CHAPTER 1

AIDS

Rare Cancer Seen in 41 Homosexuals

By LAWRENCE K. ALTMAN, M.D.

Doctors in New York and California have diagnosed among homosexual men 41 cases of a rare and often rapidly fatal form of cancer. Eight of the victims died less than 24 months after the diagnosis was made.

The cause of the outbreak is unknown, and there is as yet no evidence of contagion. But the doctors who have made the diagnoses, mostly in New York City and the San Francisco Bay area, are alerting other physicians who treat large numbers of homosexual men to the problem in an effort to help identify more cases and to reduce the delay in offering chemotherapy treatment.

The sudden appearance of the cancer, called Kaposi’s Sarcoma, has prompted a medical investigation that experts say could have as much scientific as public health importance because of what it may teach about determining the causes of more common types of cancer.

First Appears in Spots

Doctors have been taught in the past that the cancer usually appeared first in spots on the legs and that the disease took a slow course of up to 10 years. But these recent cases have shown that it appears in one or more violet-colored spots anywhere on the body. The spots generally do not itch or cause other symptoms, often can be mistaken for bruises, sometimes appear as lumps and can turn brown after a period of time. The cancer often causes swollen lymph glands, and then kills by spreading throughout the body.

Doctors investigating the outbreak believe that many cases have gone undetected because of the rarity of the condition and the difficulty even dermatologists may have in diagnosing it.

In a letter alerting other physicians to the problem, Dr. Alvin E. Friedman-Kien of New York University Medical Center, one of the investigators, described the appearance of the outbreak as “rather devastating.”

Dr. Friedman-Kien said in an interview yesterday that he knew of 41 cases collated in the last five weeks, with the cases themselves dating to the past 30 months. The Federal Centers for Disease Control in Atlanta is expected to publish the first description of the outbreak in its weekly report today, according to a spokesman, Dr. James Curran. The report notes 26 of the cases—20 in New York and six in California.

There is no national registry of cancer victims, but the nationwide incidence of Kaposi’s Sarcoma in the past had been estimated by the Centers for Disease Control to be less than six-one-hundredths of a case per 100,000 people annually, or about two cases in every three million people. However, the disease accounts for up to 9 percent of all cancers in a belt across equatorial Africa, where it commonly affects children and young adults.

In the United States, it has primarily affected men older than 50 years. But in the recent cases, doctors at nine medical centers in New York and seven hospitals in California have been diagnosing the condition among younger men, all of whom said in the course of standard diagnostic interviews that they were homosexual. Although the ages of the patients have ranged from 26 to 51 years, many have been under 40, with the mean at 39.

Nine of the 41 cases known to Dr. Friedman-Kien were diagnosed in California, and several of those victims reported that they had been in New York in the period preceding the diagnosis. Dr. Friedman-Kien said that his colleagues were checking on reports of two victims diagnosed in Copenhagen, one of whom had visited New York.

Viral Infections Indicated

No one medical investigator has yet interviewed all the victims, Dr. Curran said. According to Dr. Friedman-Kien, the reporting doctors said that most cases had involved homosexual men who have had multiple and frequent sexual encounters with different partners, as many as 10 sexual encounters each night up to four times a week.

Many of the patients have also been treated for viral infections such as herpes, cytomegalovirus and hepatitis B as well as parasitic infections such as amebiasis and giardiasis. Many patients also reported that they had used drugs such as amyl nitrite and LSD to heighten sexual pleasure.

Cancer is not believed to be contagious, but conditions that might precipitate it, such as particular viruses or environmental factors, might account for an outbreak among a single group.

The medical investigators say some indirect evidence actually points away from contagion as a cause. None of the patients knew each other, although the theoretical possibility that some may have had sexual contact with a person with Kaposi’s Sarcoma at some point in the past could not be excluded, Dr. Friedman-Kien said.

Dr. Curran said there was no apparent danger to nonhomosexuals from contagion. “The best evidence against contagion,” he said, “is that no cases have been reported to date outside the homosexual community or in women.”

Dr. Friedman-Kien said he had tested nine of the victims and found severe defects in their immunological systems. The patients had serious malfunctions of two types of cells called T and B cell lymphocytes, which have important roles in fighting infections and cancer.

But Dr. Friedman-Kien emphasized that the researchers did not know whether the immunological defects were the underlying problem or had developed secondarily to the infections or drug use.

The research team is testing various hypotheses, one of which is a possible link between past infection with cytomegalovirus and development of Kaposi’s Sarcoma.

July 3, 1981

New U.S. Report Names Virus That May Cause AIDS

By LAWRENCE K. ALTMAN, M.D.

Federal researchers announced today that they had found a virus that they believe is the cause of acquired immune deficiency syndrome, or AIDS.

They called it HTLV-3 and said they had developed a process to mass-produce it for the purpose of developing the tools needed to finally conquer the mysterious disease that has afflicted more than 4,000 Americans.

The announcement follows the attention recently given to the discovery of a virus called LAV by researchers at the Pasteur Institute in Paris. The head of the Centers for Disease Control in Atlanta said over the weekend that he believed LAV was the cause of AIDS.

Margaret M. Heckler, Secretary of Health and Human Services, said today that she thought the two viruses “will prove to be the same.”

With the new process, the Federal researchers said they had developed a test that could reliably detect the virus that causes AIDS in blood that is donated for a wide variety of uses, including the treatment of hemophilia. They said they applied for a patent on the process today and that they expected the test to be widely available within six months.

The optimism surrounding the American and French research appears to reflect a high point in what has been one of the most challenging international scientific efforts to battle any modern disease.

Finding the cause of AIDS will not necessarily lead to any treatment of the disease soon, nor will it necessarily result in a method of prevention. But the finding led the American researchers to express the hope that a vaccine would be developed and ready for testing “in about two years.”

Even as the French and American researchers’ confidence has grown steadily in recent weeks, a degree of uncertainty still clings to the findings, and the tension of the exhaustive search was apparent in interviews and visits to the research facilities. There was a sense of quiet triumph in the halls of the Atlanta centers last week, but the euphoria that might have been expected was tempered by the knowledge that months of research are still required to firmly ascertain whether LAV and HTLV-3 are the same, and whether the virus is the cause of AIDS. Dr. Robert C. Gallo of the National Cancer Institute, who headed the team that is reporting its findings in four papers in the journal Science, said that if the two viruses “turn out to be the same I will say so.”

Dr. Gallo said he had isolated the virus from more than 50 patients and had detected evidence of antibodies that are a kind of record of the existence of the virus in the blood in about 85 percent of patients with AIDS and in about 80 percent of patients with a condition he called pre-AIDS.

After the first cases of AIDS were recognized in New York and California in 1981, Federal researchers quickly identified homosexual and bisexual males as the primary group affected. Epidemiologists also identified intravenous drug users, people of Haitian descent and hemophiliacs as other groups at risk of AIDS.

Early in the course of the investigation, Federal epidemiologists at the Centers for Disease Control in Atlanta determined that a transmissible agent was the only plausible factor that could satisfactorily explain the cause of AIDS in such widely different risk groups. The researchers said they strongly suspected that the transmissible agent was a micro-organism and they presumed it was a virus.

After initial tests failed to identify any known virus—or any other micro-organism—as the cause, researchers turned their attention to a new group called retroviruses. Retroviruses are so named because they contain an enzyme called reverse transcriptase that can copy the RNA of the virus into the DNA form, thus reversing the usual direction of the flow of genetic information.

By May 1983, researchers from the National Cancer Institute, the Harvard University School of Public Health, the Centers for Disease Control, the Kimron Veterinary Institute of Israel, New York University, the New York Veterans Administration Hospital, Litton Bionetics Inc. of Maryland and the Raymond Poincare Hospital in France published several reports in Science about a retrovirus called HTLV-1, which was put forward as the leading candidate as the cause of AIDS. HTLV-1, initially reported in 1981, had been found to cause a rare type of leukemia in southern Japan and the Caribbean islands. HTLV originally stood for human T-cell leukemia virus, but now the initials are used for human T-lymphotropic retroviruses to broaden the name.

In the same issue of Science last May, a team from the Pasteur Institute in Paris reported the discovery of LAV. LAV stands for lymphadenopathy-associated virus. The French researchers had isolated LAV from one of the many swollen lymph nodes in the body of a French man who said he had more than 50 homosexual partners each year and who had traveled to many European countries, North Africa, India and the United States. His last trip to New York was in 1979.

At the time of the first LAV report, Federal and other researchers said they were not excited by the prospects of that retrovirus as the cause of AIDS.

The significance of LAV began to become apparent for two reasons. One was that researchers could not detect HTLV-1 in all AIDS cases and because AIDS was rare in Japan. The other reason was the progress made by the French researchers who were expanding their studies on LAV.

The turning point came at a meeting in Park City, Utah, last January, according to one of the participants in the meeting. “We all got very excited” at the French presentation, the scientist said. Until then, some researchers believed that the LAV was not a retrovirus but a member of an entirely different family.

Dr. Luc Montagnier said his Pasteur Institute team has isolated “about a dozen” viruses that are either identical to or similar to LAV according to electron microscope and immunologic studies.

The viruses have been isolated from patients with AIDS or from members of the high-risk groups who have swollen lymph glands throughout their body. The condition is called lymphadenopathy, and many doctors suspect that it is a form of AIDS that cannot be now diagnosed as such because of the lack of a diagnostic test.

The patients have included French men as well as people from Haiti and Zaire, two countries where large numbers of AIDS cases are being diagnosed.

One of the many challenges facing AIDS researchers is to determine why the tests for the LAV or HTLV-3 were negative in some cases of patients presumed to have AIDS.

One thesis advanced by Dr. Montagnier is that the tests themselves may not be able to detect LAV at a certain stage of the disease. Another is that the technology of LAV testing is still too crude to detect all cases.

It remains remotely possible that the viruses observed by French and American researchers are not the cause of AIDS, but part of it. They could be just a newly recognized opportunistic infection of the type that afflict AIDS victims. Opportunistic infections are those that are caused by micro-organisms that usually do not make ill those people whose immune systems are working properly.

Dr. Montagnier said that his team considered that possibility “unlikely” because LAV was isolated from a patient whose immune system was not depressed and because similar isolates have come from people who had no evidence of a reversal of the so-called T4-T8 lymphocytes that seems to develop in patients with AIDS and suspected of having it.

After the Pasteur Institute team reported its findings with LAV, it began sending samples of the virus to any other scientific team that asked for it. As of today, Dr. Montagnier said the number of laboratories was “about 10” and they were located throughout the United States and Europe.

Cooperation between labs was further indicated today by Dr. Gallo, who recalled that one of the French researchers had trained in his laboratory in Bethesda, Md.

The French virus was sent to Dr. Gallo at the National Cancer Institute last July, Dr. Montagnier said, “but he told me this isolate did not work, so we sent it again in September.”

It is customary for researchers to send specimens of new organisms to other laboratories interested in the problem. But in the words of Dr. Donald Francis, who heads the Centers for Disease Control team of virologists investigating AIDS: “Not many people are calling the French every week asking for that virus. You have to be cautious about working with what you think is the cause of AIDS.”

Because the disease at present is so insidious and incurable, it generates some fear among the public and considerable concern even among the scientists working with it.

One of the classic ways to determine if a micro-organism causes disease is to inject it into animals. Thus, researchers at the Atlanta centers, the Pasteur Institute and elsewhere have injected the AIDS-linked viruses into animals but, as of today, none have shown any evidence of AIDS.

If the suspect viruses become indisputably linked to AIDS and a test to detect the virus in blood for transfusion is successfully developed, it would be applied an estimated 23 million times a year for the 3 million blood transfusions given in the United States each year, the researchers said today.

The risk probably was not great in any case. Reassuring data already comes from tests the French researchers have made on blood donated for transfusions in France. Dr. Montagnier said that the team could find evidence of LAV in “only one out of more than 100” units of blood tested.

Researchers are hoping that the LAV and HTLV-3 are the same. Dr. James Curran, who heads the Atlanta centers’ AIDS investigating team, said that if tests show the viruses to be different in major ways, “then something is wrong because one virus causes AIDS.”

Dr. Curran said that there may be several other so-called co-factors involved in explaining why some who are exposed to the virus that causes AIDS get it and others do not. “Not everyone who smokes gets lung cancer,” Dr. Curran said.

It is possible that genetic factors or certain infections could act to increase the vulnerability of an individual to the virus.

Research growing out of the new work may help explain why AIDS has such a long incubation period—a period that can range apparently from nine months to more than five years.

April 24, 1984

AIDS Drugs Offer Hope but Cure Remains Distant

By HAROLD M. SCHMECK JR.

This year the AIDS epidemic is being transformed from an utterly hopeless situation to one in which many, perhaps most American victims of the disease will have access to drug treatments that may give precious extra months of life.

One anti-AIDS drug appears to be nearing Federal approval, and trials of potential new drugs are being set up or expanded at a fast pace. But like every other aspect of the deadly epidemic, the drug outlook is marked by controversy and anguish.

The pace of progress seems agonizingly slow to patients who know they only have 6 to 18 months more to live.

“They Are Desperate”

“Many of them are much better informed about AIDS than the average physician, and they are desperate,” said Dr. Michael Lange, of St. Luke’s–Roosevelt Hospital Center in New York.

At present only a handful of drugs look promising enough for trial in patients. Most are in short supply and many patients have to be told they must wait, even for a spot in an experiment.

“I would like to try something even if it doesn’t work,” one patient told Dr. Lange. “Just to sit there and think and do nothing about it is very, very difficult.”

Push for Treatments

On the other side is the huge effort medical scientists are making to cope with the growing menace of acquired immune deficiency syndrome. The virus that causes AIDS was discovered less than five years ago. Today, knowing its identity and having already discovered a wealth of detail about it, scientists are trying to exploit every weak point the virus offers.

Medical scientists are mounting what is probably the greatest concentrated effort ever made to find therapies for a single virus disease. And, in an unusual approach that they hope will quicken the pace of progress, Federal officials are sponsoring new research consortiums involving Government, university and industry scientists.

The drug most widely tried against the AIDS virus is azidothymidine, AZT. Nearly 5,000 patients have used it and the numbers are growing rapidly. The Food and Drug Administration is expected to approve the drug within weeks.

The evidence indicates that AZT has prolonged many lives. But so far the success is measured in months only, and the drug has harmed some patients. No one expects AZT to actually cure AIDS or to rid victims of the AIDS virus.

Almost every drug or antiviral treatment that has ever shown any prospect of combating any virus infection is being tested. The Federal drug agency has granted permission for early tests in patients of about 30 different substances that have demonstrated potential against the AIDS virus in test-tube experiments.

The Search for New Drugs

Thousands of chemicals, synthetic and natural, are being screened for activity against the AIDS virus in the laboratory. But the drug search goes far beyond screening. Working on the frontiers of biology, chemists, virologists, immunologists and molecular biologists are trying to engineer new substances to attack the virus at every specific point in its life cycle.

The new collaboration among Government scientists, universities and drug companies is being sponsored by the National Institute of Allergy and Infectious Diseases, a unit of the National Institutes of Health in Bethesda, Md.

Dr. Anthony Fauci, director of the allergy and infectious disease institute, says there are five such consortiums now. He hopes to get 20 more started by Sept. 30, the end of this fiscal year, and 20 more next year, if Congress will provide the money. A separate effort is being developed to work out the complete three-dimensional structure of all the proteins the AIDS virus makes.

These studies should reveal more “little nooks and crannies of the virus” that may be good targets for drug designers, Dr. Fauci said. “Those are the kinds of approach that are going to yield results two or three years from now.”

Viruses are organisms that exist on the very border between the living and the inanimate. A virus particle is a protein-coated package of genes wandering through the world of life, looking for living cells to infect. Its genes subvert the normal genetic apparatus of the infected cell and cause it to make a new crop of viruses, often killing the cell to do so.

In a recent article, Dr. Hiroaki Mitsuya and Dr. Samuel Broder of the National Cancer Institute listed eight points in its reproductive cycle at which the AIDS virus might be attacked.

The first is the actual contact between invader and victim—the binding of the virus to its target cell. From then on there are several opportunities to counterattack as the virus gets inside, sheds its coat and goes to work. The last stages are the assembly of virus particles within the infected cell and the budding of new viruses from the cell surface. Drugs are also being sought to hamper the action of key genes of the virus.

In addition, many studies are planned to test the effectiveness of combinations of antiviral drugs and substances known to strengthen the immune defense system. Many scientists believe that, in the end, such combinations will provide the best treatment for AIDS victims.

Dr. Lionel Resnick of Mount Sinai Medical Center in Miami Beach has noted that most of the drugs now used against the AIDS virus have some effects against a key viral enzyme, the reverse transcriptase, which acts inside an invaded cell to direct formation of DNA that encodes the virus’s genetic message. Toxicity is a major problem with these drugs, he said, suggesting that they are not selective enough and therefore may interfere with normal cellular enzymes that assemble strands of DNA that the cell needs.

AZT and dideoxycytidine attack at the point at which the reverse transcriptase acts. They halt the production of the DNA strands that are normally manufactured from virus RNA with the enzyme’s help. DNA and RNA are the principal genetic chemicals for all living things.

Suramin and HPA-23, drugs whose early promise has now faded, were designed to inhibit the action of the reverse transcriptase.

Ribavirin throws a chemical monkey wrench into the genetic machinery at a later stage, when the nucleus of the infected cell is sending out blueprints that the cell’s production sites would use to begin assembly of new virus particles. Interferon alpha is believed to attack at the final stage of virus production, the point at which a new virus particle begins to bud from the surface of the infected cell.

Many other experimental drugs are being considered, including AL-721, thought to hamper the virus’s ability to attach itself to cells; peptide T, which interferes with virus attachment in a different way; and Foscarnet, which attacks the action of a key viral enzyme. Other potential drugs are artificially produced pieces of DNA that glue themselves to key segments of the virus’s genetic blueprints and take them out of action.

Doctors at several research centers are planning to try AZT in combination with other drugs, in AIDS patients and in people infected with the AIDS virus who have not yet developed AIDS. One new study will also test the drug in patients who have developed dementia or other symptoms of brain and central nervous system infection.

The question of possible drug benefit to patients who are infected by the virus but have no symptoms of AIDS is considered particularly important. Scientists see this strategy of early counterattack as probably the main hope for drugs against AIDS, whether the drug is AZT or something equally effective but less potentially toxic.

Few, if any, experts seem to expect to find a drug that will eliminate the virus from the patient’s body altogether and cure the disease. Dr. William S. Robinson, a virologist and professor of medicine at Stanford University, for example, thinks a cure is “a slim hope.”

For the present, at least, the hope is for a drug or combination of drugs that will keep the virus in check so that it neither kills the patient nor cripples the immune system. But the virus is known to be capable of lingering in the human body relatively inactive for years. In addition, some seemingly logical combinations of drugs may turn out to be deadly, or counterproductive. A recent study of ribavirin and AZT together, for example, found that in test-tube experiments the two drugs seem to cancel out each other’s effectiveness against the virus.

Drugs to keep the AIDS virus under control would probably have to be taken for years, perhaps decades, and that goal implies the use of something harmless enough to the patient to be tolerated over long periods.

Prospects for Treatment

In the immediate future, AZT will remain the best hope of many AIDS patients, experts say. By the end of the year, enough is expected to be available to treat at least 30,000 patients, although the drug is expected to be in short supply at the outset. And the manufacturer, the Burroughs Wellcome Company, has said that even after the drug, to be marketed under the name Retrovir, has been approved for prescription sale, its distribution will be restricted to patients in whom prior evidence indicates the drug is more likely to help than harm.

Two other drugs, dideoxycytidine and ribavirin, also show promise although they are in less advanced stages of clinical research than AZT.

In a clinical trial, ribavirin apparently helped prevent some patients with early signs of AIDS virus infection from progressing on to AIDS, according to the manufacturer, ICN Pharmaceuticals. But few data have been released and many experts have reservations about the drug.

The near-term prospect is that the lives of many patients afflicted with AIDS will be prolonged. But that is about as far as experts will go in predicting what lies ahead, even though the number of drugs that look promising in laboratory experiments is expected to increase substantially.

In laboratory experiments, dideoxycytidine, which is chemically related to AZT, has shown promise of being at least as effective as AZT but less toxic. The drug is now in early safety testing in patients and its therapeutic promise awaits confirmation.

As to AZT, scientists stress the potential dangers as well as the benefits. The chemical has a destructive effect on the bone marrow, the ultimate source of the blood and cells of the immune defense system. But the reaction to AZT seems to vary greatly from person to person. Some people with AIDS have tolerated the drug for many months. Others have been forced to stop using it.

The F.D.A., while considering the application for licensing of AZT, has permitted a special distribution to patients who fit the profile of those in whom benefits have been established—essentially, AIDS patients who have suffered pneumocystic carinii pneumonia, an indication of severe damage to the immune system. Since the beginning of October, the number of patients receiving the drug has grown by 30 to 50 a day.

The results have been encouraging. “We’ve had a handful of patients who have gone a year and a half,” Dr. David W. Barry, research vice president of Burroughs Wellcome, said. “Several dozen over a year and several hundred over nine months.”

But some patients have died despite the drug treatment and, in others, the inexorable course of the disease has begun again despite their treatment.

The original clinical trial of AZT began in the spring of 1986 with a division of patients into groups who received the drug and others who received a placebo, a harmless, ineffective substance. The use of the placebos was cut short last fall, however, and all patients were given the drug when scientists discovered that there had been only one death among 145 patients receiving the drug and 19 among an almost equal number who received the placebo.

As of last Jan. 12, the most recent date for which figures are available, there had been only eight deaths among the original 145 who took the drug from the start, and 32 deaths among the others. Among 3,247 patients involved in a subsequent, widespread research trial, there were 97 deaths through Jan. 12, but only 21 deaths among those who had used the drug for three weeks or more.

“I think there are a lot of things we don’t know about AZT yet,” said Dr. Martin Hirsch of Harvard and Massachusetts General Hospital in Boston. “We know the short-term toxicities. We know the short-term ability to prolong life.” But he added that there had not been enough time to analyze the long-term effects.

Cost is another problem; patients will presumably keep taking the drug for as long as they live, and the retail price is expected to be $8,000 to $10,000 a year for the needed doses.

Burroughs Wellcome, in justifying the price, says that production of AZT is complicated and expensive and that it has already borne enormous development costs. In January a company official said the company had spent more than $80 million developing the drug, with no assurance that it would ever reach the market.

Meanwhile, the spread of AIDS is increasing. Thirty-two thousand cases have been reported in the United States so far. The Federal Centers for Disease Control in Atlanta has estimated that there will be at least 21,000 new cases and 13,000 to 15,000 deaths during 1987. That averages out to three deaths every two hours.

As they search for drugs that attack the AIDS virus infection, doctors are also working feverishly to find better treatments for the related diseases that strike AIDS victims. These include a rare form of cancer, Kaposi’s Sarcoma, and many infections that would not bother normal people but that attack patients whose immune defenses are ruined.

There has been progress against many of these diseases, but it is still unclear how much, if at all, the life expectancy of AIDS patients has been increased.

A common problem and one of the most fateful stages in the progression of any AIDS case is the first episode of one particular infection, pneumocystis pneumonia.

A few years ago, patients often died from the first attack of this infection. Today 70 percent to 75 percent survive, according to one expert, but it is crucial that further attacks be prevented. Studies have shown that only one patient in 20 lives 18 months after that first episode occurs. Sometimes the patient dies during another attack, sometimes from other complications of AIDS.

The treatment that seems to be best against the pneumonia, specialists say, is not a new frontier anti-infection drug, but dapsone, an old and respected substance that has been known since the 1940s as a treatment for leprosy.

A study is needed to determine whether dapsone actually increases the survival of patients, said Dr. Michael Grieco, head of immunology and infectious diseases at St. Luke’s–Roosevelt. It appears to do so, but the data are not sufficient to be statistically significant.

Conflict Over Access

Today the knowledge that there is no cure, that no patient has ever been known to survive AIDS and that there is a temporary shortage of many experimental drugs against the disease, has apparently generated a black market as well as amateur attempts at treatment. Some much-publicized patients, such as Rock Hudson, the film star, have made a futile journey to France for treatment with an unproved drug. More frequently, patients have gone to Mexico for ribavirin. Doctors in New York say there appears to a black market for both ribavirin and AZT in this country.

Some patients seeking AL-721 have evidently taken the matter into their own hands, making a crude version at home.

Some doctors, familiar with this self-treatment, say they do not really object to it. Others worry over any use of a “homemade” drug because the patient has no way of knowing just what it really is and whether it is safe to take.

The F.D.A. has established special procedures for evaluating and approving potential AIDS drugs much faster than usual. The process has led to wide, though controlled, distribution of AZT years earlier than normal procedures would have dictated. Federal officials have also established a network of 19 leading medical research centers around the country to coordinate clinical trials of promising drugs—controlled scientific experiments that offer the only way of determining whether a drug helps, scientists assert.

For many dying patients and their supporters, that has not been good enough. Health officials have faced constant, anguished pleas to let patients have access to drugs before their worth is proved.

Some officials admit to having suffered sleepless nights over the matter. But most scientists have concluded that controlled trials offer the only means of establishing the merits of new drugs. They also warn that potential AIDS drugs tend to be extremely toxic, akin to cancer drugs, and could rob victims of months of life as they offer a cruel false hope.

Without proper studies, Dr. Broder of the Cancer Institute said, “a good drug could be lost or a bad drug could be accepted as effective,” causing immeasurable and perhaps irreparable harm.

The Outlook

Many experts regard AIDS as the final stage of a long virus infection that advances at a different pace in different patients. If that is true, the damage may be close to irreparable by the time the full-scale disease appears.

Doctors who take this view tend to be much less pessimistic about the chances of learning how to cope with the early virus infection, perhaps keeping it at bay for years or even permanently if the right combination of drugs can be found. That is why there is much current emphasis on trying the new drugs in people who are infected with the AIDS virus but have not yet developed symptoms of serious illness.

In the search for drugs of this kind, it may be a source of hope as well as challenge that the AIDS virus is the most complex example known of the class known as retroviruses. The complexity offers many different points of attack because the virus life cycle involves so many different interrelated steps.

“Although the precise mechanisms are matters of future study,” Dr. Mitsuya and Dr. Broder wrote in their review, “it is clear that this retrovirus has evolved an astonishingly complex system of genetic regulation.”

“With luck,” the two scientists said, “the very complexity of the virus could contribute to its defeat.”

March 17, 1987

New Picture of Who Will Get AIDS Is Dominated by Addicts

By GINA KOLATA

The AIDS epidemic, continuing its demographic evolution, is becoming ever more closely tied to the drug epidemic, a new study shows. Not only are intravenous drug users becoming infected, but so are crack addicts and other drug abusers, many of whom are women.

An extensive, unpublished analysis by researchers at the Federal Centers for Disease Control and Prevention in Atlanta has found that nearly three-quarters of the 40,000 new infections with H.I.V., the virus that causes AIDS, last year were among addicts.

Many of the addicts are IV drug users who share infected needles, but an increasing number are crack addicts who are contracting the AIDS virus through unprotected sex, often with multiple partners. Men and women alike often go on binges, having sex with many partners in exchange for crack or the money to buy it. “Maybe as much as half of the new infections among heterosexuals are occurring in relation to crack cocaine,” said Dr. Scott Holmberg, a C.D.C. epidemiologist who conducted the study.

Data and analyses from the C.D.C. show that the people diagnosed with AIDS in 1993, the most recent year for which statistics on the disease are available, are a very different group from those the 1994 statistics show are now being infected with the virus. Development of AIDS generally occurs about a decade after infection.

Of those newly diagnosed with AIDS in 1993, who were probably mostly infected in the early to mid-1980s, about half were gay men and a little more than a quarter were intravenous drug users. Fewer than 10 percent were heterosexuals. The remaining cases were hemophiliacs and gay men who injected drugs.

Now, in his analysis of national data for new H.I.V. infections in 1994, Dr. Holmberg finds a very different pattern, which is continuing this year. Only a quarter of the most recent infections are in gay men. About half of the new infections are among drug users who shared needles. And about a quarter are heterosexually transmitted. Dr. Holmberg said that 70 to 80 percent of people who are getting H.I.V. infections through heterosexual transmission are women and the majority of those are women who had sex with men who got infected when they injected drugs. Many had sex with these men during crack binges, or while they were abusing other drugs or alcohol, when they were not inclined to think about safe sex, Dr. Holmberg said.

The crack addicts who are becoming infected, Dr. Holmberg said, are mostly young men and women who live in inner cities and are members of minority groups. They often have other sexually transmitted diseases, which is thought to make it easier for the AIDS virus to infect them.

Recently published statistics—that AIDS is now the leading killer of young adults and that the largest-percentage increases in new infections are among women—take on a different tone when read in the context of Dr. Holmberg’s study. There are not many competing causes of death among those under 45. And although new infections are spreading fastest among women who acquire the infection through heterosexual intercourse, as many as half of these women are crack addicts.

Experts caution that the data do not mean that the virus is no longer a threat to Americans who do not use illicit drugs, and say that men and women should practice safe sex. Some researchers and advocates for people with AIDS are also concerned that the information carries another risk: that the nation will turn its back on these infected groups.

“That’s a real worry,” said Dr. Don C. Des Jarlais, an AIDS expert who directs the chemical dependency unit at Beth Israel Medical Center in New York. But, he said, fear of telling the truth about the epidemic is “one reason we have our priorities so out of order.”

He added: “You’re never going to have good public policy and stop an epidemic if you base your policy on misinformation or wrong information. You have to know where the disease is occurring and how to go after it.”

Two years ago, Dr. Des Jarlais, a member of a committee of the National Research Council, argued that efforts to stamp out the epidemic should have a tighter focus. A report by the committee said that the epidemic was “settling into spatially and socially isolated groups and possibly becoming epidemic in them.” The latest data provide a clearer picture of the characteristics of these isolated groups.

“It’s a real dilemma,” said Stephen Soba, communications director for the Gay Men’s Health Crisis, an advocacy group for people with AIDS. “But we have to acknowledge that the face of the epidemic has changed and continues to be changing.”

Mark Barnes, executive director of the AIDS Action Council, said: “These are tough issues. What this has meant for AIDS advocacy is that we have to not simply advocate around safer sex but for substance abuse treatment and for substance abuse treatment research, particularly for crack cocaine.”

Others, however, fear that if the AIDS prevention message becomes a drug abuse prevention message, people outside the inner cities will falsely feel that they are not at risk.

“There is no magic ring around the inner city,” said Dr. Mindy Fullilove, an associate professor of clinical psychiatry and public health at Columbia University in New York. “I think you can do targeting that makes people in the suburbs feel safe, and I don’t agree with that.”

But Dr. Des Jarlais said he feared more for the addicts, adding that the problem of redirecting AIDS prevention efforts hinges to a greater extent on the tendency of society to turn its back on addicts than on the dollars involved. He points out that it costs $3,000 to $4,000 a year to treat a heroin addict with methadone and that it costs $6,000 to $20,000 for residential treatment for a cocaine addict. But, he said, “The cost of just medical care for an H.I.V. infection is $120,000.”

Perhaps the biggest surprise in the new image of H.I.V. infections is the rapid spread of the virus among crack users. Yet it makes sense, said Dr. James Yorke, a mathematician who has modeled the spread of AIDS and other diseases and who is director of the Institute for Physical Sciences and Technology at the University of Maryland. Dr. Yorke noted that transmission of H.I.V. differs from that of other sexually transmitted diseases in that it is riskier to have sex with many partners, only some of whom are infected, than to have sex the same number of times with one infected person.

The reason, Dr. Des Jarlais said, is that H.I.V. is transmitted more easily during two periods of the infection: when a person first contracts the virus and a decade or so later when the immune system is collapsing. If a woman, for example, has sex 100 times with a man who is infected with H.I.V. but is in the long latent stage when the virus is more difficult to transmit, she is much less likely to get infected than if she has sex just once with one man who may be in the infectious stage. So a woman is at much greater risk having sex once with 100 partners, most of whom are infected, than having sex 100 times with a man who is infected but in the latent stage.

Knowing who is becoming infected, and how, investigators say that they can envision strategies that could push down the rate of new infections. But, they say, it will take a shift of emphasis and resources. It means aggressively offering drug treatment and social programs, including jobs and support for addicts who often are homeless and have lost hope of being part of society. It means finding much better treatments for crack addiction. It means stopping transmission from infected heroin addicts, by supplying them with clean needles and by providing them with methadone. It means viewing AIDS as a consequence of the drug epidemic, and not as a separate entity.

The problem, said Dr. Sten Vermund, chairman of the department of epidemiology at the University of Alabama in Birmingham, is that to fight AIDS, “we have to have the political will to make investments in drug treatment and drug control.” And to do that means giving inner city residents resources. “If we are hostile to drug treatment and job creation, then the epidemic will rage,” he added.

Dr. Vermund said that he would like to see some money and effort diverted from the search for treatments and vaccines and put into prevention. “I, for one, think that the balance is distorted,” he said. But, he said, at the very least, the way money is spent on AIDS prevention should be reconsidered.

AIDS prevention funds, “which are miserably inadequate to begin with, are largely spent on counseling and testing centers and in somewhat ineffectual mass media approaches,” he said. To have an impact the money should be redirected to provide drug treatment. “I’m talking about removing the waiting lists for drug treatment,” Dr. Vermund said. “Now a motivated addict who wants treatment in a city like New York is put on a waiting list for six months. That is a national disgrace.”

Dr. Des Jarlais said that it is also crucial that “legal access to sterile needles should be implemented on a nationwide basis.”

Mr. Barnes of the AIDS Action Council said that not only must advocates for people with AIDS start demanding research on substance abuse and substance abuse treatment, but they must also start insisting that education about AIDS prevention be incorporated into existing substance abuse treatment programs.

And those efforts, Mr. Barnes said, should include “everything from talking about issues of responsibility toward others and responsibility toward yourself to offering, even aggressively offering, partner notification strategies.” Such efforts, he added, “are not something we have traditionally done as a nation,” but that is in part because “we have separated prevention from treatment” of AIDS.

Dr. Vermund said, “It’s a tough nut to crack.” But he added: “We pay the price, and not merely in diseases like H.I.V. and sexually transmitted diseases and hepatitis, but also in our crime losses and correctional institutions.”

As a society, he said, “we reap what we sow.”

February 28, 1995

New Studies Offer Powerful and Puzzling Evidence on Immunity to AIDS

By GINA KOLATA

Scientists have long suspected that some people might be immune to the AIDS virus. But now they are accumulating powerful, direct evidence of the extent and strength of such immunity. And many researchers are stunned.

The most recent study, published today in the journal Science, provides the most detailed and convincing evidence yet that 1 in 100 whites have complete immunity to infection by the AIDS virus and 1 in 5 whites have inherited a resistance to the progress of AIDS once infected with the virus.

Almost no blacks have the particular protective mutation investigated in this study, but scientists say that other forms of genetic immunity almost certainly exist in both blacks and whites.

The findings raise numerous questions and offer remarkable opportunities for research, scientists say. Among the puzzles are why some ethnic groups have such a mutation and others do not, how and when this mutation arose and what other genetic variants exist that protect against AIDS.

One of the study’s surprises was that of 1,850 people, all of whom were at risk for infection, about 600 never became infected with H.I.V., the virus that causes AIDS. Since only 17 of them had the mutation identified as prevalent in whites, presumably the other people had some other form of genetic protection.

“The number that’s impressive is the 1 in 5” who are resistant to the AIDS virus, said Dr. Michael Kaback, a geneticist at the University of California at San Diego. “Now you’re getting up into the frequencies of blood group types or genes for eye colors,” Dr. Kaback said.

A double dose of the mutated gene CKR5 confers complete immunity to AIDS, the researchers said. People who have inherited a single dose of the mutated gene can become infected with H.I.V., but AIDS progresses more slowly and they live on average three years longer than people who do not have the mutated gene.

In addition, the researchers who published in Science, directed by Dr. Stephen J. O’Brien of the National Cancer Institute’s research center in Frederick, Md., found that much more genetic resistance was still to be understood. Although blacks, for example, virtually never have the mutated gene, they may have other genes that confer resistance to AIDS.

The 1,850 people in the study had been repeatedly exposed to H.I.V. because they were gay men who had sex without condoms, intravenous drug users who shared needles or hemophiliacs who injected themselves repeatedly with tainted blood products at the beginning of the AIDS epidemic. Since about 600 people in the study never became infected with H.I.V., the researchers report, the CKR5 mutation, as prevalent as it is, accounted for only 3 percent of the resistance.

The discoveries are making researchers ask why genes that confer resistance to AIDS are so common. Usually a mutation that knocks out a gene, as the CKR5 mutation does, would disappear from a population. It would only become common if it conferred a survival advantage.

Could it be, asked Dr. David Baltimore, a Nobel laureate molecular biologist at the Massachusetts Institute of Technology, that AIDS ravaged Europe centuries ago and that people with immunity today are the descendants of survivors? Or did the AIDS resistance genes also confer resistance to a different plague, like the Black Death?

Others researchers are asking how they can take advantage of the discoveries to develop new vaccines or drugs for AIDS and whether testing people to see if they are immune to AIDS is ethical.

It is, AIDS scientists say, an extraordinary time in the history of the AIDS epidemic, with new discoveries about AIDS coming so quickly that researchers’ heads are spinning.

“In a way, this whole set of discoveries is really like an epiphany in AIDS research,” said Dr. Jerome Groopman, an AIDS researcher at Harvard Medical School.

Last December, Dr. Robert Gallo, of the University of Maryland Medical School in Baltimore, a discoverer of the AIDS virus, identified mysterious substances in serum that could protect cells from infection with H.I.V. The substances were chemokines, chemicals used by the immune system to guide white blood cells to the sites of infection.

Researchers then asked why chemokines protected cells from H.I.V. Five groups simultaneously discovered last spring that H.I.V. uses a protein on the cell surface to slip into cells. That protein, CKR5, just happens to be the same protein that chemokines use to signal cells. Chemokines apparently protected cells from H.I.V. infection by tying up the CKR5 proteins on their surfaces, blocking H.I.V. from entering.

Finally, investigators asked whether there were people with mutations in their CKR5 genes that destroyed their cells’ ability to make CKR5 proteins. If so, those mutations could prevent H.I.V. from entering cells and so provide immunity to AIDS. That led to papers published in August by Dr. Nathaniel Landau and his colleagues at the Aaron Diamond AIDS Research Center in New York, that identified two gay Manhattan men who had the CKR5 mutation and had never been infected with H.I.V.

In fact the two men had pushed researchers to explain their apparent immunity. The report published today extended those findings because researchers scrutinized the genetics of a large number of people clearly at risk for infection with H.I.V. The research on which today’s paper was based was already in progress when the earlier papers were published.

The Science paper on genetic resistance to AIDS, whose principal authors were Dr. Michael Dean and Dr. Mary Carrington of the cancer institute in Frederick, involved analyses of stored blood from people who had been repeatedly exposed to the AIDS virus, including hemophiliacs, intravenous drug users, and gay men.

Many developed H.I.V. infections and so the researchers could ask if there were genetic differences between those who became infected and those who did not. They also could ask if there were genes that affected the course of the disease. Out of 200 genes they examined, only CKR5 mutations conferred resistance, Dr. O’Brien said.

As Dr. O’Brien and his colleagues were conducting their study, other groups pursued the CKR5 lead. Dr. Marc Parmentier of the University of Brussels studied a population of more than 700 Caucasians who were not at high risk for AIDS and found that 1 percent had two copies of mutated CKR5 genes. The group could not find the mutations in 124 Africans or in 248 Japanese.

The discovery of the CKR5 mutation, researchers say, opens doors to understanding AIDS and how to treat it. For example, Dr. Baltimore said, “it means that the receptor that has been identified is in fact the key receptor through which people get infected.”

Secondly, he said, “people can live perfectly well without CKR5.” And that means, he said, that “if you can develop a drug that blocks CKR5, it could block H.I.V. without serious side effects.”

Stephen Soba, a spokesman for the Gay Men’s Health Crisis, an advocacy group in New York, said there was something chilling, horrifying even, in the idea of testing for such a gene. Nonetheless, Mr. Soba said, a CKR5 test “would be an irresistible temptation.”

Larry Kramer, the playwright and advocate of a gay rights, said gay men would want a CKR5 test.

“My lover and I each have buried a previous lover,” Mr. Kramer said. “I’m H.I.V. positive and he’s not.” If a test disclosed that his lover was immune to AIDS, he said, it “would remove the sword of Damocles that’s hanging over our heads.”

But Dr. Norman Fost, an ethicist at the University of Wisconsin who is a visiting professor this year at Princeton University, urged caution.

“It’s all very exciting and very promising,” Dr. Fost said, but adding that with an AIDS immunity gene, the consequences of being wrong could be deadly. “You don’t want someone to say, ‘You have the gene so you don’t have to practice safe sex anymore.’”

September 27, 1996

The Genesis of an Epidemic: Humans, Chimps and a Virus

By GINA KOLATA

Three years ago, Dr. Beatrice Hahn got a call from a colleague asking if she wanted some body parts from a chimpanzee that had died a decade ago.

The colleague said, “I have the spleen, the brain and the lymph nodes in my freezer. I need to clean my freezer, so before I throw it out, do you want to look at it?”

Then the scientist said the animal had antibodies in its blood very much like ones that people develop when they are infected with the AIDS virus.

Dr. Hahn leapt at the chance. It was a long shot, but it was possible that the long-dead chimpanzee could be a missing link in the search for the origins of AIDS. A few days later, Federal Express delivered a huge box of frozen chimpanzee parts, packed in dry ice, to Dr. Hahn’s laboratory at the University of Alabama at Birmingham, where she is a professor of medicine.

Three days later, she had her answer. That chimpanzee, which had been healthy until she died in childbirth at age 26, held clues that eventually enabled Dr. Hahn and an international group of 11 others to unravel the mystery of the origin of the epidemic. It was a mystery that took years to solve and that had frustrated researchers and the public, stunned by the sudden emergence of such a terrible new disease.

Some said AIDS was caused by a mutant virus, a sort of Andromeda strain. Others favored conspiracy theories suggesting that H.I.V. had been created by scientists and escaped from germ warfare labs. There was a Western medicine disaster theory, which held that the virus was injected into Africans in bad batches of polio vaccine.

Then there was a more pedestrian idea—that people got H.I.V. from primates in Africa.

Scientists tended to favor the primate hypothesis because they knew that diseases can jump from animals to people. Dengue fever, Hantavirus, influenza and hepatitis B all originated in other species. But, researchers learned, it was not easy to trace the virus causing the human AIDS epidemic, H.I.V.-1, to an animal. And even when they started seeing provocative hints about the origins of AIDS, those hints soon turned contradictory.

The first evidence that H.I.V.-1 jumped to humans from primates came about a decade ago, when scientists isolated a virus from an African chimpanzee that very closely resembled the AIDS virus now infecting tens of millions of people. The chimpanzee virus looked so much like H.I.V.-1 that it was almost irresistible to think that the animals had somehow given the virus to people. Its genes were arranged the same way, and it even had a distinctive gene, called vpu, that had never been seen in any other virus.

While AIDS-like viruses were starting to emerge in other primates and in other animals, none looked so much like H.I.V.-1 as this chimpanzee one did.

Adding to the evidence was a tantalizing snippet of another AIDS-like virus found in a tube of blood from a baby chimpanzee that had died. While the fragment was too small for anyone to be certain that it closely resembled H.I.V.-1, the genetic sequence from this second chimp lined up exactly with a piece of the first chimpanzee’s virus.

But soon the picture became clouded. A few years ago, scientists found a third chimpanzee with an AIDS-like virus, but when they analyzed that virus, they discovered that it was only distantly related to H.I.V.-1. So, some asked, were chimpanzees really the source of the human AIDS epidemic? Or were chimpanzees, and humans, becoming infected by some other animals?

One way to find out would be to study wild chimpanzees and see whether they had a virus like the human form, H.I.V.-1, whether they had a different virus like the third chimpanzee’s virus or whether they were infected with a variety of AIDS-like viruses. But the only way to find viruses was to look for them in blood. And researchers could not draw blood from the elusive animals without stunning them first with a tranquilizer gun, and the stunning effort was impractical.

To make matters worse, no one could show that the animal with a virus like H.I.V.-1 came from the region where the human epidemic first exploded.

That was when Dr. Hahn examined the frozen chimpanzee organs, and the mystery began to crack. That animal, she discovered, also had a virus in its tissues that looked like H.I.V.-1.

Suddenly, said Dr. Edward Holmes, an evolutionary biologist at Oxford University, he and others who had questioned whether chimpanzees really were the source of H.I.V.-1 in humans became convinced. While scientists had found only two, or possibly three chimpanzees that had the virus, Dr. Hahn’s information, added to three other lines of evidence, was enough.

One line of evidence pointed to west-central Africa—a region where chimpanzees live—as the place where the human AIDS epidemic began.

Scientists, analyzing the genetic sequences of AIDS viruses found in patients from around the world, were discovering that the viruses in west-central Africa were the most diverse. And it is a general rule that the more diverse an organism’s genes are, the longer it has been around. That is because as the years go by more and more variations accumulate in an organism’s genes.

For example, Dr. Holmes said, human DNA is most diverse in Africa, supporting the idea that the human species originated on that continent.

The second line of evidence was a plausible way for the virus to get from chimpanzees to humans. People in west-central Africa eat chimpanzees. It was entirely reasonable to think that an infected animal’s blood gave the virus to a person who was handling the chimpanzee meat, infecting the person and setting the stage for an AIDS epidemic.

“People eat chimpanzees,” Dr. Hahn said. “We expect that transmissions occurred through the exposure to blood through hunting or preparation of meat.”

Finally, researchers were discovering AIDS-like viruses in other animals and other primates in Africa, but none were as closely related to H.I.V.-1 as the viruses in the three chimpanzees.

The only species that fit all the evidence as the source of H.I.V.-1 was the chimpanzee, Dr. Holmes said.

A scientific paper that Dr. Hahn had published about the frozen chimpanzee “was extraordinarily important,” Dr. Holmes said. “It really made people believe that chimps were the ancestral species.”

Dr. Paul M. Sharp, a professor of genetics at the University of Nottingham who worked on the analyses of the viruses, said: “It had been a gradual shift in our perceptions. At first we had been saying that either chimps are the source or they are recipients, like humans.” Dr. Hahn’s chimp made all the difference, Dr. Sharp said.

Now, researchers say, they have found two more chimpanzees that were infected in the wild with a virus like H.I.V.-1. The animals were among a group of 29 captured in Cameroon, in the west-central region of Africa.

It would be ideal, of course, to find stored blood from the original people who contracted H.I.V.-1 and stored tissue from chimpanzees in the same area, and then show they had exactly the same virus, Dr. Holmes said. But, he added, that is not going to happen.

“You haven’t got a smoking gun, but you’re never going to have one,” Dr. Holmes said. “The gun’s long gone. You’re never going to find it.”

Yet, he said, there is the virus in chimpanzees, there is the geographical overlap between where chimpanzees live and where H.I.V. started, and there is a mechanism.

“That was it for us,” Dr. Holmes said.

But knowing the virus came from chimpanzees left two pressing questions. When did the virus take hold in the human population? And how?

Dr. Bette T. Korber, a molecular geneticist at Los Alamos National Laboratory, and her colleagues had a way to get an answer to the question of when. They had the genetic sequences of viruses isolated from people and knew when those viruses were found, starting with the oldest human H.I.V. sample available. It was from a man in what is now Kinshasa, Congo, in west-central Africa, in 1959.

Since the viruses mutate at a roughly constant rate, the researchers could construct a path of how the virus had mutated and determine how long it would take to move from one virus to another one with the amount of genetic diversity found today. From those calculations, they found a date when the spark of the epidemic was lit: 1931, plus or minus 15 years.

“You might think, if the virus was present in 1930, how on earth did we not see it?” Dr. Korber asked. “But if it is only present in a few thousand individuals and it takes a decade to get sick, it could easily have been missed.”

Researchers say the virus almost certainly infected humans repeatedly as they killed and ate chimpanzees over the years, but that it is hard to start an AIDS epidemic. For it to develop, the virus must be prevented from dying with its victims and a steady chain of transmissions must occur.

“We think that these transmissions have gone on forever and a day, for all the centuries that people hunted chimpanzees,” Dr. Hahn said. “The rule is that these transmissions go nowhere. They just peter out, unless you have additional factors that promote subsequent spread in the new human host.”

One possible explanation for the extensive spread of H.I.V.-1, several scientists said, was that people began congregating in cities in Africa. There, the conditions were ripe for an AIDS epidemic.

“If you look at the population of Kinshasa, it’s an exponential curve going up,” Dr. Sharp said. “During the 20th century, you have far more movement of people into urban areas and perhaps changes in behavior.” In addition, doctors in clinics in Africa commonly reused needles without sterilizing them between patients, a practice that, he said, “would have played a role in getting the virus kick-started.”

Another possible explanation is less comforting.

Dr. Korber asked if it was possible that nothing really special made the epidemic grow, other than an initial transmission that, by chance, did not die out. Could a very slow curve of exponential growth, starting around 1930, end up in an epidemic that finally caught the world’s attention around 20 years ago?

Her mathematical models showed that it made sense. For the first 30 years, the number of cases would have climbed into the hundreds. As the web of infections grew, the numbers would jump, reaching large numbers in Africa by 1980. At that point, enough people would be infected that the epidemic would be noticed. That model is particularly troubling, Dr. Hahn said.

“If you say, ‘I don’t know how it got started; it could have been this, it could have been that,’ and if all you need are a certain set of circumstances in the beginning so that it doesn’t die out, then it could happen again,” she said.

“People don’t want to hear that.”

September 4, 2001