August 2, 2010

By Caitlin McHugh and Courtney McQueen
Published: Aug 2, 2010 1:44 pm

Several studies presented at the 2010 International AIDS Conference examined lipodystrophy and the effects of antiretroviral medications on cholesterol levels.

Lipodystrophy is a common side effect associated with HIV treatments. It causes changes in fat distribution that can lead to changes in body shape, increased levels of lipids (cholesterol and fatty acids) in the blood, and greater risk of heart problems.

Symptoms of lipodystrophy include loss of fat in the legs, face, arms, and buttocks; and an increase of fat in the stomach, upper back or neck, and breasts.

One of the studies looked at factors affecting lipodystrophy and poor body image. Another study showed that ultrasonic liposuction is an effective treatment for “buffalo hump,” excess fat on the back of the neck.

Several other studies focused on antiretroviral drugs, particularly protease inhibitors, and their association with high cholesterol.

Switching from Epzicom (abacavir/lamivudine) to Truvada (emtricitabine/tenofovir) was found to improve cholesterol levels.

An evaluation of protease inhibitors showed that although they do not always cause increased lipid levels, combining protease inhibitors is more likely to cause increased lipids. Another study found that protease inhibitors caused high cholesterol and high triglycerides in children and adolescents.

Also, once daily administration of Prezista (darunavir) plus Norvir (ritonavir), with a lower total dose, improved lipid levels compared to twice daily administration.

Factors Associated With Lipodystrophy And Poor Body Image

This study followed 337 people with HIV for three months to examine any links between lipodystrophy, poor body image, and other conditions such as depression and anxiety.

Poor body image increased as participants experienced more lipodystrophy symptoms, including increased stomach fat, thin arms or legs, fat on the back of the neck, and visible leg veins.

Lipodystrophy symptoms were more frequent in patients who were white or Hispanic, had AIDS, or whose antiretroviral medications were all in the same drug class. Participants with undetectable viral loads showed fewer lipodystrophy symptoms.

Most participants with lipodystrophy also reported other conditions, including depression (62 percent), fatigue (62 percent), nerve damage (58 percent), anxiety (50 percent), diarrhea (43 percent), and nausea (38 percent).

The researchers concluded that even with improved antiretroviral regimens, lipodystrophy and poor body image are still a problem. They also suggested other conditions, such as nausea and depression, may affect development of poor body image.

Ultrasonic Liposuction May Successfully Treat “Buffalo Hump”

In this study, Spanish surgeons removed excess fat accumulation on the back of the neck (“buffalo hump”) of 26 HIV-positive patients, using ultrasonic liposuction. Patients were evaluated 24 and 48 weeks after the surgery.

Ultrasonic liposuction is a form of liposuction, or fat removal, which uses sound waves to liquefy fat.

The surgeons were able to use ultrasonic liposuction to remove an average of 47 fluid ounces of liquefied fat from the patients.

The most common side effects of the liposuction were bruising and swelling. None of the patients had serious side effects from the surgery after 48 weeks; one patient had to undergo additional surgery after 42 weeks because fat had reappeared.

Most of the patients (92 percent) reported that they were “satisfied” or “very satisfied” with the results of the liposuction.

Researchers concluded that ultrasonic liposuction is an effective and safe treatment for the removal of fat accumulation on the back of the neck.

Rate And Predictors Of Metabolic Syndrome Development After Starting Antiretroviral Treatment

In this study, researchers examined the rate of and risk factors for metabolic syndrome development in people with HIV who had been on antiretroviral therapy for less than four years.

Metabolic syndrome is characterized by insulin resistance (pre-diabetes), high blood pressure, and high blood lipid levels.

Metabolic syndrome occurred in 18 percent of the study participants, which is similar to the rate found in previous studies of people with HIV taking antiretrovirals.

The results revealed that older age, hepatitis C infection, high cholesterol, and longer exposure to protease inhibitors increased the risk of developing metabolic syndrome.

Length of HIV infection, CD4 (white blood cell) count, and viral load (amount of virus in the blood) were not associated with risk of developing metabolic syndrome.

Switching From Epzicom To Truvada Reduces Cholesterol

In a 12-week study of 85 adults with HIV, participants were randomly assigned to either continue on Epzicom and Kaletra (lopinavir/ritonavir) or switch to Truvada plus Kaletra. Results showed that switching to Truvada improved cholesterol levels slightly while maintaining viral control.

Previous studies have shown that medications containing abacavir, such as Epzicom, can cause high cholesterol.

Researchers predicted that switching from an antiretroviral therapy regime with Epzicom, a combination of abacavir and lamivudine, to one with Truvada, which does not contain abacavir, would improve cholesterol levels in participants.

As predicted, the results revealed that switching from Epzicom and Kaletra to Truvada and Kaletra maintained HIV viral control, improved cholesterol levels, and decreased the participants’ risk of heart disease.

Combining Protease Inhibitors May Increase Cholesterol And Triglyceride Levels

Another study evaluated the effect of protease inhibitors on levels of lipids – cholesterol and triglycerides.

In the past, protease inhibitors have been associated with increased cholesterol and triglyceride levels. This study examined patients on protease inhibitor-only regimens to allow researchers to see the drugs’ effects on blood lipid levels without other types of antiretrovirals complicating the results.

Researchers analyzed lipid levels of a total of 78 adults with HIV who were taking protease inhibitors only. Although cholesterol and triglyceride levels both increased slightly over 48 weeks, the researchers did not consider the changes large enough to be significant.

However, the researchers did observe that combining protease inhibitors, such as Reyataz (atazanavir) plus Kaletra, or Lexiva (fosamprenavir) plus Invirase (saquinavir mesylate) and Norvir, raised “bad” cholesterol levels significantly more than just a single protease inhibitor.

They concluded that protease inhibitors do not always raise lipid levels, but combining them may increase the risk of developing high cholesterol.

Protease Inhibitors May Increase Cholesterol And Triglycerides In Children And Adolescents

An HIV clinic in Romania evaluated cholesterol and triglyceride levels in 130 children and adolescents between the ages of 9 and 18 whose antiretroviral regimens included protease inhibitors.

After 12 months, the researchers found that a large number of the children had high cholesterol (35 percent) and/or high triglyceride levels (39 percent). In addition, 8 percent had high blood sugar levels.

These abnormalities were more common in patients who had previously been treated with protease inhibitors than in patients taking protease inhibitors for the first time.

Although most of the cases were mild, three of the children did experience severe metabolic abnormalities that forced them to discontinue antiretroviral therapy.

Lower Cholesterol And Triglyceride Levels Are Associated With Once Daily Prezista/Norvir, Compared to Twice Daily Therapy

A Phase 3b study compared the effectiveness and impact on lipid levels – cholesterol and triglycerides – of once daily versus twice daily dosages of the protease inhibitor Prezista plus Norvir. The total dosage per day for once daily administration was lower (800 milligrams) than for twice daily administration (1,200 milligrams).

The study took place over 48 weeks and examined treatment-experienced HIV-positive adults.

High cholesterol and triglyceride levels occurred significantly less in the group of participants taking the once daily dosage of Prezista/Norvir than in the group taking the twice daily dosage.

The researchers also showed that the once daily dosage was as effective as the twice daily dose and was well tolerated.

For more information, please see the AIDS 2010 conference website.

Source

A Plan to Recover More Organs for Transplant Runs Into Difficulty

By ANEMONA HARTOCOLLIS
Published: August 1, 2010
 
For years, even as the medical community persuaded more people to become organ donors, it faced a seemingly insurmountable problem: Most people do not die in hospitals, making saving their organs for transplant nearly impossible.
 
Three years ago, an emergency doctor at Bellevue Hospital Center in Manhattan proposed a groundbreaking plan. The city would have an “organ preservation vehicle” monitor emergency radio frequencies and chase after ambulances, ready to swoop in as soon as a person was declared dead.

But with a deadline to qualify for $1.5 million in federal grant money just a month away, the idea has run into what might be another insurmountable barrier: How to meet the needs of law enforcement officials who want to preserve the bodies — with all the organs intact — of people who die under circumstances that might need to be investigated?

The objections come after exhaustive attempts by the plan’s architects to overcome things like ethical concerns about making sure no life-saving treatment was withheld, and the more visceral reaction that having an organ-harvesting crew shadow a medical crew sounds ghoulish.

“We’re in favor in principle and are working to have it happen,” Paul J. Browne, a spokesman for the Police Department, said last week. “The issue is essentially the city law on who is in charge of the body.”

The police are required to report to the medical examiner deaths that result from apparent homicide, accident or suicide, or that occur in a correctional facility or in any suspicious or unusual manner, including people who are young and seemingly healthy. The medical examiner or a representative is then required, according to the city code, to go to the scene to “take charge” of the dead body and investigate the cause of death.

But there is only a short window of time after death — perhaps 20 to 30 minutes — for the organs to be preserved. That leaves little time for the medical examiner to arrive at the scene and release the body. Mr. Browne said the concern was that responsibility for making the right call would be shifted to a police officer at the scene.

Dr. Lewis R. Goldfrank, the leader of New York’s project, and chairman of emergency medicine at Bellevue, the city’s premier public hospital, said last week that he was working hard to overcome the concerns. He said the project had been configured to exclude “anyone who is conceivably involved in a crime — a gunshot or stab wound, someone who might be strangled, you wouldn’t touch.”

He said that the exclusions would be based on the examination of a physician at the scene, paramedics and police officers, and that the medical examiner could be consulted by phone. “We have already reached agreement with the office of the chief medical examiner that that’s probably adequate,” he said. An agreement had been made, he said, to take a blood sample to test for poisoning.

Ellen Borakove, a spokeswoman for the medical examiner’s office, said that the medical examiner wanted the project to work out but declined to comment further.

On Friday, Jessica Scaperotti, a spokeswoman for Mayor Michael R. Bloomberg, said: “Because rapid organ recovery requires important decisions to be made in new ways under tight deadlines, we have to think through the procedures for releasing a body to the hospital to prevent the policy from having unintended consequences.

“The city is very interested in promoting organ donation and continues to discuss the possibility of a rapid organ-recovery ambulance to expedite the process and save lives.”

Dr. Goldfrank said the protocol had also been adjusted to address uneasiness about the approach.

The organ-recovery vehicles would be parked out of sight of the ambulances, and the emergency medical crews would not be made aware of their presence, to avoid influencing their efforts to save the person. Also, a person’s consent for organ donation would no longer be presumed, even if, for example, it said so on the person’s driver’s license. A family member would have to be at the scene to assent to the donation, he said.

Dr. Goldfrank said the pilot was meant to last six months in the area around Bellevue and would involve kidney donation. He hoped it could then be expanded citywide.

“Ninety-five percent of people die outside a hospital,” he said. “They die when walking on the street or in their homes in bed.”

He estimated that nationwide every year, recovering organs outside the hospital could result in about 20,000 additional people becoming donors.

While that would help, it would make only a dent in the demand: Nearly 6,000 people are waiting for kidneys in the New York area alone, according to the New York Organ Donor Network.

Another barrier the project may encounter is the relatively small number of New Yorkers who have registered as organ donors. In New York City, about 580,000 residents are registered as potential donors, according to the New York Organ Donor Network.

New York’s proposed organ recovery project would be the only one of its kind presently operating in the United States, officials said, although it is based on models in Europe.

Source
Article Date: 02 Aug 2010 - 0:00 PDT
 
Vanishing bile duct syndrome (VBDS) refers to a group of disorders characterized by destruction and disappearance of intrahepatic (inside the liver) bile ducts. Multiple causes have been identified including infections, malignancies, autoimmune conditions and adverse effects of medications. The usual course of this condition is variable and many patients with VBDS respond to treatment of the underlying condition and/ or removal of the offending agent. However, others progress to cirrhosis and end stage liver disease requiring liver transplantation.
 
VBDS is rare in patients with HIV infection, and only one case has been reported in the literature, that of an HIV patient with advanced disease and cytomegalovirus infection. In addition, there are no reports of nevirapine, an anti-retroviral (anti-HIV) drug causing VBDS even though hepatotoxicity is an important side effect of the drug.

A case report published in the World Journal of Gastroenterology describes VBDS secondary to nevirapine use in an HIV-positive, pregnant female. The patient received care at the University of Texas, Memorial Hermann Hospital and the Texas Liver Center in Houston by Dr. Rajan Kochar and colleagues. A 28-yr-old African American female in the 3rd trimester of pregnancy presented to the emergency room with jaundice and itching for 3 days. She also complained of pruritus, light colored stools and dark urine. She was diagnosed with HIV infection in 2000 and had not been on highly active anti-retroviral therapy (HAART) since 2003, but recently started triple drug therapy to minimize risk of vertical transmission with zidovudine, lamivudine and nevirapine 4 wk prior to presentation. She had no history of any opportunistic infections and was not taking any prophylactic medications. Liver tests were abnormal and after liver biopsy was performed, a diagnosis of vanishing bile duct syndrome (VBDS) was made. Liver transplant evaluation was subsequently initiated for the patient.

The most likely cause of VBDS in this patient was drug-induced liver injury (DILI). Nevirapine, a non-nucleoside reverse transcriptase inhibitor, is being increasingly used in pregnant patients owing to its favorable side effect profile and lower teratogenicity compared to protease inhibitors. However, hepatotoxicity is the major adverse effect of nevirapine (5%) and most often manifests as a hypersensitivity reaction with fever, rash and elevated liver tests within the first few weeks of therapy. Late onset hepatotoxicity after several weeks of nevirapine use has also been described in several cases and may be an idiosyncratic reaction to the drug. Although several case reports have demonstrated a cholestatic pattern of nevirapine toxicity, VBDS has never been reported. Ms. B did not have fever and rash, but had evidence of cholestatic hepatitis and a temporal association between nevirapine use and development of biochemical abnormalities. Therefore, nevirapine toxicity was felt to be the most likely cause of cholestasis and VBDS.

To the best of the authors' knowledge, this is the first reported case of nevirapine induced cholestatic hepatitis in a patient with HIV leading to severe ductopenia and VBDS. Therefore, VBDS should be considered in all HIV patients with chronic cholestasis, especially those with a history of nevirapine use. In addition, the possibility of this potentially irreversible adverse event should be kept in mind before making the decision to prescribe nevirapine.

Reference:
Kochar R, Nevah MI, Lukens FJ, Fallon MB, Machicao VI. Vanishing bile duct syndrome in human immunodeficiency virus: Nevirapine hepatotoxicity revisited. World J Gastroenterol 2010; 16(26): 3335-3338

Source:
Lin Tian
World Journal of Gastroenterology

Source

A Potential Chemotherapeutic Drug To Treat Hepatocellular Carcinoma

Article Date: 02 Aug 2010 - 0:00 PDT

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, particularly in China. However, HCC remains one of the more difficult cancers to treat. It is important to screen for new anti-cancer drugs. A number of dietary compounds possess anti-cancer properties. These dietary compounds may modify the activity of specific targets that control cell proliferation and apoptosis. Galangin could inhibit the methoxyresorufin O-demethylase activity of CYP1A2, CYP1A1 and P-form phenolsulfotransferase. Galangin induced apoptosis in several cancer cell lines and arrested the cell cycle, modulated the expression of cycline/cdk, and decreased Bcl-2. It was suggested that galangin may be a potential anti-tumor agent. However, the mechanism by which galangin exerts its anti-tumor activity is unknown.

A research article published in the World Journal of Gastroenterology addresses this issue. This is the first study to report that galangin mediates apoptosis through a mitochondrial pathway.

Their data demonstrated that:
  • galangin induces HCC cell apoptosis by triggering Bax translocation to the mitochondria;
  • galangin-treated HCC cells causes the release of AIF and cytochrome c into the cytosol from the mitochondria; and
  • overexpression of Bcl-2 attenuated galangin-induced HepG2 cells apoptosis, while down-regulated Bcl-2 expression enhanced galangin to induce cell apoptosis.
Understanding the mechanism by which galangin induces apoptosis may lead to its use as an anti-cancer treatment of HCC. This study may represent a future potential chemotherapeutic drug in the treatment of HCC with galangin.
 
Reference:
Zhang HT, Luo H, Wu J, Lan LB, Fan DH, Zhu KD, Chen XY, Wen M, Liu HM. Galangin induces apoptosis of hepatocellular carcinoma cells via the mitochondrial pathway. World J Gastroenterol 2010; 16(27): 3377-3384

Source:
Ye-Ru Wang
World Journal of Gastroenterology

Source
Article Date: 02 Aug 2010 - 1:00 PDT

Recent studies suggest that MSCs possess a greater differentiation potential than once thought and several hepatic differentiation protocols from bone marrow cells have been established. However, the incidence of bone marrow-derived hepatocytes was low. Moreover, a long culture period is needed in most cases.

A research article published in World Journal of Gastroenterology addresses this issue. The research team led by Professor Shao JZ from College of Life Sciences of Zhejiang University used mice to investigate the role of VPA on hepatic differentiation of mBM-MSCs. The article indicates that additional exposure of mBM-MSCs to VPA considerably increased the hepatic differentiation in vitro and improved the liver injury by increased homing efficiency of cells to the damaged site in vivo.

The MSCs were successfully isolated from mouse bone marrow and demonstrated that they could differentiate into hepatocytes induced by VPA and well-defined cytokines in a sequential way. The present study demonstrated that VPA-mediated facilitation of hepatic differentiation was regulated by the selective expression of fibroblast growth factor (FGF) and hepatocyte growth factor (HGF) receptors, the increased amounts of acetylated H3 and H4 as well as the structural de-condensation of chromatin. These results provide new insights into the relationships between the epigenetic modification mediated by VPA and the hepatic differentiation from mBM-MSCs.

These findings may also be applicable to study endoderm differentiation and offers an unlimited source of functional hepatocyte-like cells applicable for pharmaco-toxicological research and testing, also this induced system has numerous potential advantages in clinical application.

Reference:
Dong XJ, Zhang H, Pan RL, Xiang LX, Shao JZ. Identification of cytokines involved in hepatic differentiation of mBM-MSCs under liver-injury conditions. World J Gastroenterol 2010; 16(26): 3267-3278

Source:
Lin Tian
World Journal of Gastroenterology

Source

Exciting Changes to Scientific Program at The Liver Meeting® 2010

AASLD News: July 29, 2010
By Arun J. Sanyal, MD, AASLD President

This year’s Liver Meeting® received a record-breaking number of abstracts and registration is now open. I recently had the opportunity to meet with the Scientific Program Committee and put the scientific program together for the meeting and would like to share my excitement and provide a preview of some of the offerings at The Liver Meeting® which make this the premier meeting related to liver diseases worldwide.

Hepatitis at the Liver Meeting

This year, the Postraduate Course will focus on viral hepatitis. This course is also extraordinarily timely given the intense interest generated by the Institute of Medicine (IOM) report and the follow up actions by AASLD outlined previously in this column. The Presidents Choice Lecture will be delivered by the honorable Dr. Howard Koh, Assistant Secretary of Health, United States government, who will outline federal initiatives to translate the IOM report into a plan to control the burden of viral hepatitis in the United States. These talks will be complemented by the clinical Leon Schiff State-of-the-Art Lecture, to be delivered by Dr. David Goldstein, on how recent advances in the genetic determinants of treatment response may allow tailoring treatment to the individual.

Clinical Trials

Several large clinical trials will be presented that are likely to be game changers in the practice of hepatology. These include the final results of telaprevir with interferon and ribavirin (ADVANCE trial), and the use of Boceprevir in non-responders or relapsers to first-line therapy for hepatitis C. The final results of the TONIC trial of metformin or vitamin E versus placebo for NAFLD in children performed by the NIDDK NASH Clinical Research Network will also be presented and will have a major impact on the future management of this disease both in children and in adults.

Cancer as a Theme

A major theme to emerge this year relates to liver cancer. The Liver Cancer Special Interest Group (SIG) will host a symposium on cholangiocarcinoma to highlight the burning issues in the field. A detailed molecular classification of cholangiocarcinoma with specific clinical implications will also be presented in a plenary session. Also, a number of scientific advances in the understanding of the molecular pathogenesis of hepatocellular cancer will be presented. These will synergize with a special session on stem cells and their role in neoplastic transformation in the liver. The Thomas E. Starzl Transplant Surgery State-of-the-Art Lecture will be given by Dr. Michael Abecassis who will discuss the role of liver transplantation in the management of liver cancer.

State-of-the-Art Lectures

In addition to the aforementioned Schiff and Starzl State-of-the-Art Lectures, the Hyman Zimmerman Hepatotoxicity State-of-the-Art Lecture will be delivered by Gyongi Szabo, MD, PhD, on the role of innate immunity in modulating liver injury and the high-quality science in the areas of cell signaling and cell biology that have broad implications for both a healthy liver and a wide range of liver diseases. This is complemented by three sessions on nonalcoholic steatohepatitis and alcohol-related liver disease – an increase from the one session at last year’s meeting and based on the exceptionally high quality of science that was submitted.

The role of bile acids in hepatic physiology has been recognized for many decades. It is now recognized that the process of enterohepatic circulation of bile acids sends signals to the rest of the body about the availability of nutrition from the gut and the cross talk between the intestine and liver via bile acid signaling plays a central role in nutritional homeostasis. The cellular mechanisms of how this is accomplished will be the focus of the Hans Popper Basic Science State-of-the-Art Lecture to be delivered by Prof. Johann Auwerx. This information will be particularly relevant for everyone interested in the current epidemic of obesity, diabetes, and fatty liver disease.

A Focus on Clinicians and Surgeons

For the practicing clinician, the offerings will continue to increase with the General Hepatology Update, a selection of early morning sessions, clinical symposia on liver cancer, portal hypertension, and a new session called the Hepatitis Debrief, which will place all of the new information presented at the liver meeting in perspective. Another new feature at The Liver Meeting® is the Emerging Trends Symposium, which will focus on advances in imaging in liver diseases with a focus on the imaging of tumors, assessment of fibrosis, and measurement of hepatic venous pressure gradient. Similarly, for our surgical colleagues, a workshop on split liver transplantation, donor related issues, the role of genetics in determining post transplant outcomes for those with hepatitis C, and engineering a transplantable liver are just some of the highlights.

These are only some of the many novel and innovative scientific advances in hepatology that will be presented at The Liver Meeting®. There is no question that the scientific and clinical content of the meeting will exceed your expectations and I hope to see you all in Boston to celebrate the best that the field has to offer.

This electronic newsletter is a bi-weekly publication of AASLD and replaces the former bi-monthly print newsletter and weekly e-news. Members are welcome to submit articles and may send suggestions to aharan@aasld.org.

Source
Norra MacReady

August 2, 2010 (Vienna, Austria) — Life expectancy is increasing for people with HIV and AIDS, and with it, cancer risk and incidence, Eric A. Engels, MD, MPH, reported here at AIDS 2010: XVIII International AIDS Conference.

This means that cancer prevention and treatment among people infected with HIV will become more and more important in the years ahead, said Dr. Engels, senior investigator at the Division of Cancer Epidemiology and Genetics at the National Cancer Institute.

In an analysis of data collected by the Centers for Disease Control and Prevention during 15 years from 15 regions of the United States, Dr. Engels and coauthors found that the proportion of the US AIDS population aged 50 years or more increased from 8% of 93,802 people in 1991 to 29% of 399,762 people in 2005.

During the same time period, the incidence of non-AIDS-defining cancers increased, from 416 in 1991 to 2437 in 2005, with a total of 76,558 cancers in this cohort.

In contrast, AIDS-defining cancers such as Kaposi's sarcoma and non-Hodgkin's lymphoma decreased from 7284 cases in 1993 to 1736 cases in 2005.

Cases of anal cancer increased from 18 in 1991 to 358 in 2005, and cases of prostate cancer increased from 10 to 123 from 1991 to 2005, largely as a result of rising rates of those malignancies, Dr. Engels said during an oral abstract session. The rates of lung cancer and Hodgkin's lymphoma remained relatively stable, but the absolute number of cases increased from 112 to 478 and from 72 to 169, respectively.

The authors also estimated cancer incidence between 2004 and 2007 for people in 34 states who were HIV-positive but did not have AIDS. In that population, 4388 cancers occurred, including 381 anal cancers, 892 lung cancers, and 327 cases of Hodgkin's lymphoma.

Immunosuppression and coinfection with the human papillomavirus may explain, in part, the dramatic rise in the number of anal cancer cases, Dr. Engels told Medscape Medical News.

These findings are "in large part due to the increasing number of people living with HIV infection and the fact that they are getting older," he said. "Non-AIDS-defining cancers are now roughly as common as AIDS-defining cancers [in this population] and represent a priority for cancer prevention, screening, and treatment."

Treatment challenges among people with HIV and AIDS include immunosuppression and drug interactions between highly active antiretroviral therapy and chemotherapy. In addition, "many HIV-infected people present late to care, which can impair their response to cancer treatment," the investigator pointed out.

Strides in medications and management are allowing patients in this population "to enter the prime years for cancer development," noted Susan E. Krown, MD, head of the Human Papilloma Virus Working Group of the AIDS Malignancy Consortium at the National Cancer Institute.

Patients infected with HIV "are also more likely than HIV-uninfected individuals to smoke and to have coinfections, such as HPV and hepatitis B and C, that increase the likelihood of certain cancers. A particular challenge is to learn how best to manage the sometimes profound interactions between cancer therapeutic agents and antiretroviral drugs," said Dr. Krown, who is also a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York City. She was not involved in this research.

"The link between non-AIDS-defining cancers and HIV is not entirely clear, but appears to be related to factors beyond HIV and the associated immunosuppression," said Michael Fisch, MD, MPH, chairman of the Department of General Oncology at the M.D. Anderson Cancer Center in Houston, Texas. Along with lifestyle factors such as smoking and sexual behavior, "testosterone replacement, and perhaps even adherence to screening recommendations, may play a role in the association" between HIV and non-AIDS-defining cancers, he added. Dr. Fisch was also not involved in this study.

He took a brighter view of treatment than Dr. Krown. "In most instances, standard cancer therapy can be safely provided to HIV-infected patients," he told Medscape Medical News. "And I am optimistic that similar potential exists for the HIV population to reduce suffering and death due to cancer through standard screening and advice related to lifestyle and behavioral modifications."

Dr. Engels, Dr. Krown, and Dr. Fisch have disclosed no relevant financial relationships.

AIDS 2010: XVIII International AIDS Conference: Abstract WEAB 0101. Presented Wednesday, July 21, 2010

Source

The Next Pandemic

Author
Jeffrey Fried
 
Hepatitis C (HCV) is the next pandemic. 250-300 million people worldwide are carrying the virus. This is 5, five, times the number of people carrying HIV. HCV is the main cause for liver transplants. As of a few years ago, for every 20 people who die of HIV in the US, 11 people die of HCV because they cannot get a liver transplant. And what makes it particularly dangerous is that when contracting HCV the symptoms are usually mild, or none at all, and there are no obvious symptoms until 20 years later when the liver starts to fail. This means that people are giving the disease to other people simply because they don't know that they have it, so, they don't know what they should do to prevent transmitting it to others. Also, the period where most people appear to be without symptoms, is in fact not the case. During that time some people develop related disorders (http://www.webmd.com/hepatitis/connection-between-hepatitis-c-autoimmune-disorders) that can be very debilitating.

Currently the only drug therapy, interferon, works about 50% of the time for those who can afford it. It requires loading your body with interferon, the same chemical that your body uses to kill colds, and other viruses, producing the same side effects for 26 to 52 weeks. The cost of the therapy can be prohibitive for people with low income or no health insurance.

Surprisingly the effort needed to protect yourself is relatively simple, its just that most of us are unaware so we don't take any precautions. The story should explain the problem, present current, and emerging therapies, and provide a sense of what the reader should do to ensure that they are not carriers or receivers.

Source

New study to turn cancer research on its head

David Binning (Australian Life Scientist)
02 August, 2010 16:30

Research challenges conventional wisdom that cell death impedes tumour growth

Researchers at the Walter and Eliza Hall Institute (WEHI) have shown that programmed cell death or apoptosis, a process which has typically been assumed to prevent or slow the development of cancer, may in some instances contribute to its spreading.

“In general everything we’ve known indicates that if you have impaired cell death that helps the tumour to get going,” Professor Jerry Adams told Australian Life Scientist. “What’s exciting about this result is it’s the first case in which the opposite happens.”

For example, when the DNA in many cells is damaged, as occurs after repeated exposure to low doses of radiation, this leads to repeated cycles of cell death in the body’s tissues.

“Attempts by the body’s stem cells to repopulate the depleted tissue can then actually drive the tumour development,” project leader Professor Andreas Strasser said.

“That’s because the radiation, while killing many cells within a tissue, will create mutations in some of the surviving stem cells. When such abnormal (mutated) stem cells repopulate the tissue, they will divide many times and this can promote the development of tumours.”

A particular focus of the teams’ research was comparing the effects of radiation exposure in mice with and without the so-called Puma gene, which is essential for the death of cells with damaged DNA.

“If normal mice (which have the Puma gene) are given a low dose of radiation it destroys around 80 per cent of the white blood cells,” Professor Strasser said. “That does not kill the mouse but it does mean the stem cells in the bone marrow have to work extra hard to replenish the blood system. This can lead to the formation of tumours of white blood cells, called leukaemia’s, if the stem cells doing the re-populating have cancer-causing mutations."

In contrast, mice without the Puma gene did no experience this type of tumour development at all.

“If mice don’t have the Puma gene when they receive low doses of radiation the white blood cells are not destroyed, so you don’t force mutated stem cells to become activated (and divide) to replenish the blood system,” Professor Strasser explained.

The findings point to an increased risk of cancer development in people who have experienced cycles of cell damage followed by tissue re-population by stem cells. Examples include liver cancers such as those arising from viral infections like hepatitis C, or alcohol-related liver damage. The research may also help to shed light on the causes of secondary cancers which can appear in patients cured of their primary cancer by chemotherapy drugs which typically result in damaged DNA.

Further, these findings are expected to lead to a deeper understanding of the role and effectiveness of the new class of BH3 mimetics cancer drugs, which are designed to kill cancer cells.

Professor Adams said that the study results would likely be of interest to Abbot Laboratories, which is currently conducting similar research into cancer treatments. Abbott and the WEHI have a research collaboration agreement.

Funding for the WEHI study was provided by the National Health and Medical Research Council, the Leukaemia and Lymphoma Society, the National Institutes of Health (US), the Juvenile Diabetes Research Foundation, Cancer Council Victoria and the Victorian Government.

The complete findings were published this week in the international journal Genes and Development.

Source

Thousands may not know they have fatal blood infections

THOUSANDS of people in Nottingham could have potentially fatal infections such as hepatitis and HIV – but not know it.

The NHS says as many as 3,000 people in the city may have one or more blood-borne infections.

Hepatitis B and C and HIV can be spread though sex with an infected person, sharing needles or through a broken area of skin.

And 80% of sufferers – around 2,400 people – may not know they have them.

GPs are now routinely testing "at-risk" people from countries with high rates of blood-borne viruses, those who inject drugs or the sexual partners of sufferers.

And experts are calling for people in such groups to get themselves tested – to avoid putting themselves and others at risk.

Mick Mason of sexual health charity the Terrence Higgins Trust said those at risk should get tested as early as possible. "The earlier you can get people diagnosed, the less risk there is of passing it on," he said.

People can get test results for HIV within 20 minutes and for hepatitis B and C within a week from the charity's base at Barker Gate, the Lace Market.

The number of people thought to have HIV has risen sharply in recent years, with 428 new cases in 2007.

Infections rates have gone up in Nottingham due, in part, to people from countries with higher rates of blood-borne viruses coming to the city.

Hepatitis B and C are infections of the liver caused by a virus, which can cause significant damage if left untreated.

Human immunodeficiency virus (HIV) is a virus that attacks the body's immune system. It leaves an infected person with a high risk of developing a serious infection or disease, such as cancer.

Mr Mason contracted HIV as well as Hepatitis B and C in 1983 from contaminated blood plasma. "We do see more and more cases of cross-infection, when someone has hepatitis and HIV," he said.

"That is an added complication because the two conditions accelerate each other and the treatments have an adverse effect on the other condition."

The rise in the number of blood-borne virus cases was revealed in the annual report of the primary care trust's director of public health, Chris Packham.

Source

Conquering HIV, hepatitis C requires ongoing research, expert says

Publish date: Aug 1, 2010
By: John Jesitus

Key Points
  • More than a dozen drug candidates under development for HCV
  • Researchers are applying combination modalities established in cancer and HIV to HCV
Atlanta — Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may be out of the public eye, but curing these unseen epidemics requires ongoing research, says an expert who spoke at the 2010 annual meeting of the Society for Investigative Dermatology.
 
Although more than two dozen HIV drugs can alleviate suffering and prolong life, "The epidemic is not over," says Raymond Schinazi, Ph.D., D.Sc., professor of pediatrics, Emory University School of Medicine and Atlanta VA Medical Center. "We also know that more than 1 million people have been infected with HIV in the United States," and an estimated 60 million will be infected worldwide by 2015, he says, adding that only 28 percent of those who need treatment actually get it.
 
Before the advent of modern treatments in 1985, HIV had a 73 percent mortality rate, Dr. Schinazi says. But by 2008, more than 94 percent of people infected with HIV who receive Western standard-of-care treatment survive at least five years.
 
"More than 90 percent of HIV-infected subjects are taking one or more drugs invented at Emory University," he says. Examples include Atripla (efavirenz 600 mg, emtricitabine 200 mg, tenofovir-DF 300 mg; Bristol-Myers Squibb/Gilead), 3TC (beta-2',3'-dideoxy-3'-thiacytidine, also called Lamivudine; GlaxoSmithKline), Truvada (tenofovir-DF 300 mg/emtricitabine 200 mg, Gilead) and Viread (tenofovir-DF 300 mg, Gilead). As a professor of pediatrics, Dr. Schinazi says, "Probably the most important accomplishment is the fact that maternal-to-fetal transmission today is history. We rarely see it in the United States, although it still occurs in Africa" and elsewhere.
 
Hepatitis C
 
For hepatitis C virus (HCV), "We only have two drugs — ribavirin and interferon (IFN). Both are relatively toxic," Dr. Schinazi says. About 280 million people worldwide are infected with HCV. "There are 3 to 4 million infections per year globally, and we expect more than 800,000 U.S. patients to develop HCV-related cirrhosis this decade," he says.
 
Up to one-third of those with HCV are coinfected with HIV, Dr. Schinazi says, adding that coinfection complicates treatment because physicians must consider dangerous drug interactions. Both viruses share routes of transmission, which are all very dynamic.
 
"The number of patients with HCV treated in the United States is very small compared to the number of chronic carriers," Dr. Schinazi says. Treatment failures are common, he says, because the current standard of care does not work well against certain HCV genotypes. Only 30 to 60 percent of patients achieve sustained virological response (SVR, or a cure) on currently available HCV therapies, all of which require intravenous administration, he says.
 
Up-and-coming drugs
 
More than a dozen drug candidates are under development for HCV (Sarrazin C, Zeuzem S. Gastroenterology. 2010 Feb;138(2):447-462. Epub 2009 Dec 16. Review), Dr. Schinazi says. These include small molecules and interferon-related therapies.
 
"There are various classes of compounds, including nucleoside and non-nucleoside polymerase inhibitors, cyclophilin inhibitors, protease inhibitors (PIs) and, more recently, the very potent NS5A inhibitors," he says.
 
However, Dr. Schinazi says, only two candidates are in Food and Drug Administration phase 3 trials: telaprevir (Vertex) and boceprevir (Merck/Schering-Plough). "These PIs are having a remarkable effect on viral load in persons infected with HCV," he says. NS5A inhibitors also show promise in reducing viral load, though they're only in phase 1/2.
 
HCV drug candidates often fail, Dr. Schinazi says, due to side effects such as anemia, gastrointestinal issues, body composition changes or dermatologic side effects. Telaprevir can cause severe rashes, he notes, a fact which "probably should have been picked up in earlier development. Unfortunately, it wasn't," which has required investigators to cut the treatment duration from six or 12 months to 12 weeks.
 
HIV updates

People infected with HIV also can experience various dermatologic manifestations. Some, such as psoriasis, are associated with declining CD4 T cell counts, Dr. Schinazi says. Others — eczema/dermatitis, Kaposi's sarcoma, warts — occur despite adequate treatment. Still others, such as lichen planus, occur commonly with HIV-HCV coinfection.

Nevertheless, modern HIV therapies have simplified the complex multi-pill regimens of the 1980s and 1990s into a single pill with three active ingredients (Atripla, Truvada), which frequently achieves strong virus suppression. Meanwhile, Dr. Schinazi says, researchers are applying the combination modalities that have been established in cancer and HIV to HCV.

Researchers also must address HIV's persistence, he says. Even after extensive treatment, the virus rebounds without continued treatment, or when resistance develops. Additionally, persons on successful long-term treatment can experience "blips" wherein viral load climbs from undetectable levels to detectable levels. "Even one virus is enough to light the fire again and cause problems with reinfection (Pierson T, McArthur J, Siliciano RF. Annu Rev Immunol. 2000;18:665-708)," Dr. Schinazi says.

Researchers believe HIV's persistence stems at least partly from anatomical and cellular reservoirs of virus (in areas such as the gut or the brain) where current drugs cannot penetrate effectively, and from ongoing low-level replication. Accordingly, Dr. Schinazi says eradicating HIV will require systematic study of drug penetration into various compartments and its impact on local viral replication.

"Tissue macrophages are a major reservoir for HIV, in addition to the active and memory CD4+ T lymphocytes in the peripheral circulation," he says. En route to developing therapies that can eradicate HIV, Dr. Schinazi says, "We must develop systems to measure virus below current detection levels." Additionally, he says that researchers need preclinical tools that can identify and validate specific biochemical targets and rapidly screen drug candidates, perhaps using cell lines and/or primary cell assays.

Study details

In a recent study, Dr. Schinazi and his coauthors showed that after highly active antiretroviral therapy, viral "sanctuaries" persisted, with the highest levels of viral DNA and RNA found in the spleen, lymph nodes and gastrointestinal tract (North TW, Higgins J, Deere JD, et al. J Virol. 2010 Mar;84(6):2913-2922. Epub 2009 Dec 23).

For eradicating latent integrated HIV, he says the "shock and kill" strategy involves activating the virus and then stimulating it, leading to cell death (Hamer DH. Curr HIV Res. 2004 Apr;2(2):99-111). "The challenges are, how do we specifically kill the cells that are latently infected and deliver the drugs or deadly punch to initiate the cell apoptosis?" Dr. Schinazi says. Other potential approaches involve using anti-TNF-alpha treatment. "That will also be tested in the animal system we have developed."

In combating HCV, Dr. Schinazi says researchers have an advantage, because this virus does not establish latency. "Theoretically, we can eradicate this virus much more easily than HIV." Here, a promising drug candidate under development is a nucleoside developed at Emory in conjunction with Pharmasset, called R7128 (Roche). "The advantage of this nucleoside is that even when there is resistant virus, it is still active," he says.

In clinical testing, investigators combined R7128 (500 mg to 1,500 mg daily) with IFN and ribavirin for 28 days. "Preliminary results showed we had 85 percent rapid virological response in four weeks," Dr. Schinazi says. Researchers then combined the drug in doses of 500 mg or 1,000 mg daily with a PI (R7227, Roche; 100 mg or 200 mg daily) in an attempt to develop an IFN/ribavirin-free regimen.

"By day 14 there was a nearly five log10 drop irrespective of the dose (Gane EJ, Stedman C. First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: Safety, pharmacokinetics, and virologic results from INFORM-1 [abstract]. J Hepatol. 2008;50 (Suppl. 1): Abstract 1046, S380). Unfortunately, the PI caused some toxicity, so the dose has now been reduced to 100 mg daily, with a protease booster, a bit like we do with HIV," Dr. Schinazi says.

"This is where the future lies — the INFORM study demonstrated that two compounds with different targets can achieve tremendous viral reduction," he says. With HCV, "Cures are already possible with IFN and ribavirin. We just need to improve the SVR." He predicts that in the next year or so, drug combinations will provide SVR for more than 90 percent of patients with HCV.

Disclosures: Dr. Schinazi is founder and major shareholder of Pharmasset, Idenix and RFS Pharma. He also receives royalties from 3TC and LdT.

Source
Public release date: 2-Aug-2010

Contact: Cody Mooneyhan
cmooneyhan@faseb.org
301-515-0371
Federation of American Societies for Experimental Biology

New research published in the Journal of Leukocyte Biology suggests that blocking a membrane protein called Programmed Death 1 improves survival in a clinically relevant model of severe infection

Scientists have made an important discovery that could lead to new drugs that reduce the severity of blood infections leading to sepsis. Research presented in the August 2010 issue of Journal of Leukocyte Biology (http://www.jleukbio.org) shows how interfering with the function of the cell membrane protein called "Programmed Death 1" (PD-1) improves survival in a clinically relevant model of severe infection.

"Clinical trials of anti-PD-1 are currently underway in patients with cancer and in patients with hepatitis C," said Richard S. Hotchkiss, M.D., co-study author from the Department of Anesthesiology at Washington University School of Medicine in St. Louis, MO. "It is hoped that blocking PD-1 will lead to enhanced immune function and a resultant improved tumor elimination and viral eradication respectively."

To make this discovery, the researchers studied two groups of mice with a surgically induced severe infection that simulates a ruptured appendix in humans. One group of mice received an inactive antibody while the other group of mice received an antibody that blocked PD-1. The mice that received the PD-1 blocking antibody had a greater survival rate when compared to the mice that received the inactive control antibody. Results show that PD-1 inhibits the ability of the immune system to fight infection by suppressing the function of immune cells. Thus, blocking PD-1 can restore the ability of the host to combat infections, also helping to improve chances for survival.

"This research may lead to a new class of drugs that could treat severe bacterial infections, including those that are becoming increasingly resistant to today's antibiotics," said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology, "This study is one of science's many steps to keep pace or a step ahead of the evolutionary progress that these microrganisms are making."

###

The Journal of Leukocyte Biology (http://www.jleukbio.org/) publishes peer-reviewed manuscripts on original investigations focusing on the cellular and molecular biology of leukocytes and on the origins, the developmental biology, biochemistry and functions of granulocytes, lymphocytes, mononuclear phagocytes and other cells involved in host defense and inflammation. The Journal of Leukocyte Biology is published by the Society for Leukocyte Biology.

Details: Pavan Brahmamdam, Shigeaki Inoue, Jacqueline Unsinger, Katherine C. Chang, Jonathan E. McDunn, and Richard S. Hotchkiss Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol 2010 88: 233-240. doi: 10.1189/jlb.0110037 ; http://www.jleukbio.org/cgi/content/abstract/88/2/233

Source

New York To Reduce The Spread Of HIV And AIDS

Source: Governor of New York
Posted on: 2nd August 2010

Governor David A. Paterson has announced the enactment of two bills to reduce the spread of HIV/AIDS by updating New York’s HIV testing law to encourage increased testing rates and remove disincentives to participation in needle exchange and syringe access programs.

The Governor signed into law S.8227/A.11487, which will allow patients to agree to HIV testing as part of a general signed consent to medical care that remains in effect until it is revoked or expires.

The bill will also require health care providers to offer testing to their patients between 13 and 64 years of age, as recommended by the federal Centers for Disease and Control (CDC), and will facilitate authorization for testing in the case of certain occupational exposures to HIV infection.

“The enactment of this bill represents a significant step forward in combating the HIV/AIDS epidemic,” Governor Paterson said. “By making HIV testing a routine part of health care, this legislation will increase HIV testing rates, letting people learn their status and begin treatment at an earlier stage, which can significantly improve the length and quality of life and help reduce transmission of the disease.”

The bill will also, among other things:

  • Allow oral consent to an HIV test for a “rapid HIV test,” a newer type of testing that is generally available in settings that include hospitals and clinics;
  • Require, in accordance with the CDC’s 2006 recommendations, that an HIV related test be offered to every individual between the ages of 13 and 64 years of age receiving health services in any health setting, including hospitals, emergency rooms, hospital outpatient departments, and primary care settings including physician, physician assistant, nurse practitioner and midwife offices;
  • Permit anonymous testing of the blood of a person who is deceased, comatose or otherwise lacks the ability to consent, if someone such as a health care worker is exposed to the person’s blood and no one with the authority to consent to testing can be found in time for the exposed worker to begin medical treatment for HIV.
The Governor also signed into law his Program Bill No. 23 (A.8396-A/S.5620-A), which will clarify and enhance existing law regarding the possession of syringes or needles by individuals who participate in needle exchange programs.

These public health programs that provide intravenous drug users with access to clean syringes and to substance abuse counseling and health care have operated in New York for many years. Numerous State, national and international studies have found that such programs are very effective in reducing transmission of blood-borne diseases such as HIV and Hepatitis C.

A number of participants in such programs have been arrested for possession of needles and syringes which, although permitted under the Public Health Law, is not reflected in the Penal Law where the crimes are defined.

In addition, residue in such syringes could subject someone to criminal charges under the Penal Law, which is clearly in conflict with the spirit of the Public Health Law provisions and the objectives of the needle exchange and syringe access programs.

“The success of needle exchange and syringe access programs has been repeatedly verified to be instrumental in reducing the transmission of blood-borne diseases,” Governor Paterson said. “I proposed this legislation to prevent people from being arrested unnecessarily, thus ensuring that syringe users are not deterred from participating in these important programs.”

The Governor’s Program Bill No. 23 will:
  • Clarify in the Penal Law that a person does not act unlawfully by possessing a hypodermic needle or syringe if he or she participates in a needle exchange or syringe access program authorized under the Public Health Law;
  • Provide that possession of a residual amount of a controlled substance on a needle or syringe does not constitute a criminal act if the individual is permitted to possess such needle or syringe under the Public Health Law; and
  • Require the Division of Criminal Justice Services to periodically notify law enforcement agencies and prosecutors about the right of individuals to possess syringes under a qualifying public health program and how to verify that a person is participating in such a program.
Source