Johns Hopkins Magazine -- February 1998

FEBRUARY 1998
CONTENTS

H E A L T H & M E D I C I N E

A remaining reservoir of HIV... litigation looms large... where worrying originates... staying tuned "Following ER"... the controversy over placebos... avoiding the eye patch

HIV evades triple therapy
Over the past few years, doctors have found that "cocktails" of anti-HIV medications virtually eliminate the AIDS virus from the bloodstream of many HIV-positive patients. Might combination therapy cure AIDS completely? clinicians and patients cautiously wondered, while also worrying that the deadly virus would still evade the powerful new drugs.

Hopkins AIDS researchers Robert Siliciano, Diana Finzi, and their colleagues now find that, indeed, combination therapy does not vanquish HIV. But they also add some positive news.

In the November 14 Science, the team shows that while combination therapy reduces HIV in the blood to below detectable levels, a small reservoir of HIV remains in a group of T cells that are in a resting, or inactive, state. "Basically, HIV is not going away over the course of several months," says Siliciano, associate professor of medicine, who with his colleagues studied 22 patients who had been on strictly controlled antiretroviral therapy for as long as 30 months.

The researchers found that only one out of 10 to 20 million T cells harbors HIV, and those cells are in a resting state, not producing new virus. But even that tiny fraction could rekindle the infection, says Siliciano. His team demonstrated that in the test tube, HIV from resting T cells still has the ability to replicate and infect healthy T cells.

Patients on combination therapy should continue to follow their prescribed drug regimen, says Joel Gallant, an AIDS clinician who directs the Johns Hopkins Moore Clinic. The cost isn't slight: Patients on combination therapy must swallow 12 to 18 pills per day, which adds up to $12,000 to $15,000 per year, he notes.

The good news, however, is that the HIV in the resting T cells did not mutate to develop resistance to the anti-HIV combination drugs. Therefore, the drugs may continue to suppress infections in patients for years. --Melissa Hendricks

Litigation looms large
Fear of lawsuits appears to be a driving force behind emergency room doctors' decisions to resuscitate heart attack patients, according to a national survey of 1,200 emergency physicians conducted by Hopkins's Catherine Marco and colleagues.

Only 10 percent of heart attack patients who receive resuscitation in the ER survive long enough to be admitted to the hospital or to be discharged, notes Marco, herself an emergency physician. Nonetheless, 55 percent of those she surveyed said they've recently attempted resuscitation despite expectations that their efforts would be futile. Why? Sixty-two percent said they make resuscitation decisions because of fear of litigation or criticism from colleagues, rather than because of expected medical benefits.

Perhaps the most telling statistic of all: 98 percent of physicians said they have attempted resuscitation on patients in conditions in which they themselves would not want to be resuscitated.

Cardiopulmonary resuscitation involves using defibrillators and medications to restart the heart, and generally involves six to eight doctors and nurses. The majority of the ER staff can be called in to help resuscitate a patient, notes Marco. "One of our concerns is whether this is right for the other patients. Is this the correct allocation of resources?

"We undertook this study because in a lot of situations doctors know in their heart that [resuscitation] is not the right thing to do," says Marco. "But doctors feel obliged to do everything, even though they know a patient is dead and should rest in peace."

The researchers, who reported their findings in September's Academic Emergency Medicine, plan next to survey patients about how they would like doctors to make resuscitation decisions. --MH

Illustration by Bonnie Matthews

Worrying news to mull over
Worrying is not an analytical act, according to Johns Hopkins psychiatrist Rudolf Hoehn-Saric, who finds that the right side of the brain--known as the emotional side--is ground zero for fretting.

Hoehn-Saric, director of the Hopkins anxiety disorders unit, asked volunteers to tape-record themselves discussing their worries. Volunteers then listened to the recordings while undergoing functional positron emission tomography (PET), a technique that measures differences in blood flow in the brain. As a control, volunteers also listened to recordings about such tranquil topics as flower-arranging.

Hoehn-Saric found that worrying increased activity in the right frontal lobe, which is involved in planning and decisions; the basal ganglia, which integrates information from various brain areas; the amygdala, which is associated with emotions; and the cerebellum, which stores past experiences that the mind uses to rehearse possibilities.

"The right side of the brain is more intuitive," he explains. "It is where decisions are made on a more global scale--about like or disgust, for example. The left side is more analytic. With worries, you usually don't come to an analytic decision." -- MH

Langlieb (right) with ER star Anthony Edwards.
Photo by Tammara Langlieb

The medical truth behind ER
Every Thursday, 35 million viewers tune in to watch ER, the nation's top-rated TV show. To Public Health's Alan Langlieb, this audience represents a not-to-be-missed opportunity for educating the public about health issues.

So he and others at Public Health created a 90-second medical news segment called "Following ER," which airs on the 11 p.m. news on 240 NBC affiliates around the country. "Viewers have just spent 50 minutes tied to story lines and characters,"says Langlieb, instructor of health management. "They're a captive audience for health facts and information about prevention. ER does it magically, and we're trying to draw off that energy."

During the past 18 months, the segments on "Following ER'" have covered topics ranging from human bites to testicular cancer. For each installment, a medical reporter interviews a medical expert at Hopkins or elsewhere, as well as a patient who has, or had, the particular ailment. Public Health's Department of Public Affairs and WBAL co-produce the segment, with support from the Kaiser Foundation. The Public Affairs staff also maintains a Web page (er.jhu.edu/follower.html) that expands upon each week's medical issue.

On a recent afternoon, WBAL's cameras roll into the Johns Hopkins Emergency Department to film a segment about the risk of contracting HIV from a healthcare worker. The segment will air after an ER episode in which a physician's assistant who is HIV positive, jumps in to save a patient's life by performing an invasive--and bloody-- procedure.

Action in the Hopkins emergency room is not quite as adrenalin-pumped as it is on ER. No one is running through the halls, and romantic sparks don't fly between nurses and doctors. But a patient moaning "aaah" is audible throughout the afternoon's filming.

With a gurney and IV bags as backdrop, WBAL medical reporter Lisa Robertson interviews Emergency Department director Gabe Kelen. "The risk [of contracting HIV from a health worker] is so low that of all the other things I'd worry about, HIV comes far behind," Kelen tells the camera.

The crew moves on to an examining room, where nurse Debra Marblestone, wearing latex gloves and a face mask, inserts an IV into a patient's arm. Then it's onto the critical care cart, where emergency medical resident Chris Freer dons paper gown, mask, cap, and gloves, to demonstrate the "universal precautions" that medical staff take to protect themselves and their patients.

Reporter Robertson, after quickly applying hairspray, then wraps up, concluding that the risk of contracting HIV from a healthcare worker is "next to zero."

After editing, only a small fraction of the afternoon's filming will be included in the final segment. But the pithy dose of medical news will make millions of medical consumers a bit wiser about health. --MH

Neal Halsey defends the use of placebo-
controlled studies.
Photo courtesy School of Hygiene and Public Health, Public Affairs

Doing the right thing
Every year, more than 300,000 infants in developing countries are infected with HIV, the virus that causes AIDS. More than 20,000 children in these countries will die from AIDS each month. Everyone, of course, would like to prevent this scourge from claiming more young lives. But in searching for economically feasible ways to reduce mother-to-baby transmission, is it ethically sound to give pregnant women placebos when a drug (AZT) has already proved to be effective?

This question has embroiled medical commentators, a consumer health group, and AIDS researchers at Hopkins and elsewhere in an intense and sometimes vicious debate.

Ironically, the whole contentious discussion stems from a remarkable lifesaving discovery. In 1994, placebo-controlled clinical trials done in the U.S. and France, and sponsored by the National Institutes of Health, revealed that the antiviral drug AZT (zidovudine), if administered through a regimen now known as protocol 076, reduced the mother-to-baby transmission of HIV by about two-thirds (from 26 percent to 8 percent). The dramatic results prompted authorities to stop the trial before it had been completed.

Protocol 076 involves administering 100 milligrams of AZT five times daily to HIVinfected women from mid-pregnancy to delivery; delivering AZT intravenously during labor; and administering AZT to the newborn infant four times daily for the first six weeks of life. It is now the standard of care for pregnant women and their babies in the United States.

But the price tag and resources required to administer 076 are more than many developing nations can afford or safely and practically carry out. (Consider that $2,700 per person per year is spent on healthcare in the U.S., while in many developing nations that figure is only $10. ) So in 1994, AIDS experts convened by the World Health Organization called for new investigations that would examine whether a shorter course of AZT could also reduce transmission rates. The experts recommended placebo-controlled trials of short-course AZT therapy.

In a host of placebo-controlled AZT studies in pregnant women funded by the NIH, federal Centers for Disease Control, and others, researchers are now investigating variations on protocol 076. In some studies conducted in developing nations, volunteers receive a shorter course or fewer dosages of AZT. In others, they receive AZT orally rather than through IV during labor. In most of these studies, some women are given AZT, while others (the control group) receive a placebo.

But over the past several months, critics have charged that giving placebo to a group of HIV-infected individuals is unethical. In August, Public Citizen, a non-profit consumer health group founded by Ralph Nader, sent a letter to U.S. Department of Health and Human Services Secretary Donna Shalala urging her to request the researchers to drop the placebo arm of the studies. Public Citizen lambasted the researchers for carrying out "a new African-Asian-Caribbean Tuskegee," referring to the now infamous U.S. Public Health Service study in which researchers examined the course of syphilis, left untreated, in more than 400 black men for years--long after antibiotics were proved to be effective in treating the disease.

Marcia Angell, editor of the New England Journal of Medicine, followed with similar criticism, writing in an editorial that NIH and the Centers for Disease Control should not fund the placebo studies. She, too, used the Tuskegee analogy. The editorial drew national attention and prompted two AIDS experts to resign from the journal's board.

At Hopkins, where several groups of researchers are involved in such AIDS studies, professor of international health Neal Halsey staunchly defends the scientific design and ethics of the placebo-controlled studies.

"There is no comparison with Tuskegee," he says. "In Tuskegee, there was no informed consent, no institutional review board. There was no informing people of their diagnosis, no randomization of treatment, and they withheld the standard of care in the community."

For the ongoing AZT studies, all of those ethical standards have been applied, says Halsey; ethics boards went over the studies with a fine-toothed comb. Furthermore, he says, while international guidelines assert that researchers should apply universal ethical standards, they do not call for researchers to guarantee universal standards of medical care.

But Public Citizen's Peter Lurie says researchers are expected to give volunteers the best medical care, when possible. He also says that there is scientific evidence, including results from the 076 study, demonstrating the efficacy of short-course AZT therapy. Further comparisons between short-course AZT and placebo are not necessary, he says.

"Researchers seem to think the question is, Can we find something that is better than nothing? We think the right question is, Is it possible to design a cheaper regimen that retains most or all of the ethics of the 076 protocol," says Lurie.

Hopkins's Halsey and others say that proving the efficacy of short-course AZT therapy is more complicated. HIV transmission rates in untreated women are not well established. Several studies in developing countries show mother-to-baby transmission rates in untreated women ranging from 15 to 50 percent, he says. Why the wide variation? Halsey says several factors are involved, including variable methods for testing HIV antibody, whether or not a child is breastfeeding, and possibly the presence of additional sexually transmitted diseases in the mother. Because of the wide discrepancy in transmission rates among untreated women, says Halsey, it is unreliable to compare transmission rates following short-course therapy to these historical controls.

While Halsey and his colleagues designed a placebo-controlled trial of AZT in pregnant women and their newborns in Ethiopia, the study was postponed due to administrative delays. In the meantime, the researchers revised their protocol in October, and dropped the placebo arm. They revised the study, Halsey says, because they are anticipating that the results of AZT studies in Thailand, the Ivory Coast, and elsewhere, which are expected within the next few months, will show the efficacy of short-course AZT. --MH

Avoiding the eye patch
Many children who wear an eye patch to correct a lazy eye suffer the taunts of their classmates and the prickles of an irritating patch. "We've discovered that patching stops working because kids take off the patch," says David Guyton, an ophthalmologist at the Johns Hopkins Wilmer Eye Institute.

Now Guyton, research associate Kurt Simons, and their colleagues report that an alternative treatment apparently works just as well as patching. In this treatment, drops of a non-toxic chemical called atropine are used to blur the vision of a patient's "good," or non-lazy eye. The patient is forced to use his lazy eye (similar to the way a patch worn over a good eye forces a child to exercise his lazy eye).

Patching and atropine both improve vision by two or three times, the researchers report in two papers in the December Ophthalmology. But atropine may actually be more effective, says Guyton, since only about 60 percent of young patients comply with wearing an eye patch as prescribed, while about 95 percent of patients follow the atropine regimen. -- MH

12,000
That's the number of hours that 31 School of Nursing students volunteered last year, in programs in and about the East Baltimore community. The students did everything from providing flu vaccines for the elderly to signing up women for free mammograms.

RETURN TO FEBRUARY 1998 TABLE OF CONTENTS.