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Issue #211: January 8, 1999
fastfax is available by fax in the 215 and 610 area codes at no cost, or by mail anywhere for $20.00 per year, by calling 215-545-6868, and by E-mail by contacting and type the message SUBSCRIBE in the message section. Sources for some articles in this issue include Annals of Internal Medicine, Associated Press, Clinical Infectious Diseases, Nature Medicine, Reuters, San Francisco Examiner.
HIV may prevent new T-cells from developing
Researchers say surgeon may have infected patient
Kidney stones may continue after stopping Crixivan
Teleconference set on PI side effects
Penn starts trials on new microbicide
Clinton seeks tax break for caregivers
HIV may prevent new T-cells from developing
In a research study which challenges some of the underlying assumptions of how HIV works to erode the immune system, a team of California AIDS researchers has found the first direct clinical evidence that HIV does more than kill off T cells in the body's immune system.
The virus may also prevent the production of new, healthy versions of these vital cells, according to the study.
The scientists -- from the Gladstone Institute of Virology and Immunology at the University of California-San Francisco and from UC-Berkeley -- report the results of their 21-patient study in this month's issue of Nature Medicine.
"These studies focus our attention on the ways that HIV infection might stop the production of new T cells," said Joseph McCune, MD, PhD, senior study investigator and associate professor within the Gladstone Institute at UCSF. "To treat the disease, not only do we need potent anti-retroviral drugs to stop the virus from spreading and destroying T cells, we may also need additional therapies to ensure that T-cell production starts anew." The lead investigator for the study was Marc Hellerstein, MD, Ph.D.
The findings are significant in understanding the puzzle of T-cell turnover in the HIV population, an area that has remained controversial among leading AIDS researchers who have proposed different theories to explain why T-cell counts decrease during the course of HIV disease. Scientists use turnover to describe the natural process of T-cell death and new cell production that takes place in all individuals but that is altered after HIV infects the body. The precise mechanism that HIV uses to derail the different parts of this process have been unclear, but the end result is a collapse of the immune system that makes the body vulnerable to the opportunistic infections that cause full-blown AIDS.
Richard Jeffreys, an AIDS treatment activist with New York's AIDS Treatment Data Network, cautions against reading too much into the study's contentions.
"From the abstract, it appears that there may be some danger of this study being over interpreted," he wrote to the AIDSACT email discussion group. "Like the original Ho tap and sink model, the Hellerstein study appears to ignore the shift of T-cells into the lymph tissue, away from the blood.
"Although it's not entirely clear from the abstract, my initial impression is that the Hellerstein data could be consistent with the idea that HIV antigens are constantly activating newly-produced naive T-cells, thus truncating their lives. Presumably this would show up as a decline in the average lifespan of T-cells overall. However it pans out, it certainly looks as if a decent model of pathogenesis would factor in all three variables: T-cell redistribution from blood to lymph, T-cell destruction/apoptosis, T-cell production/thymic output."
The results of the new study run counter to the widely held view among AIDS scientists that HIV strikes mainly by killing T cells, the body's front-line defenders, as fast as the immune system can produce them. The controversial new findings include the first direct measurements showing how the human immune system becomes locked in a lethal battle with HIV.
The results challenge a core tenet in the scientific dogma of AIDS, a view that has dominated the field ever since a landmark 1995 study co-authored by famed New York AIDS expert David Ho. The Ho group's research pictured HIV as a virulent attacker that destroys immune cells by the millions, which spurs a flood of new cells --which also become infected and die.
In the end, according to this view, the immune system collapses from exhaustion. That leaves the infected victims vulnerable to all the deadly opportunistic diseases that mark the AIDS syndrome.
The new studies indicate that a more important contribution to disease may be the ability to stop T-cell production altogether.
Using a new diagnostic tool, the research team determined the rates of production of two types of T cells -- CD4 and CD8 -- that are major players in the immune system and prime targets of HIV.
"We found that the virus had an impact on both the rate of T-cell production and the rate of their destruction," Hellerstein said. "But it was the body's ability to produce new cells that was most important in determining T-cell counts."
Study participants included both men and women, and all were patients in the General Clinical Research Center at San Francisco General Hospital Medical Center. They represented three groups: HIV-negative and healthy; HIV-positive who had not undergone anti-HIV drug treatment; and HIV-positive who had completed a 12-week course of effective treatment with the potent antiretroviral drugs known as protease inhibitors after previously being untreated.
Major findings include:
-- For the first time, the daily rate of production of normal CD4 and CD8 T cells was directly measured in HIV-negative adults.
-- In untreated HIV-positive patients, CD4 and CD8 cells were being destroyed at a more rapid pace than in HIV-negative subjects and the body did not compensate by increasing the rate of production above the normal rate. Accordingly, the T-cell count decreased.
-- In HIV-positive patients whose virus was suppressed by potent therapy and whose T-cell counts increased, the rate of new cell production increased dramatically. The rise in new cell production was responsible for the increase in T-cell counts.
Crucial to the study was the new diagnostic tool that makes it possible to mark any human cell with a non-toxic label at the time of cell division and then to use the label to directly measure the numbers of new cells produced. In this study, the label was incorporated in a specially formulated glucose solution that was administered to patients intravenously. After passing through complex biochemical pathways, the label attaches itself to the DNA of dividing cells.
The researchers took periodic blood samples from patients during the infusion and during the next two- to three-weeks. With the label serving as a marker for newly divided cells, they analyzed samples by using a cell sorter to isolate pure populations of circulating T cells and a mass spectrometer to measure the number of labeled cells.
Because the labeling was carried out in living people, the results serve as the first direct clinical evidence of cell production in the human bloodstream. In the past, cell generation could not be directly measured in clinical studies because techniques involved radioactive or toxic chemicals unsuitable for human consumption.
Based on the study findings and previous work, McCune said it appears that HIV may disrupt T-cell production in two key ways.
First, virus infection may short-circuit the division of memory T cells, whose function is to ward off foreign invaders that the body encountered in earlier years. Without a continuous supply of these cells, the immune system doesn't remember that it can successfully fight off previous enemies and a person becomes susceptible to a variety of infections.
Second, virus infection may prevent the production of new T cells from the bone marrow and the thymus, the major organs of T-cell production. In either case, the immune system would collapse and the HIV-infected patient would become immunodeficient, McCune explained.
"It remains unclear whether all HIV-infected patients will be able to increase T-cell production and restore their immune systems after treatment," he said. "For those who cannot, additional therapies may be required."
The California study could prove important in developing new therapies to combat AIDS by jump-starting new T-cell production, researchers said.
"These results have important implications on new approaches to therapy aimed at augmenting T-cell production rather than simply blocking T-cell destruction," Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology at the University of California-San Francisco, said in a news release.
"They promise to reshape our view of T-cell dynamics in HIV infection."
Dr. Paul Volberding, a veteran AIDS specialist at San Francisco General, called the new cell-tracking system at the heart of the study a "tremendously exciting" tool, because it uses a harmless sugar molecule that can be easily detected in the DNA of the target cells, avoiding the health risks of radioactive or chemical markers in human test subjects.
"This gives us a tool we've been waiting for for a very long time," Volberding said.
Anthony Fauci, head of the infectious-disease branch of the National Institutes of Health and a noted AIDS expert, said the new study is drawing close scrutiny and could be widely influential -- if the results, which run counter to those from other well-respected laboratories, hold up.
"This is a controversial area," Fauci said. "I think it will remain a controversial area. It's a good paper, using an interesting technique . . . but the jury is still out."
An editorial in Nature Medicine portrayed the UCSF-Berkeley study as definitive evidence, but David Ho indicated through a spokeswoman at the Aaron Diamond AIDS research center in New York that he is not yet convinced. UCSF's Greene, by contrast, called the new study a "paradigm shift."
"This completely alters the way we think about the pathogenesis of AIDS," he said.
By all accounts, the AIDS virus infects and kills T cells. The argument is whether that's the main cause of fatal illness or if something else is at play.
"This study tells us HIV does two things," said UCSF researcher McCune. "It does destroy cells, but its main affect appears to be on the systems of cell production. What that tells us is that we have to get rid of the virus, no question about that, but we really need to focus our attention on the systems of cell production."
Researchers say surgeon may have infected patient
The first known case of an infected surgeon transmitting HIV to a patient during surgery has occurred in France, researchers have concluded.
In response to the report, an expert at the US Centers for Disease Control and Prevention (CDC) is urging tighter monitoring of surgical safety precautions.
"HIV transmission may occur during surgery," warn researchers at the Réseau National de Santé Publique in Saint Maurice, France, and other French health institutions. Their report is published in the January 5th issue of the Annals of Internal Medicine.
The case involves Dr. Patrick Cohen, a 53-year-old orthopedic surgeon who, it is suspected, contracted HIV in 1993 from a needle-stick injury during surgery on an HIV-infected patient.
Dr. Cohen claims he first learned of his seropositivity in March 1994, after he developed encephalopathy. He had stopped working at the Hospital a few months earlier. In 1995, the Hospital of Saint-Germain-en-Laye began to notify patients who underwent surgery by Dr. Cohen between 1983 and 1993.
One of his patients, a 73-year-old woman who had undergone lengthy hip-replacement surgery in 1992, was found to be HIV-positive. The woman had no previous history that might have put her at risk for infection, and testing revealed that the DNA of the virus carried by both herself and the surgeon were "closely related," suggesting a common source. The French General Manager of Health, Jean-François Girard had asked Dr. Luc Montagnier to compare viral samples of the patient and the surgeon. In January 15, 1997, Dr. Montagnier reported that there was "very great probability" of transmission of HIV from the physician to the patient.
Surgeon-patient transmission of HIV during surgery would require that the infected surgeon sustain an injury during the procedure that leads to active bleeding. Orthopedic surgery presents an environment conducive to such an injury, note the study authors, due to the regular use of cutting wires and sharp pins or tips on devices.
In fact, the investigators say the surgeon in question "observed blood under his gloves more than once a week." This phenomenon was not restricted to the infected surgeon -- the authors say "blood exposures were frequently reported by the other orthopedic surgeon (on staff)," as well. They add that operation room infection-control efforts at the hospital "were in accordance with current recommendations."
In a commentary, Dr. Julie Gerberding of the CDC's Hospital Infections Program, noted that "(healthcare) provider-to-patient HIV transmission is exceedingly rare in the United States."
However, prompted by the French finding, Gerberding recommends that surgeons and other US healthcare providers:
-- remain aware they are at risk for HIV infection from infected patients.
-- take all possible steps to reduce risks of intraoperative injury.
-- report all injuries occurring during surgery and other clinical settings.
-- undergo regular HIV testing to ascertain their ongoing infection status.
-- receive proper, ongoing care from a personal physician should they become infected.
Gerberding also recommends that all patients who are suspected of having had direct contact with a healthcare provider's blood be tested for infection with HIV and other pathogens. Prompt reporting, she explains, helps physicians detect HIV early in the infection process, when HIV medications are most effective in suppressing the virus.
Meanwhile, the elderly patient who may have been infected by the surgeon is asking for 2.5 million francs in damages, an attorney for the physician said.
After reaching a settlement of 500,000 FF with the hospital in exchange for dropping any further legal action, the patient has continued to pursue the matter with the surgeon in the County Court of Versailles, according to a Reuters report. Sources say this case will probably be decided " quickly."
However, the lawyer for Dr. Cohen, Sabine Paugam, believes there remains elements of uncertainty about the cause of the infection of this patient. An editorial that accompanies the Annals of Internal Medicine article lends limited support for this position.
The CDC's Gerberding, in her article, observed that the patient may have had an additional HIV risk besides exposure to the blood of Dr. Cohen. In March 1994 the women received dental care in Indonesia, a country with a high HIV prevalence.
Kidney stones may continue after stopping Crixivan
Researchers at Walter Reed Medical Center in Washington, D.C., have reported two cases of prolonged indinavir nephrolithiasis (Crixivan-induced kidney stones) in HIV-positive patients who had interrupted indinavir treatment.
In the December issue of Clinical Infectious Diseases, Drs. Mark E. Polhemus and Naomi E. Aronson reported that two HIV-positive men who stopped indinavir treatment due to nephrolithiasis still had the problem after six months without the medication.
One patient had the kidney stones for 11 months after indinavir treatment was stopped. The researchers note that while indinavir cessation is the conservative treatment for HIV-infected patients with kidney stones, not all cases resolve with conservative treatment, and physicians should strongly consider withdrawing indinavir with any episode of indinavir nephrolithiasis.
Teleconference set on PI side effects
A free, one-hour interactive telephone teleconference on ""Altered Body Shape in HIV Disease: A Side Effect of Therapy?" sponsored by the AIDS Wasting Foundation, will be held on Wednesday, January 20, 1999, beginning at 8:00 p.m. Eastern Time. Panelists will include Donald Kotler, MD, Professor of Medicine, Columbia University College of Physicians and Surgeons, New York; Andrew Carr, MD, Staff Specialists, HIV Medicine and Immunology, St. Vincent's Hospital, Darlinghurst, Australia; Gabe Torres, MD, Co-Director of the Bentley-Salick Medical Practice, PC, New York; Matthew Sharp, Person with AIDS, Member ACT UP Golden Gate; Ronald Baker, PhD, Editor-in-Chief, BETA.
Some people on anti-HIV therapy, including those using protease inhibitors, are experiencing a loss of fat in their arms and legs, but also an increase in abdominal fat. Others have developed fat deposits ("buffalo hump") at the base of the neck and severe wrinkling of the facial skin; some women report similar changes as well as enlarged breast size. In addition, instances of diabetes and serious heart disease have been linked to the syndrome. The teleconference panel will discuss and answer questions about this unexpected new phenomenon, its characteristics, possible cause, potential treatment, and ongoing and planned studies.
Participants must register in advance by calling 1-800-880-5121.
Penn starts trials on new microbicide
Biosyn, Inc., a drug research and development company, has announced that patient enrollment has begun in its Phase I clinical trial of Savvy (glyminox vaginal gel) at the University of Pennsylvania Medical School.
Savvy is a vaginal gel that will be used to prevent pregnancy and the transmission of sexually transmitted diseases (STDs), including HIV. This study will compare the safety and contraceptive effectiveness of Savvy versus the present market leader in topical contraceptives, Nonoxynol-9.
Anne-Marie Corner, the President & CEO of Biosyn, stated that "this study is a step toward the approval of a product that will give women the ability to protect themselves from acquiring sexually transmitted diseases. This would help to satisfy a huge unmet need for millions of women around the world."
Using microbicides to prevent transmission of HIV and other STDs is gaining support from the United States government, health organizations, and AIDS researchers worldwide. This interest is due to the exponential increase in the number of AIDS cases that are being contracted annually and the lack of a viable cure or vaccine likely to be available in the near future.
Worldwide, the number of people infected with the disease has reached about 30 million. The World Health Organization (WHO) has stated that one in every 100 sexually active adults is living with HIV infection and only one in ten of these infected persons is aware of their HIV status. Savvy and other microbicides in development will prove critical in preventing transmission of HIV, which, without intervention, could infect more than 40 million people worldwide by the year 2000.
Studies will also be undertaken on SAVVY for prevention of the transmission of other STDs, including chlamydia and gonorrhea. Chlamydia is the leading sexually transmitted disease in the U.S., with an estimated four million new cases occurring annually. This disease is asymptomatic in 75% of women and 50% of men and, if left untreated, chlamydia may cause infertility in women. Gonorrhea is contracted by one million American men and women annually. If left untreated, it can have repercussions such as painful joints, tubal pregnancy, and sterility.
Savvy is expected to be available in the market by the year 2001 for contraception and by the year 2002 for prevention of STDs and HIV.
For information on the trial, call 215-387-5338.
Clinton seeks tax break for caregivers
President Clinton has proposed a $1,000 per year tax break to help families who are taking care of disabled and elderly relatives in their own homes.
The proposal, carrying a price tag of $6.2 billion over five years, drew praise from many Republican members of Congress, who said Clinton was resurrecting a GOP idea he once opposed.
"I'm delighted he has changed his tune," said Rep. Bill Thomas, R-Calif., chairman of the House Ways and Means subcommittee on health. "This GOP initiative the president has adopted can make a difference." He said House Republicans made a similar proposal in their 1994 "Contract With America."
Sen. Charles Grassley, R-Iowa, chairman of the Senate Special Committee on Aging, applauded Clinton and said he plans to introduce two bills this year to make long-term care more affordable.
"President Clinton does the nation a great service by educating Americans about long-term care," Grassley said. He called the main elements of Clinton's plan "small but helpful steps" in the right direction.
The Republican praise was tempered by concerns about how Clinton intends to pay for the proposals, which include a $1,000 tax credit meant to compensate caregivers for such expenses as adult day care and lost wages in cases in which they must work less in order to be home to provide care.
In announcing his initiative at a White House ceremony, Clinton said the revenue loss from the tax cuts would be fully offset in a balanced budget he will submit to Congress in February, but he provided no details.
Several members of Congress, including Rep. Phil English, R-Pa., said the plan must not be paid for with tax increases.
"The president's idea has an excellent chance of moving forward if he does not raise taxes or propose other creative revenue-raising schemes that have been defeated two and three times in the last several Congresses," English said.
Clinton called his plan "a critical new initiative to give care to the caregivers." He said long-term care would become an increasingly important issue in the 21st century as the baby boom gives way to a "senior boom."
Appearing with Clinton to provide personal testimony to the needs of family caregivers was Patricia Darlak of Waldorf, Md., who told the White House audience she is struggling to care for her mother, who is suffering from dementia. Praising the idea of tax credits for caregivers, she said the cost of her mother's care is such a burden that she may have to delay her own retirement in order to pay the bills.
Clinton's four-part initiative also proposes that the government start offering federal workers and retirees private, long-term care insurance, in the hope that other employers would follow suit. Officials estimate that 300,000 government employees would participate in the model program.
The $1,000 tax credit would be available to parents of disabled or chronically ill children and any other person providing family care to a person -- of whatever age -- with three or more limitations in activities of daily living, including people with AIDS.
Paul Willging, president of the American Health Care Association, representing nursing homes and other health care providers, called Clinton's plan "great news" and a "balanced approach" that at least will stimulate debate on a topic that has gained little attention in recent years.
Mrs. Clinton, who appeared with the president at Monday's announcement, said help for family caregivers is long overdue.
"Everyone knows that there is not a substitute for families being able to care for their loved ones," Mrs. Clinton said. "But we sometimes forget that caregivers also need care. They, too, carry enormous burdens."
Some advocates were critical of the plan, saying that the $1,000 credit does not begin to compare with the actual cost of providing home-based care, and that many poorer families, whose incomes are too low to require them to pay income taxes, would still receive no benefit for their efforts.
Highlighting its opposition to New Jersey Gov. Christine Todd Whitman's activism against syringe exchange programs in her state, ACT UP Philadelphia has scheduled a rally and protest at Whitman's annual "State of the State"address in Trenton on Tuesday, January 12, 1999, 11:00am, at the New Jersey Statehouse, 135 W. State Street, in Trenton.
Buses will leave from two locations in Philadelphia for those who wish to participate in the protest. The locations are Broad and Walnut Streets in center city and 333 W. Girard Avenue in North Philadelphia, and the buses are scheduled to leave at 9 am sharp. To reserve a free seat, call 215-731-1844 or write jdavids@critpath.org. Participants will be provided lunch.
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