomirov and his colleagues tested collected blood samples for 23 alleles in 15 genes.
The only significant genetic switch not included was the HLA-B5701 allele, because all people who took abacavir had already been tested for the allele and only those without it were allowed to take abacavir. With some drugs, the researchers looked at whether a single allele affected a drug’s tolerability, and with other drugs, Lubomirov’s team looked at the combined effect of several alleles.
The team did not directly assess the effect of certain alleles on specific side effects. They focused only on whether the alleles predicted dose adjustments or treatment discontinuation (though the most common reason for switching treatment in the study was side effects).
The team found that the presence of drug-specific alleles was highly predictive of a switch from efavirenz or Reyataz, but not for the other drugs.
Lubomirov’s group found that 71 percent of people with alleles in the CYP2B6 gene combined with secondary alleles to other genes had to switch off efavirenz or change the dose of the drug compared with only 28 percent of those who did not have the alleles. The risk was even higher in women.
Likewise, Lubomirov and his colleagues found that 62 percent of people with a double substitution in the UGT1A1 gene had to change or discontinue Reyataz, compared with 24 percent with a single substitution and only 15 percent with no substitutions.
“The study suggests that assessment of the genetic markers could lead to improved prescription of atazanavir and efavirenz,” the authors state. They conclude that “a prospective clinical trial should ideally formalize the analysis and provide the basis for measuring the cost effectiveness of this approach.”
Source
A new study published in the January 15 issue of The Journal of Infectious Diseases suggests genetic testing might help predict whether a person will have side effects from some HIV drugs. This could allow people to avoid those drugs or at least take them with greater caution.
Previous studies have found that side effects can result in switching meds or discontinuing treatment in up to 45 percent of people starting HIV therapy for the first time. Thus far, however, researchers have found only one form of a gene (an allele) conclusively responsible for side effects: The HLA-B5701 allele, which causes people to have a hypersensitivity reaction to abacavir (found in Ziagen and Epzicom).
Other alleles have been linked to changes in drug blood levels or increased side effect risks for other HIV medications, but the influence of these alleles isn’t as predictable as that of the HLA-B5701 allele.
To determine whether other alleles might predict poor tolerability to drugs other than abacavir, Rubin Lubomirov, MD, PhD, from the University of Lausanne in Switzerland, and his colleagues analyzed data from 577 people enrolled in the Swiss HIV Cohort study. All of the people were starting HIV treatment for the first time.
The specific drugs they studied were abacavir, tenofovir (found in Viread, Truvada and Atripla), efavirenz (found in Sustiva and Atripla), Kaletra (which contains lopinavir and ritonavir) and Norvir (ritonavir)–boosted Reyataz (atazanavir).
Based on data linking alleles to side effects or drug level changes in previous studies, Lubomirov and his colleagues tested collected blood samples for 23 alleles in 15 genes.
The only significant genetic switch not included was the HLA-B5701 allele, because all people who took abacavir had already been tested for the allele and only those without it were allowed to take abacavir. With some drugs, the researchers looked at whether a single allele affected a drug’s tolerability, and with other drugs, Lubomirov’s team looked at the combined effect of several alleles.
The team did not directly assess the effect of certain alleles on specific side effects. They focused only on whether the alleles predicted dose adjustments or treatment discontinuation (though the most common reason for switching treatment in the study was side effects).
The team found that the presence of drug-specific alleles was highly predictive of a switch from efavirenz or Reyataz, but not for the other drugs.
Lubomirov’s group found that 71 percent of people with alleles in the CYP2B6 gene combined with secondary alleles to other genes had to switch off efavirenz or change the dose of the drug compared with only 28 percent of those who did not have the alleles. The risk was even higher in women.
Likewise, Lubomirov and his colleagues found that 62 percent of people with a double substitution in the UGT1A1 gene had to change or discontinue Reyataz, compared with 24 percent with a single substitution and only 15 percent with no substitutions.
“The study suggests that assessment of the genetic markers could lead to improved prescription of atazanavir and efavirenz,” the authors state. They conclude that “a prospective clinical trial should ideally formalize the analysis and provide the basis for measuring the cost effectiveness of this approach.”
Source
January 2, 2011
A New Meaning for “Antiviral”
Paul Sax • January 2nd, 2011
Paul E. Sax, MD is the Editor-in-Chief, Journal Watch HIV/AIDS Clinical Care and Clinical Director of the HIV Program and Division of Infectious Diseases at Brigham and Women's Hospital
January 1, 2011
Dear Lake Superior State University,
Clinicians are particularly concerned about this year’s “List of Words Banished from the Queen’s English for Mis-use, Over-use and General Uselessness“, as topping the list was the word, viral.
One nominator said:
Events, photographs, written pieces and even occasional videos that attracted a great deal of attention once were simply highly publicized, repeated in news broadcasts, and talked about for a few days. Now, however, it is no longer enough to give such offerings their 15 minutes of fame, but they must be declared to ‘go viral.’ As a result, any mindless stunt or vapid bit of writing is sent by its creators whirling around the Internet and, once whirled, its creators declare it (trumpets here) ‘viral!’ Enough already!
Unfortunately, those of us who make a living seeing patients could never survive without this precious word.
When we say to a patient, “It could be a virus”, or “You probably have something viral”, what we really mean is, “I realize you’re sick, but I don’t know what you have.”
And it’s not really a lie, because literally hundreds of viruses cause human illness — and our diagnostic tests for them for the most part stink.
So I am hoping that MDs, NPs, and PAs may be granted a lifetime exemption for viral’s banishment, and continue to use it in the rigorously scientific manner described above.
Thank you for considering, and Happy New Year.
Paul Sax
(on behalf of clinicians everywhere)
Source
Paul E. Sax, MD is the Editor-in-Chief, Journal Watch HIV/AIDS Clinical Care and Clinical Director of the HIV Program and Division of Infectious Diseases at Brigham and Women's Hospital
January 1, 2011
Dear Lake Superior State University,
Clinicians are particularly concerned about this year’s “List of Words Banished from the Queen’s English for Mis-use, Over-use and General Uselessness“, as topping the list was the word, viral.
One nominator said:
Events, photographs, written pieces and even occasional videos that attracted a great deal of attention once were simply highly publicized, repeated in news broadcasts, and talked about for a few days. Now, however, it is no longer enough to give such offerings their 15 minutes of fame, but they must be declared to ‘go viral.’ As a result, any mindless stunt or vapid bit of writing is sent by its creators whirling around the Internet and, once whirled, its creators declare it (trumpets here) ‘viral!’ Enough already!
Unfortunately, those of us who make a living seeing patients could never survive without this precious word.
When we say to a patient, “It could be a virus”, or “You probably have something viral”, what we really mean is, “I realize you’re sick, but I don’t know what you have.”
And it’s not really a lie, because literally hundreds of viruses cause human illness — and our diagnostic tests for them for the most part stink.
So I am hoping that MDs, NPs, and PAs may be granted a lifetime exemption for viral’s banishment, and continue to use it in the rigorously scientific manner described above.
Thank you for considering, and Happy New Year.
Paul Sax
(on behalf of clinicians everywhere)
Source
Hepatitis C infection, Cognition, and inflammation in an Egyptian sample
J Med Virol. 2011 Feb;83(2):261-6.
Farag NH, Rashed HA, Hassan M, Darweesh A, Shehata M, Hassanein T, Mills PJ.
Department of Epidemiology and Biostatistics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Abstract
Chronic hepatitis C (HCV) infection is associated with cognitive impairments which might be mediated through a secondary inflammatory cascade. Egypt has an unusually high prevalence of HCV monoinfections and is an ideal site for the study of the isolated effects of HCV infection. Therefore, in a hospital-based cross-sectional study based in Egypt, this study compared cognitive functioning and serum markers of inflammation in 11 HCV positive cases and 14 HCV negative controls. The Wisconsin Card Sorting Test was used to assess cognitive flexibility and the Brief Visuospatial Memory Test-Revised was used to assess learning and memory. Circulating levels of soluble tumor necrosis factor receptor II (sTNFR-II), monocyte chemotactic protein-1 (MCP-1/CCL2), and soluble CD14 (sCD14) were determined as indices of inflammation. HCV positive cases had higher levels of sTNFR-II (t = -3.5, P = 0.002). HCV positive cases also had significantly worse cognitive flexibility with higher number of total errors (t = -2.18, P = 0.04), and preservative responses (t = -2.12, P = 0.05), and lower number of conceptual level responses (t = 1.32, P = 0.04) on the Wisconsin Card Sorting test. In conclusion, results from this pilot study indicate that HCV+ patients have worse cognitive performance and somewhat greater inflammatory activity as compared to controls. The increased inflammation may be associated with the cognitive impairments observed in these HCV+ patients. J. Med. Virol. 83:261-266, 2011. © 2010 Wiley-Liss, Inc.
PMID: 21181920 [PubMed - in process]
Source
Farag NH, Rashed HA, Hassan M, Darweesh A, Shehata M, Hassanein T, Mills PJ.
Department of Epidemiology and Biostatistics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Abstract
Chronic hepatitis C (HCV) infection is associated with cognitive impairments which might be mediated through a secondary inflammatory cascade. Egypt has an unusually high prevalence of HCV monoinfections and is an ideal site for the study of the isolated effects of HCV infection. Therefore, in a hospital-based cross-sectional study based in Egypt, this study compared cognitive functioning and serum markers of inflammation in 11 HCV positive cases and 14 HCV negative controls. The Wisconsin Card Sorting Test was used to assess cognitive flexibility and the Brief Visuospatial Memory Test-Revised was used to assess learning and memory. Circulating levels of soluble tumor necrosis factor receptor II (sTNFR-II), monocyte chemotactic protein-1 (MCP-1/CCL2), and soluble CD14 (sCD14) were determined as indices of inflammation. HCV positive cases had higher levels of sTNFR-II (t = -3.5, P = 0.002). HCV positive cases also had significantly worse cognitive flexibility with higher number of total errors (t = -2.18, P = 0.04), and preservative responses (t = -2.12, P = 0.05), and lower number of conceptual level responses (t = 1.32, P = 0.04) on the Wisconsin Card Sorting test. In conclusion, results from this pilot study indicate that HCV+ patients have worse cognitive performance and somewhat greater inflammatory activity as compared to controls. The increased inflammation may be associated with the cognitive impairments observed in these HCV+ patients. J. Med. Virol. 83:261-266, 2011. © 2010 Wiley-Liss, Inc.
PMID: 21181920 [PubMed - in process]
Source
Dietary History and Physical Activity and Risk of Advanced Liver Disease in Veterans with Chronic Hepatitis C Infection
Dig Dis Sci. 2010 Dec 28. [Epub ahead of print]
White DL, Richardson PA, Al-Saadi M, Fitzgerald SJ, Green L, Amaratunge C, Anand M, El-Serag HB.
Section of Health Services Research, Department of Medicine, Baylor College of Medicine, 2450 Holcombe Blvd (01Y), Houston, TX, 77021, USA, dwhite1@bcm.edu.
Abstract
BACKGROUND: The role of customary diet and physical activity in development of advanced HCV-related liver disease is not well-established.
METHODS: We conducted a retrospective association study in 91 male veterans with PCR-confirmed chronic HCV and biopsy-determined hepatic pathology. Respondents completed the Block Food Frequency and the International Physical Activity questionnaires. We conducted three independent assessments based on hepatic pathology: fibrosis (advanced = F3-F4 vs. mild = F1-F2), inflammation (advanced = A2-A3 vs. mild = A1) and steatosis (advanced = S2-S3 vs. mild = S1). Each assessment compared estimated dietary intake and physical activity in veterans with advanced disease to that in analogous veterans with mild disease. Multivariate models adjusted for total calories, age, race/ethnicity, biopsy-to-survey lag-time, BMI, pack-years smoking, and current alcohol use.
RESULTS: Average veteran age was 52, with 48% African-American. Advanced fibrosis was more prevalent than advanced inflammation or steatosis (52.7% vs. 29.7% vs. 26.4%, respectively). The strongest multivariate association was the suggestive 14-fold significantly decreased advanced fibrosis risk with lowest dietary copper intake (OR = 0.07, 95% CI 0.01-0.60). Other suggestive associations included the 6.5-fold significantly increased advanced inflammation risk with lower vitamin E intake and 6.2-fold significantly increased advanced steatosis risk with lower riboflavin intake. The only physical activity associated with degree of hepatic pathology was a two-fold greater weekly MET-minutes walking in veterans with mild compared to advanced steatosis (P = 0.02).
CONCLUSIONS: Several dietary factors and walking may be associated with risk of advanced HCV-related liver disease in male veterans. However, given our modest sample size, our findings must be considered as provisional pending verification in larger prospective studies.
PMID: 21188525 [PubMed - as supplied by publisher]
Source
White DL, Richardson PA, Al-Saadi M, Fitzgerald SJ, Green L, Amaratunge C, Anand M, El-Serag HB.
Section of Health Services Research, Department of Medicine, Baylor College of Medicine, 2450 Holcombe Blvd (01Y), Houston, TX, 77021, USA, dwhite1@bcm.edu.
Abstract
BACKGROUND: The role of customary diet and physical activity in development of advanced HCV-related liver disease is not well-established.
METHODS: We conducted a retrospective association study in 91 male veterans with PCR-confirmed chronic HCV and biopsy-determined hepatic pathology. Respondents completed the Block Food Frequency and the International Physical Activity questionnaires. We conducted three independent assessments based on hepatic pathology: fibrosis (advanced = F3-F4 vs. mild = F1-F2), inflammation (advanced = A2-A3 vs. mild = A1) and steatosis (advanced = S2-S3 vs. mild = S1). Each assessment compared estimated dietary intake and physical activity in veterans with advanced disease to that in analogous veterans with mild disease. Multivariate models adjusted for total calories, age, race/ethnicity, biopsy-to-survey lag-time, BMI, pack-years smoking, and current alcohol use.
RESULTS: Average veteran age was 52, with 48% African-American. Advanced fibrosis was more prevalent than advanced inflammation or steatosis (52.7% vs. 29.7% vs. 26.4%, respectively). The strongest multivariate association was the suggestive 14-fold significantly decreased advanced fibrosis risk with lowest dietary copper intake (OR = 0.07, 95% CI 0.01-0.60). Other suggestive associations included the 6.5-fold significantly increased advanced inflammation risk with lower vitamin E intake and 6.2-fold significantly increased advanced steatosis risk with lower riboflavin intake. The only physical activity associated with degree of hepatic pathology was a two-fold greater weekly MET-minutes walking in veterans with mild compared to advanced steatosis (P = 0.02).
CONCLUSIONS: Several dietary factors and walking may be associated with risk of advanced HCV-related liver disease in male veterans. However, given our modest sample size, our findings must be considered as provisional pending verification in larger prospective studies.
PMID: 21188525 [PubMed - as supplied by publisher]
Source
January 1, 2011
A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin
Gastroenterology. 2010 Nov;139(5):1593-601. Epub 2010 Jul 14.
Swain MG, Lai MY, Shiffman ML, Cooksley WG, Zeuzem S, Dieterich DT, Abergel A, Pessôa MG, Lin A, Tietz A, Connell EV, Diago M.
Health Research Innovation Center, University of Calgary, Calgary, Alberta, Canada. swain@ucalgary.ca
Abstract
BACKGROUND & AIMS: A sustained virologic response (SVR) to therapy for hepatitis C virus (HCV) infection is defined as the inability to detect HCV RNA 24 weeks after completion of treatment. Although small studies have reported that the SVR is durable and lasts for long periods, it has not been conclusively shown.
METHODS: The durability of treatment responses was examined in patients originally enrolled in one of 9 randomized multicenter trials (n = 1343). The study included patients who received pegylated interferon (peginterferon) alfa-2a alone (n = 166) or in combination with ribavirin (n = 1077, including 79 patients with normal alanine aminotransferase levels and 100 patients who were coinfected with human immunodeficiency virus and HCV) and whose serum samples were negative for HCV RNA (<50 IU/mL) at their final assessment. Patients were assessed annually, from the date of last treatment, for a mean of 3.9 years (range, 0.8-7.1 years).
RESULTS: Most patients (99.1%) who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period. Serum samples from 0.9% of the patients contained HCV RNA a mean of 1.8 years (range, 1.1-2.9 years) after treatment ended. It is not clear if these patients were reinfected or experienced a relapse.
CONCLUSIONS: In a large cohort of patients monitored for the durability of an SVR, the SVR was maintained for almost 4 years after treatment with peginterferon alfa-2a alone or in combination with ribavirin. In patients with chronic hepatitis C infection, the SVR is durable and these patients should be considered as cured.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID: 20637202 [PubMed - indexed for MEDLINE]
Source
Swain MG, Lai MY, Shiffman ML, Cooksley WG, Zeuzem S, Dieterich DT, Abergel A, Pessôa MG, Lin A, Tietz A, Connell EV, Diago M.
Health Research Innovation Center, University of Calgary, Calgary, Alberta, Canada. swain@ucalgary.ca
Abstract
BACKGROUND & AIMS: A sustained virologic response (SVR) to therapy for hepatitis C virus (HCV) infection is defined as the inability to detect HCV RNA 24 weeks after completion of treatment. Although small studies have reported that the SVR is durable and lasts for long periods, it has not been conclusively shown.
METHODS: The durability of treatment responses was examined in patients originally enrolled in one of 9 randomized multicenter trials (n = 1343). The study included patients who received pegylated interferon (peginterferon) alfa-2a alone (n = 166) or in combination with ribavirin (n = 1077, including 79 patients with normal alanine aminotransferase levels and 100 patients who were coinfected with human immunodeficiency virus and HCV) and whose serum samples were negative for HCV RNA (<50 IU/mL) at their final assessment. Patients were assessed annually, from the date of last treatment, for a mean of 3.9 years (range, 0.8-7.1 years).
RESULTS: Most patients (99.1%) who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period. Serum samples from 0.9% of the patients contained HCV RNA a mean of 1.8 years (range, 1.1-2.9 years) after treatment ended. It is not clear if these patients were reinfected or experienced a relapse.
CONCLUSIONS: In a large cohort of patients monitored for the durability of an SVR, the SVR was maintained for almost 4 years after treatment with peginterferon alfa-2a alone or in combination with ribavirin. In patients with chronic hepatitis C infection, the SVR is durable and these patients should be considered as cured.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID: 20637202 [PubMed - indexed for MEDLINE]
Source
The impact of donor race on recurrent hepatitis C after liver transplantation
Transplant Proc. 2010 Dec;42(10):4175-7.
Moeller M, Zalawadia A, Alrayes A, Divine G, Brown K, Moonka D.
Abstract
BACKGROUND: Several studies have demonstrated mixed results regarding the influence of donor race on patient and graft survival in patients infected with hepatitis C virus (HCV) after liver transplant. However, few studies have looked at the impact of donor race on recurrent HCV. This study is a retrospective analysis of the influence of patient and donor race on the severity of recurrent HCV at a single center.
METHODS: Of patients transplanted at our center between 2000 and 2006, 222 were infected with HCV. Of these, 165 were eligible to be evaluated for recurrent HCV after transplant. We excluded those with patient and graft loss within 1 year that was not related to recurrent HCV, patients with advanced fibrosis from other causes, those who did not undergo posttransplant liver biopsy, and those lost to follow-up. Patients were given a recurrent HCV score of 1, 2, or 3. A score of 1 was assigned if the patient had no more than mild portal fibrosis at 1 year and no bridging fibrosis at any point. A score of 2 was defined as moderate portal fibrosis or focal bridging fibrosis at 1 year or bridging fibrosis or cirrhosis after 3 years. A score of 3 was defined as bridging fibrosis, cirrhosis, or graft loss from HCV within 3 years. Baseline characteristics including donor and recipient age, race, sex, body mass index, ischemia time, hypertension, and diabetes were recorded. Analysis was performed with ordinal multivariate logistic regression modeling.
RESULTS: Of the 165 patients with a recurrent HCV score, 105 (64%) had a score of 1, 29 patients (17%) had a score of 2, and 31 patients (19%) had a score of 3. In all, 132 recipients (80%) had white donors, and 26 (16%) had African American donors, 115 patients (70%) were white and 40 (24%) were African American. The mean recurrent HCV scores for the patient donor and recipient race combinations are as follows: white donor and white recipient, 1.54; white donor and African American recipient, 1.89; African American donor and white recipient, 1.18; and African American donor and African American recipient, 1.23. Having a white donor also significantly associated with a higher recurrent HCV score regardless of recipient race (odds ratio 2.93, P = .044) in African American patients, having a white donor had an odds ratio of 4.62 (P = .046). After adjusting for donor age and sex and patient age and sex, having a white donor was still found to be associated with a higher recurrent HCV score (4.48, P = .0275) on multivariate analysis. For all 222 patients, donor race was not associated with overall patient and graft survival.
CONCLUSION: Patients receiving white donor grafts had significantly worse recurrent HCV than those receiving grafts from African American donors regardless of recipient race. This difference was especially marked in African American recipients and persisted on multivariate analysis. These data suggest a graft from a white donor is potentially one more important variable in identifying patients at risk for more aggressive recurrent HCV after orthotopic liver transplant.
Copyright © 2010 Elsevier Inc. All rights reserved.
PMID: 21168656 [PubMed - in process]
Source
Moeller M, Zalawadia A, Alrayes A, Divine G, Brown K, Moonka D.
Abstract
BACKGROUND: Several studies have demonstrated mixed results regarding the influence of donor race on patient and graft survival in patients infected with hepatitis C virus (HCV) after liver transplant. However, few studies have looked at the impact of donor race on recurrent HCV. This study is a retrospective analysis of the influence of patient and donor race on the severity of recurrent HCV at a single center.
METHODS: Of patients transplanted at our center between 2000 and 2006, 222 were infected with HCV. Of these, 165 were eligible to be evaluated for recurrent HCV after transplant. We excluded those with patient and graft loss within 1 year that was not related to recurrent HCV, patients with advanced fibrosis from other causes, those who did not undergo posttransplant liver biopsy, and those lost to follow-up. Patients were given a recurrent HCV score of 1, 2, or 3. A score of 1 was assigned if the patient had no more than mild portal fibrosis at 1 year and no bridging fibrosis at any point. A score of 2 was defined as moderate portal fibrosis or focal bridging fibrosis at 1 year or bridging fibrosis or cirrhosis after 3 years. A score of 3 was defined as bridging fibrosis, cirrhosis, or graft loss from HCV within 3 years. Baseline characteristics including donor and recipient age, race, sex, body mass index, ischemia time, hypertension, and diabetes were recorded. Analysis was performed with ordinal multivariate logistic regression modeling.
RESULTS: Of the 165 patients with a recurrent HCV score, 105 (64%) had a score of 1, 29 patients (17%) had a score of 2, and 31 patients (19%) had a score of 3. In all, 132 recipients (80%) had white donors, and 26 (16%) had African American donors, 115 patients (70%) were white and 40 (24%) were African American. The mean recurrent HCV scores for the patient donor and recipient race combinations are as follows: white donor and white recipient, 1.54; white donor and African American recipient, 1.89; African American donor and white recipient, 1.18; and African American donor and African American recipient, 1.23. Having a white donor also significantly associated with a higher recurrent HCV score regardless of recipient race (odds ratio 2.93, P = .044) in African American patients, having a white donor had an odds ratio of 4.62 (P = .046). After adjusting for donor age and sex and patient age and sex, having a white donor was still found to be associated with a higher recurrent HCV score (4.48, P = .0275) on multivariate analysis. For all 222 patients, donor race was not associated with overall patient and graft survival.
CONCLUSION: Patients receiving white donor grafts had significantly worse recurrent HCV than those receiving grafts from African American donors regardless of recipient race. This difference was especially marked in African American recipients and persisted on multivariate analysis. These data suggest a graft from a white donor is potentially one more important variable in identifying patients at risk for more aggressive recurrent HCV after orthotopic liver transplant.
Copyright © 2010 Elsevier Inc. All rights reserved.
PMID: 21168656 [PubMed - in process]
Source
Subscribe to:
Posts (Atom)