January 4, 2011

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
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

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
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
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
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.

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