The Wall Street Journal, by Staff

By Michael Waldholz

"There are some important questions to be answered over the next few months about how valuable [viral suppression] is for a patient's well-being. But what we're hearing is impressive."

A new "cocktail" of three antiviral drugs can force the lethal AIDS virus into hiding, at least temporarily, according to new research.

The findings cap a 10-year search for a medicine to disable a key enzyme in the AIDS virus. When first identified in 1986, the enzyme, called protease (pronounced PRO-tee-ace), triggered a worldwide race that at times involved more than a dozen drug makers.

At a week-long conference in Washington, D.C., that started yesterday, Abbott Laboratories and Merck & Co. will show that each of their protease-blocking drugs, when combined with two existing AIDS medicines, packs an unprecedented antiviral wallop.

If early test results hold up as researchers expect, the three-drug regimen will be the first major advance in AIDS therapy since AZT was introduced in 1987. The first protease-blocking drug was approved by the FDA in December, and two more may gain marketing go-ahead in the next few months. Two others could be released for general use next year.

In preliminary tests, the triple-drug cocktail eliminated 99% of the AIDS virus detectable in the bloodstream of almost all of 45 patients tested for between four and six months. And one combination study involving Abbott's drug, Norvir, produced one of the most remarkable results yet: In six of 21 AIDS patients, the virus was impossible to detect, suggesting to researchers that they may have eliminated the virus from the patients' blood altogether.

"We're not saying we have a cure," says John Leonard, Abbott's protease project director. "But [the new results] show we are making very significant strides in that direction."

Few scientists truly expect the three-drug therapy to rid the body of HIV, the deadly AIDS virus. Past experience has shown that the virus may be lurking somewhere in the body and is likely to develop resistance to the drug cocktail eventually, perhaps re-emerging as dangerous as before. The drugs will likely produce side effects making them unusable for some patients, and the three-drug therapy costs more than $12,000 a year.

But the new results are exciting because the combination of drugs is so effective against HIV that researchers can't detect the presence of the virus in many patients' blood even when they use the most powerful detection techniques available.

"It's a very extraordinary result," says Anthony Fauci, who directs the National Institute of Allergies and Infectious Diseases. "There are some important questions to be answered over the next few months about how valuable [viral suppression] is for a patient's well-being. But what we're hearing is impressive."

Excitement about the protease inhibitors has been rising since early last year, when Merck, Abbott and Hoffmann-La Roche Inc. publicly presented results that demonstrated the drugs' significant antiviral potency in patients. Since then, all three companies have aggressively stepped up patient testing and, under a special program sanctioned by the Food and Drug Administration, offered drugs free to several thousand seriously ill AIDS patients in the U.S. and abroad.

The FDA approved the first protease blocker, Roche's Invirase, for use when combined with at least one of two already-used drugs, such as Glaxo Wellcome PLC's AZT.

In one of the new studies to be released later this week, Merck tested its protease-blocking drug, Crixivan, in combination with AZT and another Glaxo Wellcome drug, 3TC. After four months, 24 of the 26 patients taking the three drugs had virus levels so low they couldn't be detected. The same was true of 13 of 26 patients taking Crixivan alone. Patients taking AZT and 3TC had "their virus lowered, but the virus remained detectable," says Emilio Emini, Merck's director of antiviral research.

In addition, patients taking the three drugs had an apparent increase in their bodies' infection-fighting "CD4" cells, which are destroyed over time by the AIDS virus. Healthy patients have CD4 "counts" of about 1,000; many AIDS patients tested had counts below 100. The triple-drug regimen produced a median increase in CD4 counts of 146, Crixivan alone resulted in a median increase of 96, and a combination of AZT and 3TC brought a median increase of 22, Merck says.

"Leaders in AIDS research have theorized that by adding a very potent protease inhibitor like Merck's Crixivan to other [antiviral AIDS] drugs, one could knock down the virus to undetectable levels and significantly reduce the [virus's] ability to reproduce," says Dr. Emini.

"While these results are early," he adds, "they are the strongest evidence to date that this approach may work."

Dr. Emini described Merck's findings briefly in an overview speech yesterday at the Third Conference on Retroviruses and Opportunistic Infections. A full presentation of Merck's results will be presented Thursday. Abbott's 21-patient study, done in France, will be formally presented today.

Tomorrow, Abbott will present the results of still another test, which, for the first time, will describe whether patients' health significantly improved as a result of taking the triple-drug regimen. Abbott officials declined to divulge those results early.

AIDS researchers and doctors say that if the findings do remain positive, the new drugs may be used by as many as 100,000 patients in the U.S. If true, Merck and Abbott each could generate sales of several hundred million dollars each -- or more.

At present, Roche is charging about $6,000 at wholesale for a year's supply of its drug, and some people close to Merck and Abbott predict their drugs will cost about the same, possibly making the therapy inaccessible to many patients.

Researchers who have heard about the drug companies' test results are being cautious, arguing that the new therapy must be tried in many more patients over many more months before its true importance will be known. "We now must find out how long the striking effect being seen lasts," says the government's Dr. Fauci. "It's my guess that even in patients where the virus is undetectable that some virus is hiding in the body. But we now need to find that out."

Protease Drugs

DRUG COMPANY STATUS

Invirase (saquinavir) Hoffmann-La Roche Available

Norvir (ritonavir) Abbott Filed FDA application

Crixivan (indinavir) Merck Filing FDA application this week

Viracept (nelfinavir) Agouron Human testing

VX478 Glaxo-Wellcome Human testing and Vertex Pharmaceuticals

© 1996, Dow Jones & Company

Most Heterosexuals Face Scant Peril but Receive Large Portion of Funds

Less Goes to Gays, Addicts

By Amanda Bennett and Anita Sharpe

In the summer of 1987, federal health officials made the fateful decision to bombard the public with a terrifying message: Anyone could get AIDS.

While the message was technically true, it was also highly misleading. Everyone certainly faced some danger, but for most heterosexuals, the risk from a single act of sex was smaller than the risk of ever getting hit by lightning. In the U.S., the disease was, and remains, largely the scourge of gay men, intravenous drug users, their sex partners and their newborn children.

Nonetheless, a bold public-relations campaign promised to sound a general alarm about AIDS, lifting it from a homosexual concern to a national obsession and accelerating efforts to eradicate the disease. For people devoted to public health, it seemed the best course to take.

But nine years after the America Responds to AIDS campaign first hit the airwaves, many scientists and doctors are raising new questions. Increasingly, they worry that the everyone-gets-AIDS message -- still trumpeted not only by government agencies but by celebrities and the media -- is more than just dishonest: It is also having a perverse, potentially deadly effect on funding for AIDS prevention.

The emphasis on the broad reach of the disease has virtually ensured that precious funds won't go where they are most needed. For instance, though homosexuals and intravenous drug users now account for 83% of all AIDS cases reported in the U.S., the federal AIDS-prevention budget includes no specific allocation for programs for homosexual and bisexual men. And needle-exchange programs, widely seen as among the most effective methods available in fighting infection among drug users, are denied any federal funding.

Much of the Centers for Disease Control's $584 million AIDS-prevention budget goes instead to programs to combat the disease among heterosexual women, college students and others who face a relatively low risk of becoming infected. Federally funded testing programs alone, which primarily serve low-risk groups, account for roughly 20% of the entire budget.

Some scientists charge that tens of thousands of infections a year could be averted if only practical assistance were directed to the right people. Instead of aiming general warnings at non-drug-using heterosexuals, these critics say, the government should use the bulk of its anti-AIDS money to teach homosexual men to avoid unprotected anal sex and to dissuade addicts from sharing infected needles.

"You can't stop this epidemic if you spend the money where the epidemic hasn't happened," says Ron Stall, associate professor of epidemiology at the University of California in San Francisco.

Helene Gayle, who is in charge of AIDS prevention at the CDC, agrees that "increasingly, it is important to shift strategies to meet the epidemic." She says that the CDC, by giving communities more freedom to decide how to spend federal AIDS money, is now seeking to direct more help to those who need it most.

But she defends the CDC's pivotal decision in 1987 to emphasize the universality of AIDS: "One should not underestimate the fear and confusion this disease caused early on," Dr. Gayle says. "We needed to build a base of understanding before we could go for the jugular."

Certainly, powerful political and social forces at work nine years ago made it nearly impossible for health officials to focus attention on those most at risk, a reconstruction of events of that year shows. And though, as Dr. Gayle says, the CDC is now trying to revamp its AIDS-prevention efforts, the same forces that shaped public policy in 1987 are making it difficult for the government to change directions, even now.

By 1987, CDC officials already had a fairly clear picture of where and how AIDS was spreading -- and how much risk different groups faced. The disease was proving less likely to be transmitted through vaginal intercourse than many had feared. A major study that was just being completed put the average risk from a one-time heterosexual encounter with someone not in a high-risk group at one in five million without use of a condom, and one in 50 million for condom users.

Homosexuals, needle-sharing drug users and their sex partners, however, were in grave danger. A single act of anal sex with an infected partner, or a single injection with an AIDS-tainted needle, carried as much as a one in 50 chance of infection. For people facing these risks, it was fair to say AIDS was truly a modern-day plague.

A key player in the CDC's earliest AIDS-prevention efforts was Walter Dowdle, a virologist who was a veteran of the war on herpes and had helped create the CDC's anti-AIDS office in the early 1980s. Like most people in his operation, he understood that AIDS had to be fought hardest in the places it was most prevalent.

But by the spring of 1987, Dr. Dowdle had already been rebuffed repeatedly in efforts to prepare AIDS warnings aimed directly at high-risk groups. TV networks were refusing to air announcements advocating the use of condoms. And Dr. Dowdle had failed in his attempt to disseminate a brochure that mentioned condoms as effective in slowing the spread of AIDS. At the time, all AIDS material had to be cleared by the president's Domestic Policy Council, and the Reagan White House objected to pro-condom messages on moral grounds. The 1986 brochure went into the White House for review and never came out.

Searching for clues about how to proceed, CDC officials began a series of internal meetings at their red-brick headquarters on Clifton Road in Atlanta. They also reached outside for high-powered marketing help, retaining Steve Rabin, then a senior vice president of the advertising giant Ogilvy & Mather. In August, Mr. Rabin, openly gay and deeply committed to the effort, ran focus groups in a half-dozen cities to gauge attitudes toward the disease.

The results were discouraging: In city after city, the focus groups made clear that concern about AIDS hadn't taken hold in much of the country, despite the widely publicized announcement two years earlier that Rock Hudson had the disease. With some exceptions in big cities like New York and San Francisco, homosexuals continued to engage casually in unprotected sex, as did heterosexuals everywhere. The prevailing attitude: It was somebody else's problem.

For gays and drug users, this view was flatly wrong and potentially fatal. Moreover, the focus-group results highlighted a huge policy issue: Would the public support funding for AIDS prevention and research if the majority of heterosexuals believed they and their families were only minimally at risk? Would they be compassionate toward the victims of the disease?

Poll data suggested otherwise. A 1987 Gallup Poll showed that 25% of Americans thought that employers should have the right to fire AIDS victims. In that same poll, 43% felt that AIDS was a punishment for moral decline. In meetings within the CDC, many people, including Messrs. Dowdle and Rabin, expressed particular concern about the growth of housing and job discrimination against people with AIDS.

It was in this environment that the idea of presenting AIDS as an equal-opportunity scourge began to form. Politicians, including Republican Sen. Jesse Helms of North Carolina, were blocking campaigns aimed at gays anyway. And homosexual and minority groups were concerned about being linked too closely with the disease. Some CDC scientists, watching the spread of the disease among heterosexuals in Africa, worried that AIDS might yet make inroads among non-drug-using heterosexuals in the U.S. In any event, CDC officials believed that fighting AIDS was everyone's responsibility, even if everyone wasn't equally at risk of getting it.

"We were drawing on gut instinct," recalls Paula Van Ness, who had come to the CDC after serving as chief executive of the AIDS Project, a community program in Los Angeles. "The aim was, we thought we should get people talking about AIDS and we wanted to reduce the stigma." Earlier, in Los Angeles, she had reached out directly to high-risk groups: "Don't go out without your rubbers!" warned a motherly woman in one announcement the AIDS Project had sponsored. But now, on the national scene, she too felt that such a direct approach was impossible.

Dr. Dowdle, burned by the response to his earlier, more targeted efforts, agreed with his colleagues that the CDC's best bet was to present AIDS as everyone's problem: "As long as this was seen as a gay disease or, even worse, a disease of drug abusers, that pushed the disease way down the ladder" of people's priorities, he says.

After considerable soul-searching and debate, officials fixed on a dramatic approach they believed would do the most good in the long run: a high-powered PR and advertising campaign to spread a sobering yet politically palatable message nationwide.

In subsequent meetings in the summer and fall of 1987, the CDC team developed the idea of filming people with AIDS and building a series of public-service announcements around what they had to say. Subjects wouldn't be identified as gay, and the dangers of intravenous drug use would get little attention.

Early on, the staffers stumbled on their defining slogan when they interviewed the son of a rural Baptist minister. As Ms. Van Ness recalls it, the man said, "If I can get AIDS, anyone can." His remark "wasn't scripted. That's what he actually said." Other similar public-service announcements were prepared, all with the same personal approach. "If you want your audience to be more receptive about this, you had to touch their hearts," Ms. Van Ness says.

The CDC's award-winning campaign, deftly pitched to a general audience, was launched in October 1987 and featured 38 TV spots, eight radio announcements and six print ads. The initial ads steered clear of specific advice on how to avoid AIDS, instead focusing on the universality of the disease and counseling Americans to discuss it with their families.

It wasn't until the spring of 1988, when the government mailed its "Understanding AIDS" brochure to 117 million U.S. households, that the risks of anal sex and drug abuse were underlined. But even this brochure accentuated the broader risk; it featured a prominent photo of a female AIDS victim saying that "AIDS is not a `we' `they' disease, it's an `us' disease."

As public relations, the CDC campaign and parallel warnings from other groups proved to be remarkably effective, particularly because these messages were reinforced by various public agencies and the media. According to one poll, during the last three months of 1989, 80% of U.S. adults said they saw an AIDS-related public-service announcement on television.

Millions of people were thus sold and resold on the message: Though AIDS started in the homosexual population it was inexorably spreading, stalking high-school students, middle-class husbands, suburban housewives, doctors, dentists and even their unwitting patients.

In late 1991, Magic Johnson dramatically boosted the perception that everyone was at risk when he announced that his infection was due to promiscuous heterosexual behavior. Talk shows and magazines pursued the theme relentlessly. Even late last year, Redbook magazine -- written for a largely middle-class female audience -- carried a major story about married women called, "Could I have AIDS?" In it, the author wrote: "My mind automatically telescopes to AIDS every time I get sick."

Meanwhile, the CDC itself was producing research that made clear that heterosexual fears were exaggerated. And some CDC scientists, including then-epidemiology chief Harold W. Jaffe, publicly railed against the everyone-gets-AIDS message and urged that assistance be targeted to those who most needed it. But his opinion, along with the internal research on which it was based, was typically drowned out by the countervailing mass-media campaign.

Fear of AIDS spread -- and remains. Gallup surveys show that by 1988, 69% of Americans thought AIDS "was likely" to become an epidemic, compared with 51% a year earlier, before the PR campaign got in full swing. By 1991, most thought that married people who had an occasional affair would eventually face substantial risk.

Yet, as CDC officials well knew, many of the images presented by the anti-AIDS campaign created a misleading impression about who was likely to get the disease. The blonde, middle-aged woman in the CDC's brochure was an intravenous drug user who had shared AIDS-tainted needles, although she wasn't identified as such in the brochure. The Baptist minister's son who said, "If I can get AIDS, anyone can," was gay, although the public-service announcement featuring him didn't say so.

Ryan White, perhaps the epidemic's most compelling symbol, had been diagnosed in 1984, at the age of 13, after receiving a transfusion from an AIDS-tainted blood-clotting agent used in the treatment of hemophilia. Barred by his school, shunned by neighbors, he emerged with his family as a forceful opponent of discrimination against AIDS patients. But five years before he died in 1990, the availability of a blood test for the human immunodeficiency virus, which causes AIDS, had nearly eliminated the infection from America's blood-products supply. (Similarly, activist Elizabeth Glaser, who spoke at the 1992 Democratic Convention, was infected through a blood transfusion well before AIDS testing began.)

Meanwhile, Kimberly Bergalis became famous for a particularly rare case: She and five other Florida patients apparently acquired their infections from their dentist, who later died of AIDS. But although the CDC has tracked down and tested thousands of patients of hundreds of HIV-positive doctors and dentists, that single Florida dentist remains the only documented case in the U.S. of a health professional's passing the virus on to patients.

Research continued to show that AIDS among heterosexuals had largely settled into an inner-city nexus, a world bounded by poverty and poor health care and beset by rampant drug use. AIDS was also on the rise in some poor rural communities. Yet government ads typically didn't address the heterosexual group at greatest risk, a group that a CDC researcher would later define as "generally young, minority, indigent women who use `crack' cocaine, have multiple sex partners, trade sex for `crack' or other drugs or money, and have [other sexually transmitted diseases] such as syphilis and herpes."

Though scientists and anti-AIDS activists knew that the government-nurtured fear of AIDS among upscale, non-drug-using heterosexuals was exaggerated, not everyone thought this was a bad thing. Indeed, many credited rampant fear with achieving pro-family goals that no amount of moralizing alone could have accomplished. In a 1991 Gallup Poll, 57% of respondents said they believed that AIDS had already made their married friends "less likely to fool around." Singles reported being less apt to have one-night stands and more reluctant to date more than one person.

Moreover, there was no question that even mainstream heterosexuals bore some risk of AIDS and that greater caution would reduce their already-low rate of infection. "I don't see that much downside in slightly exaggerating [AIDS risk]" says John Ward, chief of the CDC branch that keeps track of AIDS cases. "Maybe they'll wear a condom. Maybe they won't sleep with someone they don't know."

The marketing campaign also appeared to be having another key desired effect: to mobilize support for public funding of AIDS research and prevention. Federal funding for AIDS-related medical research soared from $341 million in 1987 to $655 million in 1988, the year after the CDC's campaign began. (This year, the figure stands at $1.65 billion.) Meanwhile, the CDC's prevention dollars leapt from $136 million in 1987 to $304 million in 1988; $584 million was allocated for 1996.

Even the gay community, though not specifically targeted for assistance, began to see the wisdom of the everyone-gets-AIDS campaign. "This was a time of decreases in government funding," according to Jeff Amory, who headed the San Francisco AIDS Office in the 1980s. "Meanwhile, AIDS money was increasing."

It took a while before people realized that much of the money pouring in wasn't reaching the groups most at risk. In 1990, Mr. Amory took part in a telephone survey of about 50 HIV/AIDS groups funded by the CDC. Fewer than 10% even mentioned gay men as among their constituencies. (Mr. Amory died in November, after his interview with this newspaper.)

Meanwhile, the rush to testing meant that people at low risk were using up more and more of the available AIDS-prevention money just to discover they weren't infected. In 1994, 2.4 million tests were administered at government-funded locations, more than 10 times the number in 1985. Only 13% of those tests were given to homosexual or bisexual men or intravenous drug users.

As the CDC's biggest single prevention program, AIDS testing in 1995 accounted for about $136 million of the agency's total $589 million AIDS-prevention budget for that year. "It was not efficient or effective in picking up HIV-positive people," says Eric Goosby, director of the HIV/AIDS Policy Office of the U.S. Public Health Service, which oversees the CDC and other health agencies.

Moreover, because treating drug-addiction wasn't directly part of the CDC's mandate, stopping the spread of AIDS among needle-sharing addicts fell "between the cracks," says Dr. James W. Curran, who was director of the anti-AIDS office at the CDC until late last year and is now dean of the School of Public Health at Emory University in Atlanta.

State funding for AIDS prevention -- tracking public attitudes toward the disease -- was also being directed largely toward low-risk groups, says Patricia E. Franks, a senior researcher at UCSF, who spearheaded a study of California AIDS spending between 1989 and 1992. The study found that while 85% of AIDS cases were concentrated among men who had sex with men, programs targeting this group received only 9% of all state AIDS prevention dollars.

Spending for women, in contrast, grew to 29% of the state money in 1992 from 13% in 1989, even though HIV rates among women of childbearing age held steady at less than one-tenth of 1% from 1988 through 1992.

California health officials say they believe spending on high-risk groups has improved in the past few years. But Wayne Sauseda, director of the California Office of AIDS, concedes that "it's hard to take money away from groups already receiving grants." In California's last three-year state funding cycle, "we were being deluged by proposals from low- and no-risk population groups," Mr. Sauseda says. "We got two proposals for every one from a high-risk group."

Typical of the requests from low-risk groups, he says, were proposals to offer education on college campuses. "No one would say coeds are not at any risk," says Mr. Sauseda. "But in California, that's not our first priority."

AIDS officials in other states report similar frustrations. In 1994, the CDC turned to a community-planning process for dispensing AIDS funds, a system that theoretically allows local people to allocate dollars to groups most in need. But various community planners say it has been tough to redirect the funds, in large part because public attitudes have become so entrenched.

In Oregon, for example, many community AIDS workers "are unwilling to acknowledge that youth who are truly at risk [are] young gay men," says Robert McAlister, the state's HIV program manager. Thus, most of Oregon's AIDS-prevention money is still spent on counseling and testing that primarily serves low-risk individuals. "When Magic Johnson made his statement, we got overwhelmed with clients demanding service," Dr. McAlister says. "You start to cut corners. If we try to serve everybody, we wind up serving everybody poorly."

Having helped shape current attitudes and set AIDS-prevention policies in motion, the Centers for Disease Control finds itself in a serious bind. So far, AIDS has killed 320,000 Americans, according to the CDC. Between 650,000 and 900,000 others are currently infected with the virus that causes the illness.

Overall, rates of new HIV infections appear to be declining from their peak in the mid-1980s. Nonetheless, as many as 40,000 people, mostly gay men, drug users and their sex partners, will contract the virus this year alone. Despite this, the CDC aims its current education campaign, called "Respect Yourself, Protect Yourself," at a broad spectrum of young adults, rather than targeting the high-risk groups. A current focus of the campaign is to discourage premarital sex among heterosexuals.

The CDC also has been emphasizing that women constitute a growing proportion of AIDS cases. But close analyses of the data indicate that the vast majority of these victims are drug users or sex partners of drug users. Also, the data partly reflect a statistical quirk: Because the number of infections among gay men has declined, other groups -- such as women -- now represent a larger percentage of victims. Yet the infection rate among women not in high-risk groups appears to be holding roughly steady.

Meanwhile, unpublished research by the CDC itself concludes that "the most effective efforts to reduce HIV infection will target injecting drug users on the Eastern seaboard, young and minority homosexual and bisexual men, and young and minority heterosexual women and men who smoke crack cocaine and have many sexual partners."

Numerous studies have shown significant behavior changes in gay men who have been counseled by gay-outreach programs. Susan M. Kegeles, a behavioral scientist at UCSF's Center for AIDS Prevention Studies, reports that an eight-month program in Eugene, Ore., reduced one of the highest-risk acts, unprotected anal intercourse, by 27% in young gay men. The program used leaders in the gay community to demonstrate and consistently reinforce safe-sex practices.

Other studies have shown that drug users need even more intense behavioral counseling to break their addiction. But "only 15% of active drug users are in treatment on any given day, and there are not enough treatment slots to meet the demand from drug users," according to a report by the federal Office of Technology Assessment. Further, the ban of federal funding for needle exchanges continues, even though most reports conclude that locally funded efforts to distribute sterile needles or needle-cleaning supplies have been effective in reducing the spread of infection.

An epidemiologist at UCSF, James G. Kahn, recently created an academic model which, he says, shows that over five years, $1 million spent in a high-risk population averts 150 infections, compared with two or three infections if the money is spent in a low-risk population. Moreover, he argues that reducing infections in high-risk groups would "almost certainly" benefit low-risk groups by reducing the pool of people who could potentially infect others.

Then there is the separate issue of honesty in government: Shouldn't the public hear the truth, even if there might be adverse consequences? "When the public starts mistrusting its public health officials, it takes a long time before they believe them again," says George Annas, a medical ethicist at Boston University.

Yet many both inside and outside the government fear that speaking more directly about AIDS transmission, and seeking federal programs to match, poses the same dangers it did nine years ago. Congress controls the purse strings, and Sen. Helms, in particular, still monitors every AIDS-related bill. Says a Helms staff member, "We would certainly have a problem" with money going to gay-activist groups or to produce materials that illustrate gay sex acts.

"There is a real concern that funding won't be shifted, it will be cut, that if most people in the U.S. feel they are at very low risk, there will be little support for any AIDS-prevention efforts," says Don Des Jarlais, director of research at the Chemical Dependency Institute of Beth Israel Medical Center in New York. Still, he and many others believe that prevention experts have no choice -- and that it is time to fight for programs based on candor. "You can't build a good prevention program on bad epidemiology," he says.

Even back in the 1980s, Stephen C. Joseph, who was commissioner of public health for New York City from 1986 to 1990, blasted the notion that AIDS was making major inroads into the general population.

Today Dr. Joseph, who is assistant secretary of defense for health affairs at the Pentagon, says: "Political correctness has prevented us from looking at the issue squarely in the eye and dealing with it. It is the responsibility of the public-health department to tell the truth."

--- A Question of Odds

Below are rough estimates of the relative risks in the U.S. and Western Europe of various activities that can transmit AIDS. The calculations can't be used as a guide to individual behavior. Risk to any one person depends on many factors that can't be reduced to a single number. Recent research, for example, suggests that the infectiousness of the HIV virus can vary greatly over the life of an infected person; infectiousness is likely to be high both at the very outset of the infection, before symptoms have appeared, and several years later. Also, women may be several times more likely than men to be infected through vaginal intercourse, a distinction that the overall risk figure obscures.

ACTIVITY: Vaginal sexual intercourse

RISK:1 infection per 1,000 acts with HIV-positive partner

NOTES AND SOURCES: Mean per-act risk for unprotected intercourse. Source: Isabelle de Vincenzi, European Study Group on Heterosexual Transmission of HIV, 1994

ACTIVITY: Receptive anal intercourse

RISK: 5 to 30 infections per 1,000 acts with HIV-positive partner

NOTES AND SOURCES: With no condom use. Source: Victor DeGruttola, Harvard School of Public Health, 1989

ACTIVITY: Intravenous drug injection

RISK: 10 to 20 infections per with infected needle 1,000 needle uses

NOTES AND SOURCES: Source: Don Des Jarlais, Beth Israel Medical Center, New York

ACTIVITY: Accidental stick in medical

RISK: 3 infections per 1,000 sticks setting with infected needle

NOTES AND SOURCES: Source: Centers for Disease Control

ACTIVITY: Transfusion of screened blood

RISK: 1 infection per 450,000 to 660,000 donations

NOTES AND SOURCES: Source: Centers for Disease Control/American National Red Cross

© 1996, Dow Jones & Company

Companies Race to Market With 'Protease Inhibitors' After Good Test Results

'I Feel Wonderful, Incredible'

By Michael Waldholz

Fifteen years into the global AIDS epidemic, researchers are seeing the first glimmerings of a cure.

A new combination of drugs shows startling evidence of success in driving the AIDS virus into remission, making it unable to wreak its lethal havoc on the immune system. For dozens of test subjects -- and perhaps thousands of patients now in treatment -- the prospect of imminent death is giving way to a remarkable rebound in health. It is the first time any medical therapy has shown the potential for rescuing people on the verge of succumbing to the disease.

"I'm excited. I feel strong. I feel hopeful. I feel normal again," says Eduardo Torreau, a 39-year-old former dancer in New York who has been on the new multidrug treatment for 20 months. Like many of the two dozen other patients interviewed for this story, he feels as if a death sentence has been commuted.

Two years ago, with his immune system crippled by the virus, Mr. Torreau spent four months in the hospital fighting tuberculosis and pneumonia and bracing himself for certain death. Now, he says, he has gained 35 pounds of muscle and is starting a new career; this week he began taking classes in computer graphics.

Even many usually cautious physicians are astonished and inspired by the recent turn of events. While it is too early to claim an outright cure, "it now appears, at the very least, we may finally have the tools to turn [AIDS] into a long-term manageable and treatable disease, much like hypertension and diabetes," says Roy Gullick, a research physician at New York University's medical school. "Almost every one of my patients is doing significantly better."

Progress hasn't come easily. The path to the new therapy has wound through a decade of disappointment and frustration, unexpected product failures, intense corporate rivalries and secrecy -- and, in one instance, a blinding stroke of luck involving a test subject known as "Patient 142." Along the way, several drug giants shuttered their research efforts entirely. All told, researchers synthesized, analyzed and rejected tens of thousands of chemical compounds before finding a few that seem to be effective. In the process, scientists have begun to alter some long-held assumptions about how the virus does its devastating work.

Central to the current wellspring of hope is a new class of medicines known as protease inhibitors. In development for 10 years, these drugs block the workings of protease, an enzyme crucial to an early step in the reproductive cycle of the human immunodeficiency virus, HIV, which causes AIDS.

Although the new class is many times more powerful than anything tried before, even it can't defeat HIV by itself. But the new drugs are proving to be incredibly effective when used in a "cocktail" with two additional drugs based on AZT, which blocks another enzyme central to HIV replication.

Results just surfacing from clinical trials and lab studies suggest that scientists may finally have cornered the long-elusive virus, attacking it with unparalleled force from so many sides that it doesn't readily escape and spread as it has before.

Researchers emboldened by the findings are about to pursue a particularly historic undertaking: They are aiming for a full-fledged cure by working with patients who have only recently contracted HIV, instead of those in advanced stages of the disease. The new approach could fundamentally rewrite the battle plan for attacking AIDS. The effort "will answer the question of whether HIV infection can be eradicated in man," says researcher Martin Markowitz of the Aaron Diamond AIDS Research Center in New York. He adds: "We didn't have any way to even think about trying this before."

Already, almost 60,000 Americans, and 10,000 more people overseas, have received the new drugs, most of them since mid-March. Industry executives say an additional 50,000 to 250,000 people may be on the therapy in another year. Between 650,000 and 900,000 Americans are currently infected with HIV, according to the federal Centers for Disease Control.

The rollout of the new drugs is moving unusually fast: The first protease inhibitor to market, Hoffmann-La Roche Inc.'s Invirase, won approval from the Food and Drug Administration only in mid-December. Two more, Abbott Laboratories' Norvir and Merck & Co.'s Crixivan, were cleared just three months later. Two other entrants are in advanced stages of human testing, and corporate labs are racing to get several other experimental versions ready for human studies.

Despite all the enthusiasm, no one is yet ready to declare a cure. "I can't use that word, not yet," says Emilio Emini, who directs the protease project at Merck. And, certainly, there is good reason for caution. HIV has always managed to out-smart highly touted treatments in the past. Scientists suspect that a dormant reservoir of the virus still lurks inside recovering patients, ready to leap into action if they quit taking the drugs or if the virus mutates and stumbles upon a way to circumvent the cocktail's powers.

"I have enough respect for this virus to know that even if there is a very low rate of replication going on, that may be enough to reverse the gains we're seeing," says Robert Schooley, a veteran AIDS researcher at University of Colorado in Denver. "We need to watch these people and wait. Only time will tell us what we've got."

Some protease inhibitors also have painfully annoying side effects, albeit not nearly as toxic as those of AZT and its cousins, until recently the only promising class of AIDS drugs. Some of the new medicines have to be taken on a strict daily schedule: A raft of pills must be swallowed on an empty stomach three times a day, eight hours apart, and the patient must follow a rigid diet. Skipping the drugs even just a few days allows HIV to re-emerge dangerously in some patients.

Hefty Expense

Cost is another problem: Treatment will run $12,000 to $16,000 a year, and patients will probably have to stay on the drugs for many years, perhaps for the rest of their lives. The hefty expense and complicated dosing may push the new therapy out of reach for many members of the fastest-growing HIV population: the inner-city poor. Insurance coverage varies.

Still, even skeptical veterans of the AIDS struggle are finding it difficult to restrain their optimism. Says Mark Harrington, a longtime AIDS activist and critic of corporate and government efforts: "The recent abundance of good news is almost unbelievable. Fifteen years of public and private AIDS research efforts are paying off spectacularly."

Such optimism will likely gain momentum next month at the 11th International Conference on AIDS in Vancouver, where various scientists are expected to describe, albeit cautiously, the striking results of their latest clinical experiments.

In one notable trial, in which patients with advanced AIDS are taking daily doses of the multidrug regimen involving Merck's Crixivan, 25 of 26 subjects have gone eight months without any detectable signs of HIV infection in their blood. Even more impressive, eight of nine patients on the new treatment for almost a year appear to be entirely free of the virus.

Another report will come from David Ho, who directs the Aaron Diamond center in New York. He and Dr. Markowitz started giving various versions of the new therapy to two dozen healthy men a few weeks after the men became infected with HIV. In one 12-man group, 10 patients who have stayed on the therapy have no signs of virus in their blood. "We believe the way to beat HIV is to hit the virus hard and hit it early, with three drugs or more, at the first sign of infection," Dr. Ho says.

Jubilant Experiences

After a year of treatment, Dr. Ho plans to remove the therapy from several healthy patients to see whether the virus reappears; if it doesn't, that would be evidence that these patients might actually have been cured.

Encouraging clinical reports, exciting as they are, don't begin to capture the jubilant experiences of HIV patients for whom the new approach is providing, quite literally, new life. Last October, Andrew Howard of Huntington Beach, Calif., took his "last vacation," traveling to Hawaii with his companion, Charles Bouley. There, they spread the ashes of a friend who had just died of AIDS. Weakened from fever and dizziness and steadily wasting away, Mr. Howard barely had the strength to leave his bed each day. He turned over his power of attorney and installed oxygen equipment at his home.

In November, after months of badgering by Mr. Bouley, researchers at Stanford University admitted Mr. Howard into a clinical trial of Merck's new drug, Crixivan, with AZT and a related drug, 3TC. "I was desperate," says Mr. Bouley, a singer. "Andy's spirit had broken."

Just four weeks later, Mr. Howard's symptoms subsided. By March, "Andy seemed healthier than he had in years," Mr. Bouley says. The 29-year-old Mr. Howard has since gained 50 pounds, works out at a gym every day and has hired an agent to "shop around" the screenplays he writes. "I feel wonderful, incredible," he says. "I hope it lasts."

Merck Cocktail

Scott Higginson, 36, of San Jose, Calif., first tested positive for HIV in 1984. Three years ago, it turned into full-blown AIDS, forcing him to quit as manager of a child-care program. By last year, he was losing weight and suffering, daily, from diarrhea, nausea, fevers and cramps. "Everything was failing," he says.

Last summer, he started taking a cocktail containing Merck's protease inhibitor in a special trial. One month into treatment, his "T-cell count" (a measure of the infection-fighting white blood cells in his immune system) had soared to 100 from 38; by the third month, the count was up to 168, where it has remained. This is still low compared with the 1,100 mark of a non-HIV patient, but it is remarkable all the same. He has put on 12 pounds and is thinking about returning to work. "It's changed my life a lot," Mr. Higginson says. His doctor, Jonathan Shapiro, adds, "I'm seeing a lot of patients do about as well. It's pretty amazing."

Stephen Mendenhall of Kansas City, Mo., suffering from a constant fever and flu-like illnesses, started a regimen based on Roche's protease drug last January. In just three months, the amount of virus in his blood had been battered down to about 1/400th of what it was before he began treatment. His appetite has returned, enabling him to gain 24 pounds. Before he took the drugs, he says, "I was knockin' on death's door."

Such turnarounds, whether they prove to be temporary or long-lasting, are extraordinary given the litany of failures that has characterized most AIDS research. Half a dozen major campaigns to create a vaccine have all faltered. AZT and four similar drugs that followed it onto the market have never lived up to initial hopes for extending patients' lives significantly.

Isolating Protease

In 1986, scientists found a chink in HIV's armor when they isolated the protease enzyme. They soon began unlocking secrets to its crucial role in the HIV life cycle and realized that the enzyme was a new target they could hit with medical compounds. The protease breakthrough provided reassuringly familiar terrain, because most new drugs these days work by blocking some enzyme involved in the disease-causing process.

"The protease enzyme is very similar in structure to an enzyme involved in hypertension that we had been researching for years," says Andre Pernet, the head of research at Abbott Labs. "It's why we got involved in the search for an AIDS drug in the first place."

HIV destroys the immune system by invading and killing T-cells, the white blood cells that marshal an attack against an intruder. Once inside a healthy T-cell, HIV takes over the cell's genetic machinery, co-opting its components to churn out vast numbers of copies, which are dispatched to other T-cells, where the HIV copies do the same thing.

Biological Scissors

The protease inside HIV plays a key role after the virus has penetrated the T-cell's exterior. The enzyme acts as a kind of biochemical scissors, snipping apart a large protein inside the virus to form smaller fragments that the virus uses to assemble new copies of itself.

Drug-company scientists quickly realized that if they could wedge the right chemical compound between the protease and large protein, they might be able to shut down the virus's manufacturing operations. Research labs soon initiated projects to exploit the protease discovery.

But "we all soon ran into serious problems," says Suvit Thaisrivongs, the protease-project leader at Pharmacia & Upjohn Inc.'s U.S. labs in Kalamazoo, Mich. It quickly became apparent that the protease enzyme's active site, the area on its outer surface that locks onto the HIV protein to snip it into pieces, was like a yawning molecular cavern. Blocking protease would require plugging that wide gap with a new chemical -- but such a compound would, most likely, be too big to travel intact through the human digestive system.

Chemists at the drug companies synthesized bulky compounds that obstructed the protease's cutting site in test-tube experiments, but none were small enough to get into the bloodstream. "By 1990 we decided we'd have to pursue a completely different route," Dr. Thaisrivongs says. Instead of taking a big compound and trying to redesign it to slim it down, his team needed to find new, sleeker substances that might work just as well.

Trial and Error

Over the next few years, Upjohn's lab screened more than 100,000 candidates from its library of natural and man-made chemicals in its search. One chemical, a rat poison known as warfarin, worked pretty well, but it was too toxic. The chemical Upjohn ultimately would pick turned out to be a distant cousin of warfarin; the company hopes to push it into human trials by next year.

Other teams struggled. SmithKline gave up on its effort in 1991. Merck found a likely suspect, but it was too toxic when injected into lab animals. A separate project by a Merck-DuPont Co. joint venture fashioned a small and potent molecule using computer-aided design but discarded it after dangerous side effects cropped up in human trials. And at Abbott Laboratories, which in 1988 had quietly begun a large-scale protease push without telling rivals, chemists cranked out about 1,000 prototypes. By 1991, they had latched on to three that the company decided to try out in humans.

That is when a critical coincidence occurred. A top Abbott chemist, Dale Kempf, discussed the three protease prototypes at an AIDS science conference in Florida. In the audience was Dr. Ho. Then a virologist at the University of California's Los Angeles campus, Dr. Ho was pushing the unpopular notion that scientists had been wrong about key assumptions in how the AIDS virus worked and had vastly underestimated its ferociousness in the early stages of infection.

Dr. Ho realized the Abbott prototypes might provide him with an ideal tool to test his theory. He pitched the idea when he ran into Abbott's Dr. Kempf in an airport check-in line. "Dale agreed that maybe we could help each other," Dr. Ho says.

So began a collaboration that transformed Dr. Ho's career and the fortunes of Abbott's protease project.

Mutated Strains

The old view was that HIV lies dormant for years after an initial infection and kicks into high gear only later on. Then it reproduces so rapidly that, among its progeny, it churns out mutated strains that sidestep any new drug's defenses. This ability to mutate into a drug-resistant strain was seen as the central problem that limited the usefulness of every previous AIDS drug, including AZT.

So doctors usually waited as long as possible to introduce a drug that the virus is bound to find a way to beat. But Dr. Ho suggested that this may be too late. His new theory held that HIV starts reproducing rapidly immediately after invading the body but that patients and doctors don't notice it because the immune system wages a valiant defense. Only later is it outflanked and overwhelmed.

"That the surface [of the patient] is for many years relatively calm is a tribute to the heroic efforts of the immune system," Dr. Ho says. "The meanest streets are nothing by comparison." Attack early with a battery of drugs to curb the millions of new HIV copies, he argues, and the virus's chances of spinning off mutant versions that outmaneuver the medications can be sharply reduced. "Do you wait for any other kind of infection to get really bad before you treat it? Of course not!" Dr. Ho says.

By July 1993, Abbott researchers had narrowed their focus to just one possibility, which later became Norvir. As he worked with the compound, Dr. Ho says, "I was very impressed. Its power [in the test tube] was beyond anything we'd ever seen from the company or anyone else."

In a series of experiments with a handful of patients, Dr. Ho, who by then had joined the Diamond Center in New York, and colleague Dr. Markowitz were able to clear all detectable virus from test subjects in a matter of days. But within two weeks, the virus had generated drug-resistant mutants. By following how quickly these mutations arose, they calculated how many virus particles were churned out each day by infected cells, something no one had been able to measure before.

The answer took them aback, largely bearing out Dr. Ho's theory and making him realize that Abbott and other drug makers had to change their strategies if they were ever to vanquish HIV. No single drug was going to outsmart HIV; it would take a combination of drugs aiming at different vulnerabilities in the virus.

Drs. Ho and Markowitz discovered that an infected person can produce 100 million to one billion new virus particles every day, many times more than anyone had guessed was possible. The findings "told us that HIV infection is a raging blaze that is burning all the time," Dr. Ho says. Dr. Markowitz adds: "What David has argued, and we believe now has been shown, is that unless you shut off viral replication completely, you will develop resistance to the treatment -- and resistance means failure."

In working with the Abbott drug, Dr. Ho and some collaborators were the first to identify exactly how HIV gets around the protease inhibitor over time by spinning out one of three or four different mutations. He also showed that, to sidestep a two-drug remedy consisting of AZT and a related medication, 3TC or Epivir, the virus had to produce an offspring that contains about four mutations -- a more difficult but still manageable task.

High Barrier

But to thrive against the three-drug mix of AZT, 3TC and a new protease blocker, the virus would have to spin out a new version containing eight mutations all together, a near impossibility. "We have found that for one virus to produce progeny with that many mutations in the presence of such a high [drug] barrier is mathematically impossible," Dr. Ho maintains. "And that's the key, the reason multiple-drug therapy is working so well."

Many AIDS doctors, however, question whether the drugs have a long enough track record to justify such optimism. "Maybe I'm conservative, but I don't think we're there yet," says Donald Abrams, a longtime AIDS doctor at San Francisco General Hospital. Of such doubters, Dr. Ho counters: "I'm sure they are great doctors, but they haven't seen what we've learned about the virus."

Dr. Ho passed along his lab's findings to Abbott, which soon afterward began testing Norvir, known chemically as ritonavir, in a combination with other existing drugs. "By mid-1994 we knew ritonavir was a go," says Abbott's research head, Dr. Pernet. The results of the study were so encouraging that Abbott pushed up its timing by a full year, filing for FDA approval of Norvir last December.

Abbott's FDA filing stunned researchers at Merck. "It kicked us in the behind," says one person involved in Merck's protease research. The Merck scientists thought they were running comfortably in second place after Roche, which had won outright approval of its protease drug the same month. Finally, they were getting encouraging results in patient trials after two years of frustrating setbacks.

Patient 142

In fact, if not for one remarkable test subject, a 41-year-old HIV-infected man called "Patient 142," Merck might well have dropped its protease project by early 1994. "Every research project has a turning point," says Edward Scolnick, who oversees Merck's $1.6 billion-a-year worldwide research operation. "That patient kept ours going."

When Merck started testing its protease drug, Crixivan, on a dozen HIV patients in 1993, initial progress in each patient always gave way to a recurrence of the virus -- except for Patient 142.

Week after week, long after the other subjects displayed resistance, 142 "kept hanging in there and hanging in there," says Merck's Dr. Emini. In February 1994, Merck research officials gathered to discuss whether to scale back plans to expand the Crixivan test to several hundred patients.

"Because of 142, some of us argued that [Crixivan] was doing something right," Dr. Emini says. "We sat around and argued about it and finally decided to go forward, to try some new things, to up the dosage and combine [Crixivan] with other drugs. If not for 142, it's possible we might have ditched the whole thing."

Patient 142, an engaging, wise-cracking law student, is euphoric these days about his role in the research. After 130 weeks of therapy, he still has no trace of virus in his bloodstream, the longest anyone tested has gone without developing resistance. "This is the most intensely satisfying experience of my life," says the patient, who doesn't want to be identified. Three years ago, "I was spiraling down very quickly. Now, I feel I'm in remission."

He adds: "Maybe someday I can stand up in public and say I was the first person to conquer AIDS."

© 1996, Dow Jones & Company

For the Poor, High Costs, Rigid Regimens Dim Drug Cocktails' Promise

A Major Issue for Medicaid

By Michael Waldholz

NEW YORK -- As word of a promising new AIDS treatment passes from street corner to street corner in the nation's inner cities, concerns are mounting over who will get the revolutionary drugs -- and who will pay for them.

The new drugs, known as protease inhibitors, have been on the market for just a few months. But, taken in combination with two older medications, they already appear to work far better than any treatment previously devised. In many patients, they are removing all detectable evidence of HIV, the AIDS virus, from the blood, dramatically improving patients' health. More favorable test results are expected to be announced next week at the 11th International Conference on AIDS in Vancouver and to spawn new world-wide interest in the treatments.

But the new three-drug cocktail is enormously expensive: about $12,000 to $16,000 a year at retail, depending on which of several drugs are used. If only half the roughly 800,000 infected Americans eventually receive the new drug therapy, the annual bill could jump to as much as $6 billion a year, making it one of the most costly health programs in the world.

Moreover, benefiting from most versions of the drugs requires meticulous care by the patients. The therapy involves swallowing 14 to 20 pills a day in a rigid dosing schedule, often with strict dietary restrictions that may have to be continued for many years, perhaps for an individual's entire life.

Most worrisome, researchers fear that suspending treatment for even a few days, due to loss of insurance coverage, simple forgetfulness or an episode of narcotics use or crime, may generate dangerous new drug-resistant strains. With AIDS spreading most swiftly among the inner-city poor, particularly intravenous-drug users, just getting people to make proper use of protease inhibitors looms as an enormous -- and, once again, costly -- public-health problem.

At a time of intense focus on the high cost of health care, the new treatments are certain to raise anew the question of how far the nation is willing to go to care for many of its sickest, especially those who live on society's fringes. "Getting the new drugs to those who need it, especially to the inner city where AIDS is growing fastest, is going to be a real test," says William Arnold, who directs a lobbying group pressing Congress to allocate new funds for the protease medicines.

Given all the domestic complications, few U.S. health officials or pharmaceutical-company executives are currently even contemplating the outsized economics of providing the new therapy to the estimated 15 million to 20 million people infected with HIV who live outside the U.S., especially the millions in Africa and Asia where access to long-term medical care is often minimal.

Both the great promise and serious problems generated by the new drugs are already apparent at Harlem Hospital in upper Manhattan. The hospital's crowded AIDS clinic, wedged into a few examining rooms in a corner of the hospital's original 100-year-old red-brick building, is especially hectic and upbeat these days. Its clients, mostly low-income or jobless men and women in their 20s and 30s, are streaming in daily asking about the new drug treatment.

"There's a lot of excitement about the drugs," says Wafaa El-Sadr, director of infectious diseases at the hospital. "It's already changing our patients' attitudes about treatment and what's possible for them."

Yet, given the complexity of taking the medication, Dr. El-Sadr won't prescribe it to everyone. "We have many patients who can and will benefit right now," says Dr. El-Sadr. "But we have many others whose lives are in too much turmoil to prescribe them the therapy. We have patients using illicit drugs, some are homeless, some don't even have enough to eat. It won't be helpful to start them on the medication until their lives are more stable."

Dr. El-Sadr and others say that if these patients stop using the medication, the virus is certain to re-emerge in their bloodstreams, perhaps in versions untreatable by the new medicines. "From a public health point of view, for the larger community, that would be disastrous," Dr. ElSadr says.

Even for people whom Dr. El-Sadr and other AIDS doctors deem eligible for the treatment, securing funding can be complicated. Already there is evidence that U.S. demand for the new drugs is rising rapidly enough to tax existing government programs and some private insurance plans.

"The Clinton administration is committed to getting these drugs to everyone who needs them," says Patricia Fleming, the White House's National AIDS Policy director. But doing so, she acknowledges, won't be easy.

Never before has a major new class of medicines entered the marketplace so quickly. In December, the Food and Drug Administration approved the first of the protease drugs, Hoffmann-La Roche Inc.'s Invirase. Then, in early March, the agency approved two more protease drugs, Merck & Co.'s Crixivan and Abbott Laboratories' Norvir. Since then, more than 60,000 Americans have been prescribed one of the three new drugs, and pharmaceutical-company marketing officials believe that at least 50,000 to 75,000 more people will get the new drugs by year's end.

Immediately after the FDA action in March, and following intense lobbying by several AIDS advocacy groups, President Clinton asked Congress for an emergency infusion of $52 million for the states' AIDS Drug Assistance Programs, or ADAP, a special program created in 1987 for the uninsured.

Though most private insurers and managed-care concerns are currently including protease inhibitors in their coverage, some are restricting reimbursement to people in advanced stages of HIV infection. Moreover, statistics from several state programs suggest the government allocation for the uninsured is far short of what is needed.

This week, for instance, New York is making available $9 million for the protease drugs, its share of the federal grant approved by Congress. But New York's ADAP officials expect that at least 35% of the 10,000 people who currently receive the coverage may soon ask to get the new drugs. This would cost New York between $40 million and $45 million a year. If all the patients eligible for ADAP eventually seek the new therapy, the state's annual bill will reach $120 million, almost as much as the entire federal ADAP program spent in 1995.

Questions are also being raised about the capacity of Medicaid to absorb the cost of protease inhibitors for those it covers. The government health plan for the poor, jointly funded by state and federal taxpayers, currently pays the freight for about half of all AIDS drugs used in the U.S. But in late June, officials at the U.S. Department of Health and Human Services became concerned when several state Medicaid programs began restricting eligibility for the new therapy. As a result of the restrictions, the federal officials dispatched letters to all state Medicaid administrators urging them to reimburse for all three protease drugs, despite the added cost to the states.

"There's no question that doing what's right and covering these drugs is going to be a difficult burden for many of the Medicaid programs," says Eric Goosby, director of HIV policy at Health and Human Services.

For the low-income AIDS patient, the bureaucratic complexities can be numbing. Anna, a 44-year-old widow with advancing AIDS, spent two anxious months this spring trying unsuccessfully to finance the $250-a-week therapy that Dr. El-Sadr had prescribed. Because Anna works, she isn't eligible for Medicaid. Her employer's health-insurance plan, a managed-care provider, doesn't cover antiviral AIDS drugs. And at the time she was seeking treatment, the state ADAP program didn't have sufficient funds to include her.

"I was going crazy," says Anna, who asked that her last name not be used. Finally, a few weeks ago, Merck agreed to give Anna a free supply of its protease drug, Crixivan, as part of a stop-gap giveaway program it and other drug makers are offering to about 5% to 10% of patients using their medications. In recent weeks, Anna's once-deteriorating immune system has stabilized, although it still is relatively weak. "I hope I'm able to keep getting the drugs," she says.

Merck says it is committed to providing drugs to those not covered by an insurance plan who meet certain income requirements. But all the drug makers hope the giveaway programs are temporary safety nets; each company believes the government and employers are ultimately responsible for paying for most people receiving their medicines. The companies point out that they have spent hundreds of millions of dollars developing these drugs, and expensive research is continuing. For now, supplies of the drugs are barely keeping up with the burgeoning demand, and it remains to be seen whether prices will come down as supplies increase and competitive forces intensify.

Ironically, the more attention generated by the new treatments, the tougher it will be for people like Anna to maintain access to the therapy. The Vancouver AIDS conference, in particular, is expected to generate additional publicity. As reported previously in a front-page article in this newspaper, scientists at the AIDS meeting are expected to announce several significant advances. The developments include a report of one test in which 90% of patients who received Merck's Crixivan and two older medicines, Glaxo Wellcome PLC's drugs AZT and 3TC, had no detectable virus in their blood after as much as 48 weeks of use, something no other treatment has achieved.

There will also be a report that 11 of 12 newly infected test patients had no detectable trace of the virus in their blood after eight to 10 months of treatment with Norvir and the two older medicines, generating hope that the new therapy may completely eradicate the virus from people who receive treatment in the earliest stage of infection. At present, no antiviral treatment is offered to people at the beginning of the infection because none has yet shown any long-term impact on the progression of the disease.

Another factor expected to increase interest in the drugs is the recent release of a new test that can measure the precise amount of virus circulating in a person's blood and thus chart the impact of the new drugs.

"It's amazing how many patients are coming in and asking to have their viral load tested," says Charles Farthing, an AIDS physician who treats a large pool of low-income patients in Los Angeles. "Having a test that can monitor how well the drugs are working in reducing virus levels is absolutely certain to spur an even greater interest in using the new drugs."

Willie, a 39-year-old Harlem resident recovering from addictions to cocaine and heroin, was recently released after a three-year stint in New York's Rikers Island prison. He says he learned about the protease drugs from a film he was shown at a community drug-rehabilitation program and also from a friend.

His friend's viral load improved dramatically "in just a few weeks," says Willie, who asked that his last name not be used because his family doesn't know he is infected with the AIDS virus. "That really, really reinforced my desire to use the protease drugs right now. I'm not sick and I don't ever want to get sick."

Several days later, Willie asked for and received the drugs from an AIDS clinic he uses in downtown Manhattan. The treatment was paid for by Medicaid. Does he think he can continue taking 17 pills a day forever? "Well," he says, "I'm going to try my best."

Others are skeptical about how the protease inhibitors will fare on the street, as opposed to in test conditions or among well-heeled patients. Sheldon Julius, HIV-positive and recovering from almost 30 years of drug addiction, spends his days talking about the new medicines to men and women as part of volunteer work he does for Harlem Hospital's AIDS clinic. "A lot of people are saying they've heard something about this new kind of medicine that's different, more powerful, that's not like AZT," Mr. Julius says. "But I tell them, `If you want the medicine, you first gotta clean up your act.'"

Mr. Julius says he recently was "deeply disturbed" when a longtime friend of his sold a street "drug broker" her new supply of protease medicines and other drugs for $75, apparently so she could buy some narcotics. "I know if we work hard to get people these drugs, they've got to be responsible about using them right," Mr. Julius says. "My job is to make certain people understand that you can't take these drugs lightly."

Still, Steven Deeks, a physician at San Francisco General Hospital, says he is worried that even if patients get the drugs, they may quit using them abruptly because of side effects. Dr. Deeks notes that one of the drugs, Abbott's Norvir, can cause nausea and headaches during the first few weeks of treatment that are so serious "that a good number of my patients simply stopped taking the drugs." (Abbott says the side effects can be handled by using a lower dose at first.)

Adds Dr. Deeks: "The great results being reported are from tightly controlled clinical trials. I'm worried when these drugs get out into the community. People are going to have a lot of problems using them."

Dr. El-Sadr at Harlem Hospital's AIDS clinic believes her medical center's success in treating tuberculosis may serve as a model for what's needed to make proper use of the new drugs. TB can be cured with a three-drug regimen. Under Dr. El-Sadr's direction, the hospital has created a program in which TB patients receive their medication under "direct observation" of health-care workers at the hospital's clinic.

As an incentive, patients receive subway tokens and free certificates to McDonald's. As importantly, Dr. El-Sadr says, the clinic tries to provide a nurturing atmosphere for "people who often have no one else to turn to," celebrating their birthdays at the clinic and taking them on outings. All of this is funded by state and city agencies seeking to avoid the spread of drug-resistant TB if patients stop taking their medicine.

TB can be treated with drugs taken just three times a week for nine months, and the medicines cost a tiny fraction of what the new AIDS drugs cost. Still, says Dr. El-Sadr, "in an ideal world, it's exactly the kind of program we'd put in place for AIDS."

© 1996, Dow Jones & Company

By Michael Waldholz

Dawn Averitt's physical and emotional roller-coaster ride on the new combination drug therapy for AIDS demonstrates why the "cocktail" is inspiring both hope and fear.

A 27-year-old AIDS activist in Atlanta, she had reached an advanced stage of the disease in 1994 when she joined an early trial for one of the hottest new drugs, Merck & Co.'s Crixivan. A combination of Crixivan and two other drugs fueled a fivefold boost in her infection-fighting T-cells and, even more remarkably, drove down the virus content in her blood from a frightfully high measure of 650,000 virus particles per sample to virtually undetectable levels.

The good news lasted an impressive 72 weeks. But then it ended. The virus suddenly re-emerged a few months ago and has risen to 27,000 particles per sample. At the same time, Ms. Averitt's T-cell count has begun to fall. HIV, the virus that causes AIDS, mysteriously managed to muscle its way around a three-drug regimen that has extended the lives of many other patients, keeping them out of the hospital and helping them avoid costly acute care.

Now doctors and scientists are frantically trying to figure out why. Some 100,000 people are taking the new drug combinations, which include so-called protease inhibitors that were approved early this year. But doctors say it is becoming clear that some people -- perhaps as much as 10% of the group -- aren't faring as well as the vast majority.

The development has sparked a debate over how early a patient should begin the cocktail approach, which drug combinations work best and how sharply the viral count must be reduced to eradicate the virus's chances of mutating into a newly resistant form.

"It's a bit sad and scary, all right," Ms. Averitt says. Her doctor has fiddled with her therapy to add a new batch of drugs to Crixivan, and if that fails she will try a rival protease inhibitor. "I've gotten a nice long ride out of the drugs," she says, but to stay healthy she must figure out how to stay one step ahead of the mutating virus.

The struggle is all the more difficult because protease patients are, in effect, guinea pigs in one of the largest and most expensive medical experiments of our time. The new AIDS drugs won Food and Drug Administration approval so rapidly that researchers still don't have a clear understanding of which drugs work best together, when it is best to initiate therapy, and which patients will benefit best from which drug combinations. At present, researchers are planning dozens of studies, many involving patients already in therapy, to answer these questions.

For AIDS researchers, there's an upside: A huge "test" population of tens of thousands of patients can now be tracked closely to see whether any of the new drug combinations can stave off HIV for months, years or even decades -- or perhaps wipe it out of the body entirely.

But for patients, there's a major downside: Treatment today largely comes down to guesswork, and some patients will inevitably lose.

"In a perfect world we'd have the answers before we treated so many people, but that's not how things are," says Scott Hammer, a research physician at New England Hospital in Boston. "By treating patients aggressively now, long before all the answers are in, we are beginning to ask questions and get answers about the virus that would have been ludicrous to even think about a year ago."

Protease inhibitors, which block the enzyme that is crucial to a late stage in HIV's reproduction, are the most significant advance against AIDS in years. By mixing a new protease drug -- three are in use and two more are in advanced testing -- with two older AIDS medications, doctors hope to corner the virus and suppress its reproduction so tightly that it can't turn out mutated copies resistant to the cocktail's effects.

But now doctors are starting to see some cases in which, for unknown reasons, mutant copies have managed to escape. "A lot of our very advanced patients are doing remarkably well these days. Others aren't doing so well," says Steven Johnson, director of the HIV clinic at the University of Colorado's University Hospital. Adds veteran AIDS activist Martin Delaney, "This virus isn't giving in without a fight. We are foolish to think it would."

Doctors and researchers are coming to believe that it isn't enough to simply reduce HIV levels in a patient's blood. Instead, the virus must be driven down so low that it can't be detected even by the most sensitive tests. Any trace of virus left in the bloodstream, many researchers now theorize, may be enough to let HIV replicate and spin off a resistant copy that will then thrive, making the drugs ineffective.

Some scientists now think that if a patient is already resistant to any of the drugs in the combination therapy, the virus in his blood may decline for a while but re-emerge later. "This means doctors must tailor a combination of drugs that is right for each patient, based on what drugs the patients has already used and is resistant to," says Robert Schooley, of the University of Colorado. "That's going to be very expensive and very complicated, but it's what we have to do."

Yet there isn't any simple test that shows which drugs a patient is resistant to. Sleuthing and constant monitoring are required so that the doctor can alter the recipe appropriately as viral counts rise and fall.

Some researchers worry that if a patient develops resistance to one protease inhibitor, he may be resistant to all of them. Evidence emerging in recent weeks shows that the first protease blocker to hit the market, Roche Holding Ltd.'s Invirase, may be triggering dangerous resistance.

Invirase, while powerful, apparently isn't absorbed in sufficient quantities in patients' bloodstreams to adequately restrain HIV. Roche officials say there is no proof Invirase is causing problems, but the company is nonetheless rushing to develop a more potent formulation of the drug. In the meantime, many patients are doubling their dose of the drug to avoid problems.

For Fain Miller, diagnosed with AIDS three years ago, the Roche drug may already have caused some problems. Soon after he started taking a combination of Invirase and two nucleosides, AZT and 3TC, his virus level declined sharply but then rebounded to 68,000 particles in each sample, or milliliter, of blood. His doctor immediately switched him to Crixivan, but it was unable to push the virus below the 17,000 mark, and these days the level of the virus in his blood hovers at 48,000, a level doctors consider dangerous.

"It looks to us as if we've got resistance to the protease drugs," says Mr. Miller. He may soon add a new AIDS drug called Viramune, made by Boehringer Ingelheim GmbH, and he hopes to get access to an experimental protease drug called Viracept that is being developed by Agouron Pharmaceuticals Inc. He feels good enough to return to work, but he says he will probably stay on disability and Medicaid to cover his drug costs. "My main job is to fight the virus," he says.

Drug companies are testing half a dozen new chemicals that may give some hope to patients who have grown resistant to the three available protease inhibitors. Some researchers are hopeful that the mutated HIV strains dodging current protease entries won't automatically resist the next round of protease drugs, including Agouron's Viracept and another drug from Glaxo Wellcome PLC. Glaxo is also working on a powerful new type of nucleoside that could help patients who have developed resistance to AZT and drugs like it.

For Jono Weiss, 43 years old and fighting the AIDS virus for more than 10 years, the question is whether new remedies will come too late. He has been experimenting feverishly with drug combinations, hoping to keep healthy by staying out in front of the mutating virus. But his disease-fighting immune system is now severely crippled; twice he has developed a deadly strain of pneumonia, and recently he barely fought off meningitis.

Several years ago he took part in tests of Roche's drug and later tried out Merck's Crixivan. But those early experiments tested protease drugs alone. That apparently let the HIV inside Mr. Weiss recover and replicate itself enough to produce a resistant version invincible to the cocktails that are being prescribed now.

Several weeks ago, Mr. Weiss started taking several older AIDS drugs he hadn't tried before, sending his virus levels down somewhat and improving his condition. But because protease blockers can't help him, he feels his long-term health prospects are limited. "I feel better, I've put on some weight, and I'm going through with plans I've made to vacation in Italy," Mr. Weiss says. "Who know what the future holds?"

© 1996, Dow Jones & Company

Company Rushed Crixivan To Market Now It Faces Production Bottleneck

Watching the Patient-Count

By Elyse Tanouye

Merck & Co. has spent more than $1 billion over the past decade to create Crixivan, one of the most promising drugs ever to attack AIDS. It has paid off.

The drug won the fastest federal approval in regulatory history, is helping to restore health and hope to thousands of patients, and is soon expected to bring Merck a half-billion dollars in yearly revenue. After seven months on the market, it is outselling other new drugs in its class.

There is just one problem: The company has been struggling for months to keep ahead of demand.

One of the most closely watched numbers inside Merck these days is the weekly Crixivan patient count. About 90,000 patients world-wide are already on the drug, but there is only enough supply for about 110,000. Demand could increase sharply as more states approve funding for the expensive therapy and more countries allow its sale.

As a result, Merck has been in a breathless race to rev up production and avoid a public-relations disaster: the prospect of running short of supply and having to turn away AIDS sufferers.

How did one of the world's most powerful drug makers get into such a predicament?

Merck created some of its own problems. In the face of a world-wide abundance of production capacity, it chose to build its own plants rather than contract out more work to outside suppliers. And, upon learning that two rivals might beat it to market with similar therapies, Merck requested and got approval of Crixivan -- the most complex drug it had ever tried to mass-produce -- well before its plants were ready.

Much of the production crunch, however, is an unavoidable pitfall of making ever-more-complex medicines. Merck's struggles illustrate the obstacles other companies will face as they pursue new AIDS therapies.

Competition to develop a new class of AIDS drugs began in 1989, when Merck published its discovery of the three-dimensional structure of the enzyme protease, a promising target for attacking the human immunodeficiency virus that causes AIDS. Protease acts like a scissors, cutting up a key HIV protein and enabling the virus to replicate.

The new drugs -- dubbed protease inhibitors -- would mimic part of the protein's shape, creating a decoy to lure protease away from the real protein and prevent it from fulfilling its duties.

About a dozen companies jumped in, and by the early 1990s a handful emerged with promising candidates: Merck, Roche Holding Ltd., Abbott Laboratories, Upjohn Co. (now Pharmacia & Upjohn Inc.), Vertex Pharmaceuticals Inc., and Agouron Pharmaceuticals Inc.

Merck began testing Crixivan in humans in early 1993, and that summer -- long before even knowing whether the drug would work -- top scientists met for lunch in the company cafeteria to chart how to mass-produce it.

"We gulped. We didn't know how we were going to do this," recalls one of the scientists, Paul J. Reider.

Launching full-scale production of a new drug usually begins only after the drug is in advanced testing and has at least an 80% chance of success. The Crixivan effort, because of the AIDS crisis and competitive pressures, began far earlier -- when the drug had only a 5% to 10% shot.

The effort was further hampered by the huge quantities of Crixivan that would need to be produced. Each patient must take six 400-milligram pills a day, every day, in combination with other AIDS drugs to achieve the desired effect of reducing HIV levels in the blood. Supplying just 90,000 patients with Crixivan is the equivalent of producing enough Vasotec, Merck's popular hypertension drug, for more than 21 million people.

Merck pushed other projects aside, assigned 400 employees to the Crixivan team and found ways to produce small quantities while rushing to build two factories -- even before it knew exactly how the production lines would work.

"We were always trying to get our heads above water, and every time we did, the water kept rising," says Dr. Reider, an ebullient, 45-year-old chemist who oversaw the design of the chemical process. Adds Michael L. King, a 44-year-old Merck senior vice president and chemical engineer who helped implement the production line: "If we had gone through it the traditional way, it wouldn't have happened."

Most Merck pharmaceuticals are made in about four steps over two weeks. Making a batch of Crixivan is a six-week process that requires 15 chemical steps. It takes 77 pounds of 30 raw materials to produce just 2.2 pounds of the drug, enough to supply one patient for a year.

In late 1993, Dr. Reider's team began using a prototype production line at a plant in Rahway, N.J., which was able to turn out bigger batches but took up to four months to do it. Each time, only 15% of the volume of ingredients that went in emerged in the desired shape of the Crixivan molecule. Dr. Reider's team needed to cut the production time down to a month and a half and bring the yield up to 50%. Doing so in mass production -- filling vats two stories high -- would be far more difficult. That is because of Crixivan's terribly complex molecular structure.

A quick chemistry lesson: Many drugs are based on central hubs or "chiral centers," consisting of a carbon atom with four branches of various atoms attached. These hubs usually are readymade in nature; only in the past decade have scientists mastered the ability to create and link together multiple synthetic chiral centers, one of the most difficult feats in modern chemistry.

Most medicines are based on just one or two naturally occurring chiral centers; Vasotec, by contrast, is far more complicated because it has three chiral centers, including a hard-to-create synthetic one. Crixivan goes further still: It has five central hubs, all of them man-made.

One of the big problems with Crixivan's low yield lay in a crucial and especially troublesome step, in which a chemical reaction simultaneously creates two new hubs while fusing those atoms onto an already-joined pair of chiral centers. The resulting molecule kept "overcooking" because of high acidity in the process, ruining a large portion of the output. Four of Merck's best scientists tried to solve the problem but failed.

Then a 28-year-old chemist named Peter Maligres took a shot, adding a common chemical and mixing in some baking soda. He improved the yield from that step by 55%. "Sometimes kids come in and try the simplest things, and they work," Dr. Reider says. "It's a humility lesson." By November 1994, the team had designed the complete Crixivan process.

By now, Merck had to decide whether to pay an outside supplier to produce the drug or to build production from the ground up. Archrival Abbott Labs had confronted the same decision as it rushed to scale up production of its own protease inhibitor, Norvir. Abbott decided to strike deals with suppliers in Japan, Italy and France to handle up to 80% of production.

But Merck didn't entirely trust outsiders to handle its most complex chemistry experiment. Early on, the Crixivan team had hired a supplier to make 200 kilograms of a portion of the molecule for batches to be used in clinical trials. The supplier missed the deadline, threatening to set back the entire project, and Merck had to rush through a batch of its own.

So Merck restricted its outside dependence and relied on just two suppliers, Mitsui & Co. of Japan and DSM NV of the Netherlands, to handle seven early and less-complicated steps of the chemical process. Doing most of the work in-house would require Merck to commit several hundred million dollars to designing and building new production lines -- even though Crixivan wasn't expected to go before regulators for another two years.

It was a big gamble, given that Crixivan thus far had delivered promising results in fewer than a dozen patients, who were taking it in combination with the older drug AZT. HIV's uncanny ability to develop resistance had already nixed one Merck drug candidate and had weakened Crixivan's effectiveness when taken without other AIDS drugs. Clearly, Crixivan might eventually fail in clinical trials.

If Merck didn't proceed immediately, however, its new lines wouldn't be ready in time if Crixivan did work. Edward M. Scolnick, Merck's head of research and manufacturing, believed Crixivan would work, because one patient from an early trial persistently kept the virus at bay, even though all other patients relapsed.

"There was no way that patient could have been a fluke," Dr. Scolnick says now. As later tests combining Crixivan with AZT showed promise, "it provided enough assurance, at least internally, that we should go forward with the program."

In late 1994, Raymond V. Gilmartin, who had just become Merck's chairman, agreed to get production up and running -- provided Dr. Scolnick would pull the plug if the drug began to fail in clinical trials. The Merck board gave the go-ahead in February 1995, and frantic construction at two existing plants in Elkton, Va., and Albany, Ga., began a month later.

At the same time, Merck was getting pummeled by AIDS activists, who accused it of dragging its feet on funneling Crixivan to patients. One group, led by Jules Levin, executive director of the National AIDS Treatment Advocacy Project, demanded that Merck allow an outside drug-manufacturing consultant to evaluate its production efforts.

In January 1995, the consultant met with Merck scientists, who explained in detail their difficulties. But Mr. Levin was unconvinced when the consultant told him Merck was doing all it could. The activist continued to prod Merck to speed up its work, and demanded that it make supplies available on a "compassionate-use" basis, free of charge, to severely ill patients who didn't qualify for clinical trials.

Merck was supplying about 300 patients in trials at the time and needed to produce enough for 2,000 for late-stage trials. Given its manufacturing problems, Merck was hesitant about supplying hundreds more patients.

But the activists' lobbying worked. It "reminded us in the middle of this to step back and think about how important every single life is," Dr. Reider says. The chemist committed to supplying 1,400 patients on a compassionate-use basis, before knowing whether Merck could deliver. "I was risking my career," he says.

By September 1995, competitive pressures were intensifying. Abbott reported that it had compiled impressive clinical data on Norvir. It was clear Abbott's drug would win quick federal approval. The same month, Roche's Hoffmann-La Roche Inc. unit announced it had applied for Food and Drug Administration approval of its protease inhibitor, Invirase; by November, it had won an FDA panel's endorsement and FDA Commissioner David Kessler's promise of quick approval, which came the following month.

Under its original timetable, Merck was still a year away from launching Crixivan. But it was hell-bent on getting to market at the same time as its competitors. So its top researchers waged a pitched lobbying campaign to have Crixivan considered alongside Abbott's drug at a coming meeting of an FDA advisory panel. Never mind that Merck would have to file its FDA application by January 1996, eight months earlier than planned. And that its factories weren't ready.

The FDA agreed, but had a principal concern: Could Merck produce enough Crixivan to meet initial demand? If too many patients started on the drug, they might find their pharmacies out when they went for refills. Patients who stop taking the drug even for a short time risk developing resistance to it.

Merck assured the FDA it could make enough on its prototype line for up to 30,000 U.S. patients. To ensure a steady supply, Merck would funnel most prescriptions through a single major distributor, a mailorder retailer named Stadtlanders Pharmacy in Pittsburgh, which is now majority-owned by Counsel Corp. of Toronto. Merck could then control the number of patients on the drug, and bar new patients when demand matched supply. By contrast, Abbott planned to distribute Norvir to pharmacies nationwide.

Abbott's drug won FDA approval on March 1 of this year, and Merck's entry breezed through just 13 days later.

Soon, however, Merck encountered a torrent of protests over Crixivan's restricted distribution. AIDS activists accused the company of giving Stadtlanders a monopoly that let it price-gouge patients, and retail pharmacists decried getting cut out of the deal. Stadtlanders charges customers a 37% premium above what it pays Merck; however, the pharmacy says most patients pay much less than the list price because of discounts under various insurance, government and other plans.

Mr. Levin, the activist, says that despite his earlier doubts, in retrospect "it's obvious Merck does have a production problem."

Meantime, as Merck churned out small quantities of the drug at its prototype plant, construction proceeded at a furious pace at the 45,000-square-foot main plant in Elkton and the satellite in Albany.

Finally, on May 27, the big operation was ready. The first Crixivan batch entered the system at 9:30 a.m. For six weeks, Merck engineers and chemists crossed their fingers as 30,000 gallons of liquid trickled through 20 miles of pipes, vats, dryers, pressers and capsule- and bottle-fillers. On July 6, the last of the batch's white capsules were in boxes, ready for shipment.

But demand for the drug had begun to pick up after the benefits of protease inhibitors received wide press coverage following an international AIDS conference that week. The Merck crew still had months of work ahead to bring the plants up to full production.

Slowly, more Crixivan "runs" are going on-line; the plants will eventually handle 18 batches at once, each lot producing two million capsules. The question now is whether Merck will get the operation up to full-scale production before demand can overtake it.

Crixivan appears to be outselling Norvir and Invirase by a wide margin, according to IMS America Ltd., a Plymouth Meeting, Pa., market-research firm. Doctors and patients say they favor Crixivan because it has fewer side effects than Norvir and is more potent than Invirase. Demand for the drug may have been slowed by the limited availability of government funds, both in the U.S. and abroad, to pay for the treatment, which when combined with other drugs can cost $14,000 a year per patient.

A big concern is that demand could shoot up at any moment. In recent weeks, for example, the European Union and Canada, two large markets, approved the drug.

Last week, Merck said that the fast pace of international approvals and the higher-than-expected numbers of patients in the U.S. taking the drug have prevented it from building enough inventory to expand distribution to other pharmacies besides Stadtlanders by the end of the year as planned. Instead, distribution through retail pharmacies will begin "sometime in 1997," a spokesman said.

But Merck officials say they are confident they can keep pace. They estimate the new plants will be able to crank out enough Crixivan for 150,000 patients by the end of the year and 250,000 by early 1997.

"It wasn't humanly possible to be ahead of where we are, given the history of the project," Dr. Scolnick says. But he vows: "Merck isn't going to run out of this drug."

© 1996, Dow Jones & Company

Last Year This Editor Wrote His Own Obituary; Now, He Writes of Surviving When It Was Called 'GRID'

By David Sanford

"I need to tell you this directly. I have AIDS," I wrote. "I do not know how long I have to live, and I am ripe for AIDS-related diseases. But I would like to continue working on Page One as long as I am making a contribution and am trusted to do good work."

One year ago today, I told my colleagues that I was dying of AIDS. I had been fighting it for years -- the illness and the telling.

I had been taking AZT, and briefly even a drug given to lepers. But now I was gaunt, tired and rather sure I was losing the battle. I gave my boss an obituary I had written -- I'm a features editor on Page One of The Wall Street Journal, so I certainly didn't want anybody else writing it -- sent a note to my boss's boss and started saying my goodbyes.

Last week, my doctor, Jerome E. Groopman, noticed that I am getting fat and said it wouldn't be a bad idea if I went on a modest diet. At age 53, I am going to the gym again. I need to buy some new clothes. I am planning to one day retire with my partner of 28 years, who is HIV-negative.

What has happened in the past year, at least for me, is a miracle that couldn't have taken place at any other moment. The year 1996 is when everything changed, and very quickly, for people with AIDS. I have been grappling with this disease for nearly a decade and a half, almost since the beginning, when it was called Gay Related Immune Deficiency, or GRID. I've outlived friends and peers, and now I find myself in the unusual position of telling people how I've survived this scourge, something I never thought would happen. My condition could change for the worse tomorrow. But today I feel well again.

Thanks to the arrival of the new drugs called protease inhibitors, I am probably more likely to be hit by a truck than to die of AIDS. In coming alive again, I've learned the value of a good doctor and good friends -- and the importance of being honest with yourself, your co-workers and the people you love.

My battle with AIDS, I'm certain, began in December 1982, at a bathhouse in Manhattan's East Village during a sexual encounter with a man whose name I didn't catch. Like other gay men, I had kept up with newspaper reports, beginning with a July 3, 1981, New York Times story with the fateful headline: "Rare Cancer Seen in 41 Homosexuals." Nevertheless, going to the baths was a big part of gay culture back then, and here I was. Old habits die hard.

At the time, the federal Centers for Disease Control and medical authorities were saying little about this being an infectious disease. Indeed, they at first thought it probably wasn't. But it was pretty clear that GRID was caused either by the cumulative effects of too much sex (so many men, so many germs) or too much butyl nitrite (poppers), a sexual stimulant sniffed from little vials available for $5 at newsstands. The third possibility was that it was a sex-borne plague.

A week or two after that encounter, I came down with the strangest flu. It had the usual aches and respiratory symptoms, but also a high fever and a rash. It lasted for a couple of weeks at Christmas when my partner, Lewis, and I were in Denver visiting my mother, just two weeks before she died. I have since learned that when people become infected with the human immunodeficiency virus, they often have such an illness.

It was on this visit that my mother asked us over dinner one night whether we had seen a TV documentary about "the disease a lot of people in New York are getting." "Homosexual" was a word I never heard from my mother, and I didn't utter it around her. Sex wasn't anything we talked about. I had been living with the same man for more than 14 years, and my mother, who was perfectly accepting of our relationship -- a marriage in every sense but the legal one -- was still hoping for grandchildren from her only child.

Yes, we told her, we had seen the program. End of discussion. I didn't volunteer that I thought I myself might have recently been infected. My New Year's resolution was to become as chaste as a priest is supposed to be, and I did. I was determined not to get infected if I wasn't already, and I didn't want to infect anybody else.

But the signs were there. I tired easily. On a trip to Japan in 1984, I had the first of recurring night sweats, which can be a sign of infection. When I dieted, I would drop weight quickly -- 48 pounds in one four-month period.

When the HIV blood test finally became available in 1985, I wasn't interested in opening Pandora's Box. There wasn't anything you could do for HIV then anyway.

It wasn't until 1989 that researchers reported that HIV-positive people -- and not just patients with full-blown AIDS -- might benefit from the drug AZT. Now there was a good reason to be tested.

I got the news on Sept. 22, 1989, when a woman named Bea at the New York City public-health clinic on Ninth Avenue told me I was HIV-positive. I have always been health-conscious. (Lewis said to me recently: "You are the answer to the question `Can you have AIDS and be a hypochondriac?'") But at that moment I suddenly stopped worrying about twinges, radon and asbestosis and focused squarely on dying of AIDS. Bea, who knew me as a code number, said to comfort me: "If I considered this a death sentence, I couldn't do this work." She told me to go to my doctor and get on AZT.

I wasn't surprised by the test result, but I was upset. I'm not a crier, but I cried. I took a taxi from the clinic to the Journal and proceeded to sleepwalk through the day. That morning, I attended a meeting to talk about a series of articles on public schools. My only thought as I sat silently through the discussion was, "What do I care? I'm dying."

I didn't know whether I would ever care about anything again, except that I was worried about Lewis, and I felt strongly that I didn't want to endure some long, terrible final illness.

Because my helper T-cell count (T4 lymphocytes) was 457, well above 200, which represents clinical AIDS, my doctor didn't recommend that I do anything but monitor the situation with blood tests every three months.

The first year that I knew myself to be HIV-positive was the last year of my friend David Coon's life. He had been the back-of-the-house manager at the Odeon, a restaurant I liked in lower Manhattan. He gave me good tables. I bought him a subscription to The Wall Street Journal.

Lewis and I had more than one Thanksgiving dinner at the Odeon, with David working, and we became friends. Late in 1989, he lost 35 pounds and was hospitalized with what Keith Younger, a gay waiter who worked with him, told us was "a bad case of toxo" -- toxoplasmosis, a parasitic infection contracted from cat litter that can cause encephalitis.

Once out of the hospital, David said nothing of AIDS, but claimed he was found to be lactose intolerant. That was why he lost all the weight, he said.

The last time I saw David was the following summer at his apartment on Second Avenue. He had been in and out of the hospital, complaining that "there were too many people dying" around him. "It's an AIDS ward," he said. He was blind in one eye. He was being fed intravenously. He had 24-hour nursing at home. He was having to sell his weekend house. I told myself I would commit suicide before I let anything like this happen to me.

That December, I got a refund from The Wall Street Journal for the remainder of David's subscription. Someone had canceled it. I called to see if he was OK. I asked his nurse Roberta Montuori whether I could speak with him. "You can talk to him," she replied, "but I don't think he will be able to talk to you." She gave him the phone. I spoke. He made excited animal sounds that were nothing like words. Two days later, he spit out his medicine and died. Two months later, Keith was dead, too.

I wasn't even going to think of dying in such misery. I retreated into bookkeeping. According to the Kuder Preference Record, an aptitude test I took in school, my interests pointed toward a career as a certified public accountant. Fortunately I became a reporter instead, a writer and managing editor of the New Republic for 11 years in the '60s and '70s, then managing editor of Harper's magazine in 1979 and 1980.

But with my bent for accounting, and a Swedish fatalism I picked up from my mother and immigrant grandparents, I started getting my affairs in order -- revising my will, withdrawing the voluntary contributions I had made to the profit-sharing retirement plan of Dow Jones & Co., which owns The Wall Street Journal (so I could spend the money), and making lists of insurance policies.

The other thing I did was to embark on a campaign of deception.

My doctor suggested I not file for insurance reimbursement for my regular T-cell tests, which I had every three months and which were costing about $150. "You can afford it," he said, knowing nothing about my financial health. The lab test was a tip-off, he said: "Even though these things are supposed to be confidential, employers have a way of finding out."

I wasn't afraid that The Wall Street Journal would fire me for being HIV positive. The company had been good to employees with serious medical conditions, including the two people I knew of who had died of AIDS.

But 1989 was a world away from 1996 in the way Americans felt about AIDS and, particularly, about the routes of contagion. I didn't want to tell anyone I was infected and thereby change forever the quality of my relationships.

Lewis and I didn't have a gay social set. Most of our friends are married couples with children. And though I was discreet about my homosexuality, Lewis and I are a couple, and I figured people knew I was gay, if only because I had written an op-ed piece for the Journal Aug. 29, 1985, titled "Need We Guess Why Young Men Are Dying?" In it, I questioned why in a year of reading obituaries and classified death-notices in the New York Times, I could find only four listing AIDS as the cause of death. Back then, young unmarried men in the obituaries died of pneumonia, leukemia, meningitis and lymphoma, or "after a long illness," but rarely of AIDS.

I crossed the threshold into AIDS itself on Oct. 15, 1991, when my T cells fell to 198. At that point, my doctor recommended I start taking AZT, 100 milligrams, five times a day. He also prescribed a drug I had never heard of called Dapsone. I went home, looked it up in my Physicians' Desk Reference and learned that its primary use was in the treatment of leprosy.

Just filling the prescriptions took guts I nearly couldn't muster. I was as embarrassed as a teenager buying condoms. I watched the pharmacy clerk read the prescription, then glance up at me. That was an intimacy I didn't want. "Would you like counseling from the pharmacist?" he asked. I did not; I wanted to get out of there.

I also didn't want to take the medicines. Definitely not a drug for lepers. And not AZT, which had potentially bad side effects, including liver damage. I took the pills for five days and quit.

Lewis and I had always thought we would grow old together, and now it looked as if I was going to be bailing out. Together we prepared for my decline and how the two of us would get through it. My bookkeeping proclivities had me signing and notarizing a living will, a limited power of attorney for health care, and a general power of attorney. I arranged for my cremation with the Neptune Society. I wanted to be sure that if I got very sick, Lewis would have the authority to pull the plug.

I told my doctor I wanted to be treated in the most minimal way, that I wanted no heroic attempts to prolong my life if I were to become terribly ill. He said that even if I chose not to take the Glaxo Wellcome drug AZT, and had no appetite for the Jacobus Pharmaceutical drug Dapsone, I should be taking a generic version of double-strength Bactrim, an antibacterial drug that staves off Pneumocystis carinii pneumonia.

I wasn't accustomed to ignoring the advice of doctors, and I decided to be a good boy and take my medicine, joylessly. I started with a daily dose of Bactrim on Feb. 22, 1992. I went back to AZT on May 22. At first, I thought AZT ruined the taste of food, but I have never missed a dose. I would have been more enthusiastic had the doctor really believed in it. Does it do any good? I asked. "Maybe some, probably not a lot. Nothing does much good," he said.

I thus began a long slow slide in immune function, measuring out my life in 12-week increments between blood tests. My T-cell results trended down, culminating in a count of 138 on Sept. 27 last year. We tried adding to the mix the antiretroviral drug Videx (DDI), made by Bristol-Myers Squibb. Taking it made a drink of alcohol feel like a kick in the stomach. I went on the wagon and wondered what vices I had left to give up.

By November, I was sad and defeated. I weighed 161 pounds. I am 6-feet-2-inches tall, and, naked in a mirror, I could see how emaciated I was. I was exhausted at the end of the day, and I was feeling that life consisted of taking pills, going to work, sleeping very long hours and going to work again. The routines of daily living had become a burden.

Over the years, I had observed in my doctor's office and on Christopher Street -- the center of a largely gay neighborhood in Manhattan -- men walking with canes, men with sunken temples, wispy hair and sadness in their eyes. I would often encounter one of these sad men and exchange knowing looks. I knew they had AIDS and I believed they could tell I did, too. Nothing needed to be said.

My friends, it turns out, swear they couldn't see it and didn't know I was sick, though people were saying "How are you?" in a particularly earnest, heartfelt way.

It seemed that all that remained was to wait for some opportunistic horror to kill me, and I thought it would happen in 1996. I had had my first AIDS-related infection, thrush, a kind of athlete's foot of the mouth that is readily cured by a costly Pfizer drug called Diflucan.

I asked my doctor's partner, who diagnosed the thrush, whether it meant my immune system had gone over a cliff. He said no, it didn't. But I felt that now was the time to do something.

The something I decided to do was to tell my boss, John Brecher, the Page One editor, and Paul Steiger, the managing editor of the Journal, that I had AIDS. I could see the slide I was on, and I didn't want to have to lie about workdays missed and possible hospitalizations. Besides, I assumed that because I was so haggard they must already know.

Remembering what my doctor had said, I was also sure that they had heard all about it from our group insurer. For a while I did pay for my T-lymphocyte subset tests myself. But when I began taking AZT, I started to file for everything, and last November I told my doctor to begin writing AIDS -- not "viral infection" -- as the diagnosis on insurance forms. Call it another step in my coming-out process.

I wrote a difficult letter to John and to Paul. "I need to tell you this directly. I have AIDS," I wrote. "I do not know how long I have to live, and I am ripe for AIDS-related diseases. But I would like to continue working on Page One as long as I am making a contribution and am trusted to do good work." I concluded it: "This is a bummer, I realize, and I am sorry to add it to your burdens."

No, it turned out, they hadn't suspected I had AIDS. Yes, I could go on working. Both men offered carte blanche assistance: "If you need anything at all, let us know." They used about the same words.

I asked Paul if he thought it would be a good idea to send out an "all-cities" memo to the newspaper's bureaus that I had drafted for his signature. Paul didn't merely edit and sign my draft, he attributed it to me and added this in his own words: "I know you will join me in sending David our deep love and high respect, in affirming his enormous contributions and continuing value to this newspaper -- and in wishing him many more happy years here." The memo went out Nov. 8. I thought of it as a death notice, but it turns out to have been more of a rebirth announcement.

For the next month, I was utterly unable to do my job because I spent the days talking to callers and speaking to friends at work. The cards and letters poured forth. The experience was a lot like attending my own memorial service, something I have always wished I could do. I hadn't truly expected the hugs and the tears and the rest -- even the laughs. I was consoling people who were trying to console me. I had already gone through all the stages of mourning for myself.

I also sent out my first-ever personalized Christmas letter to tell friends and relatives, some of whom I hadn't seen for 20 years. Lewis, who sees clearly, warned me not to become a poster boy for AIDS, and I knew that sending health bulletins far and wide was to invite every conceivable reaction. I did expect to see some sign of disapproval, but there really wasn't any, certainly no outright hostility. A cousin in Denver did start sending me religious tracts -- and a Billy Graham tape.

One of my holiday letters went to Martin Peretz, editor in chief of the New Republic. I hadn't seen him in the 19 years since I left the magazine, but time hadn't diminished our friendship, and I wanted him to know what I was telling everybody but the deli man on the corner. The letter to him changed my life. Marty called me immediately. He said his friend Jerry Groopman, who practices medicine in Boston, "treats AIDS very aggressively." I really ought to see him.

Marty said he would be glad to make the introductions. He called me again to say that Jerry could see me in three days.

It was too soon for me. I was happily dying -- and about to go on a Mexican vacation. I felt I had made my peace with death and, in a way, was looking forward to it. I had blown my mother's estate, about $180,000, on living for the moment, eating in the best restaurants and taking three or four foreign vacations a year. There was no time to lose, and I was determined to go out in style.

Did I now want my AIDS to be approached aggressively? I wasn't sure. But I decided to make an appointment, and on Jan. 23, I flew to Boston.

Marty had told me a story about Dr. Groopman. They were at temple, and during the misha berach, the prayer for the sick, Jerry was reading off a list of his patients. When everybody else had finished praying, Jerry was still reciting his list. Marty later asked him about it: "Jerry, but you are a man of science." The doctor replied, "Yes, but I am also a Jew."

Jerry confirms that the conversation took place. He is a wonderful mixture of scientific expertise and religious faith. He has been treating AIDS patients since 1980, before anyone even knew the meaning of the pneumonia and Kaposi's sarcoma he was encountering as a 28-year-old doctor at the University of California at Los Angeles. The 6-foot-6-inch gray-bearded Harvard professor also juggles his time among his wife, Pam, and three children; a book he is writing; and the patients he sees as chief of experimental medicine at Beth Israel Deaconess Medical Center.

The day I met him was one of the most important days of my life. His secretary, Youngsun Jung, had asked me to scavenge what medical records I could and bring them with me. I had graphed all my T4 numbers, the results of 19 blood tests between Sept. 11, 1989, and Jan. 3, 1996. The high was 580 on April 19, 1990. The low, on Sept. 27, 1995, was 138. The numbers bumped around, but after January 1991 the trend was gently downward.

Jerry ("Only my mother calls me Dr.") Groopman, 44, took my medical history and said it appeared I had a very weak strain of the AIDS virus. I wasn't in as bad shape as I thought. He was very optimistic that my life could be prolonged by the Roche drug Invirase, a protease inhibitor that had been approved by the Food and Drug Administration just the month before. He said I should take it in combination with AZT and the Glaxo Wellcome drug Epivir (3TC), a "nucleoside" in the same class as AZT.

He was equally reassuring when he moved on to the physical examination. I was skinny, but I wasn't wasting. My muscle tone was fine. Looking at my tongue, he said, "You've got thrush again." I should be taking 100 mg of Diflucan prophylactically every day, he said.

I filled the prescriptions in Boston and popped my first pills on the Delta shuttle back home. There were so many pills. Generic Bactrim (SMX-TMP) and Diflucan every morning. Three capsules of Invirase three times a day, AZT five times a day, Epivir twice a day.

It would be some kind of yuppie whine to complain about how burdensome it is to swallow a lot of pills on a complicated schedule, particularly if they keep you healthy. It isn't all that difficult. But you can plan a slow day entirely around taking medicine. Each of the drugs comes with a long list of possible nasty side effects, ranging from liver and kidney damage to pancreatitis and neuropathy in the limbs. So far, I have experienced none of that.

My next big problem was what to do about my doctor in New York. On Feb. 7, I told him I had been given a chance to see Jerome Groopman at Harvard. "Do it," he said, recognizing the name. "I've already done it," I replied. "Good. What did he say?" The doctor agreed to follow Jerry's regimen, but warned: "Nobody knows what harm these drugs are going to do to your body or how long they will keep you alive."

Invirase was put on the market in December after 26 weeks of clinical trials that had such heartening results it got the quickest FDA approval of any new medication in history. (The record was broken in March by the other two protease inhibitors currently on the market, the Abbott drug Norvir and Merck's Crixivan). Who knew what would happen to patients after a year or two?

Dr. Groopman, who agreed to become my "primary-care provider," uses his own sophisticated "viral-load" test that counts viral RNA in a milliliter of blood down to 100 viral units. Below that is considered undetectable. The more AIDS virus one has coursing through his or her veins, the greater the likelihood of AIDS-related disease.

My very first viral-load test, taken before I went on Invirase, was only 5,795, which is very low, even with treatment. A viral load of 5,000 is correlated with a 100% chance of surviving five years; at 100,000, you are in bad shape.

I stopped the presses on my obituary. After several weeks on the new therapy, I also started feeling well, better than I had in 10 years. I started gaining weight, 25 pounds to date. I no longer was fading.

Oddly enough, the return from my near-death experience was at first very annoying. I had a few adjustments to make. I had to start thinking again about my bills. Lewis and I had salted all the money we could into a co-op apartment and untouchable retirement accounts, and with my mother's money running out, we now had to start living within our means. My life-insurance benefits weren't heading his way as soon as I had reckoned. Enough money was coming in from our respective jobs to pay bills, but there was no discretionary income to speak of.

Fortunately, my work is fulfilling, so I didn't need to reconsider my ambitions. But I have had to re-energize myself for the daily grind. I'm even thinking about cleaning the basement.

But I'm not out of the woods. This treatment needs monitoring. My second viral-load test, after a month on Invirase and the other drugs, was 470, a spectacular decrease. But my third and fourth tests taken 10 weeks apart showed increases in viral load, to 1,000, then to 2,000. The number was still low but headed in the wrong direction.

On June 26, Jerry doubled the Invirase to 3,600 mg a day (18 big yellow and green capsules). In August, he added the just-approved Roxane Laboratories drug Viramune, which is like AZT and 3TC but different; it is a "nonnucleoside." In September, Jerry took me off AZT, which may have played itself out after four years, and substituted the Bristol-Myers Squibb drug Zerit (D4T), another drug in the same class. The viral load on Sept. 3 had come down to 600. "An A+," Jerry said.

The battle plan has been to move to Norvir or Crixivan if the AIDS virus is still detectable. I won't get my Oct. 29 results until next week. The goal is to get the viral load down to a level that can't be measured, so as to reduce the likelihood that the virus will mutate into a drug-resistant form.

Perhaps the best news I've had is that my T4 cells rose over six tests from 157 to 292. The new drug "cocktails" haven't been resoundingly successful in raising the T4 counts of patients with truly devastated immune systems, even when viral loads decrease. But 292 is a level that can probably sustain me.

Some HIV-negative men are guilt-ridden that they aren't infected when they see so many of their friends dying. I feel guilty that I am getting the best possible medical care, because it is unavailable to most of the world's AIDS sufferers, and to the poor and uninsured in this country. According to the CDC, as of June 30, 343,000 people in the U.S. have died of AIDS. The agency estimates that as many as 900,000 are infected. About 100,000 are taking protease inhibitors.

My prescriptions for the year ended May 31, 1996, cost Dow Jones $7,634.06. Next year the bill will be higher.

Last week, on my sixth visit to Dr. Groopman's office in Boston, I had an hour to kill in his waiting room to read an issue of Poz -- a magazine for the HIV-positive -- and to watch eight or 10 other AIDS patients coming and going. The extraordinary thing about the scene was that everyone was smiling, almost constantly.

People in doctors' offices had always struck me as bored or frightened. These men bantered with Nancy Leary, the secretary, smiling all the while. The fellow sitting nearest me stepped to the desk to speak animatedly on the phone about his Crixivan prescription.

Ten months ago, he was skeletal. He had an infection and his doctor believed he had weeks to live. Now, thanks to Crixivan, his viral load is too low to count, and he looks like the professional model he once was, handsome and healthy. To see him, you would have no idea he has AIDS or, as he said, that "this has been going on for about 10 years." I told him that I believe I was infected in 1982. "You're lucky," he said. Most people infected that long ago are dead."

© 1996, Dow Jones & Company

Forced to Make a Choice Between Job or Insurance, Many Opt for the Latter

Taking a Carrier's Crawl Test

By George Anders

WASHINGTON -- Wracked with a spinal infection and other AIDS complications, Jeff Bloom quit his job selling expensive audio electronics two years ago and went on long-term disability. Today, with the help of advanced drugs, the 37-year-old Mr. Bloom feels well enough to work again. There's just one problem: If he does, he will lose the $40,000 he gets in disability income each year.

"I've thought a lot about going back to work," Mr. Bloom says. "I like meeting people, and I love the give and take of business. But I ask myself: `Do you want to give up disability -- and find you can't get it back if you need it?'"

Like thousands of other AIDS patients who are benefiting from the new drugs called protease inhibitors, Mr. Bloom is stuck in an insurance quandary. AIDS used to be viewed as a one-way street: When employees became too sick to work, disability insurers would write monthly checks without bothering to monitor those cases any further, convinced that decline was certain. Now, patients and insurers are having to reassess their approach to AIDS disability.

"Disability insurance has been a cocoon of safety," says Paul Hampton Crockett, a Miami lawyer specializing in AIDS issues. "Suddenly it's not so clear that's going to be the case. People who were expected to die are going to be coming back. Nobody is prepared for this."

Across the U.S., AIDS groups are deluged with calls from patients excited, confused or frightened about the prospect of ending disability status and returning to work. In Miami, psychologist Larry Harmon has begun weekly seminars on resume-writing and job interviews for AIDS patients who haven't worked in years. At AIDS Project Los Angeles, counselors field 100 calls each week on return-to-work issues.

The disability dilemma starts in the offices of big private insurers and Social Security, which together pay more than $1.5 billion a year in benefits to about 100,000 people in the U.S. with AIDS and other diseases related to the human immunodeficiency virus. While that is less than 4% of the overall disability market, the promise of the new drugs makes management of AIDS cases especially challenging for policy makers and underwriters.

"In AIDS, something can look like a breakthrough and then fade away in six months," says Ken Nibali, a disability expert in the Social Security Administration. "We have to be careful and responsible about how we look at these things."

Still, Mr. Nibali says Social Security might re-examine -- and tighten -- its disability criteria for AIDS patients if protease inhibitors continue to show such strong results. When taken in combination with older drugs, protease inhibitors have forced down the amount of HIV in many patients' blood to undetectable levels. It still isn't known, however, whether a significant number of patients will eventually develop resistance to the new drugs.

Private insurers such as Unum Corp. say they expect plenty of return-to-work conversations with AIDS policyholders in coming months. Another leading insurer, Fortis Corp., says that at its own discretion, it may offer retraining courses or no-risk trials of a brief re-entry into the work force -- even though such benefits aren't spelled out in its contracts.

"It's in our interests to support any reasonable plan for a return to work," says Mark Andruss, a disability specialist at Fortis.

AIDS patients face a barrage of challenges as they think about rejoining the work force. Job skills sometimes have atrophied. Old careers don't seem fulfilling any more after a brush with death. Potential employers may not want to hire someone with a costly disease, even though federal law bars discrimination against people with AIDS. And without clear knowledge of the new drugs' staying power, some patients fear that a return to work could be premature, leaving them in dire shape if protease inhibitors fail them and they lose their jobs once again.

Software engineer James Carr, 38, shudders to think about the myriad new technologies he must master if he is to resume work. He used to be a star computer programmer, deluged with consulting assignments. Then AIDS forced him to go on long-term disability in 1992.

"I'm going to need new software, new tools, new products" to be a success once more, Mr. Carr says. He estimates that retraining courses will cost $10,000; he is in talks with his disability carrier, Paul Revere Insurance Co., to see if it will help pay the bill. A spokesman for Paul Revere says he can't discuss specific cases, but says such negotiations between beneficiary and insurer would be "typical."

In Florida, a former retailing executive in his 30s, who requested anonymity for fear of losing his sizable disability benefits, says his battle with AIDS has drastically changed his priorities. "I used to have a six-figure income and a job where I put on a suit every day," he says. "But going back to the corporate world isn't what I want to do for the rest of my life."

For now, disability checks of about $100,000 a year leave him free to garden, work out at the gym and socialize. "Every day is a Saturday for me," he explains cheerfully. Protease inhibitors have eradicated nearly all traces of HIV in his blood.

But the former executive says he expects his disability insurer will soon demand that he return to work. His likely response: to set up a landscaping business that would be more fun than his old line of work, but would probably pay a lot less.

Other AIDS patients don't have such rosy choices. In New York, former real-estate broker Cliff Gilbert, 36, recently stopped taking protease inhibitors because of limited effectiveness and nasty side-effects. He has no private disability insurance and struggles to make ends meet with about $1,000 a month in Social Security disability and welfare.

He considered taking a part-time job at a friend's hat-embroidery shop but decided against it, in part for fear of jeopardizing his government benefits, and also because he isn't sure how long his health will hold up. "The biggest downside of this disease is that you stop being a dependable person," he says. "I couldn't be sure that I would be there every day. That's very hard to acknowledge."

In San Francisco, David Lewis, 43, who has qualified for AIDS disability coverage since 1988, is in a similar bind. He gets about $600 a month from Medicare and is draining down some inheritance money to help cover living expenses. He says he wouldn't mind working again if he could get good health insurance. But pay and health benefits are meager in his line of work -- managing small nonprofit organizations. As a result, he volunteers at various nonprofits while collecting disability checks.

"I've spent the past eight years working the insurance system as best I can," he says, complaining that the industry should encourage, rather than penalize, a return to work. "It's a flawed system."

All these tensions play out in Mr. Bloom's life here. Each weekday morning, he packs a leather satchel with small orange vials of medicines that he must take every few hours, including Crixivan, a protease inhibitor made by Merck & Co. Then he walks three blocks from his Dupont Circle apartment to a volunteer job that typifies his professional limbo.

A chatty man with thinning brown hair, Mr. Bloom shows few signs of his disease. He walks comfortably down city streets again, after months when he could barely creep to the end of the block. His appetite has returned, to the point that he frets about signs of a paunch. The combination drug therapy "has given me a second chance at life," Mr. Bloom says. "It isn't something I'd ever expected."

The drugs have battered down the amount of AIDS virus in his blood to 520 particles per milliliter, down from a reading of 166,000 two years ago. His T-cell count, a measure of the strength of his immune system, has rebounded to 135 from a low of 51 two years ago, though that is still below the 200 mark that denotes the onset of AIDS.

In practical terms, however, the restrictions of Mr. Bloom's insurance policies -- and uncertainties about the job market and his medical outlook -- make it very costly for him to stop being disabled. He currently gets annual disability payments of about $13,000 from Social Security and $27,000 from Delphi Financial Group Inc.'s Reliance Standard Life Insurance, with most of it all tax free. The private insurance would cease if he resumed work of any kind, including even a low-paid part-time job.

Not all disability policies are that restrictive. Many insurers actually encourage part-time work by guaranteeing policyholders combined work income and disability benefits equal to 60% of their former income. Without that freedom, however, Mr. Bloom finds his options limited.

He sees little hope of getting his insurer to relax its rules, given the hassles he endured when his doctor in 1994 certified that Mr. Bloom's AIDS condition and severe nerve damage made him "unable to do any work."

The insurer asked one of his doctors to fill out a form specifying how much Mr. Bloom could climb, kneel or crawl. "I wonder what sort of job they would have told me to get if we said I could crawl for eight hours a day," he says. Reliance says the form "was generic and asked questions that mightn't have been pertinent to Mr. Bloom, but would have been appropriate for people with other lines of work, such as repairmen."

For now, Mr. Bloom hovers uneasily on the edges of the productive economy. He is a regular volunteer at AIDS Action, a health-care advocacy organization near his home. He lives more simply, driving a Chevrolet Camaro instead of a Mercedes-Benz and taking vacations in West Virginia instead of Europe. He enjoys more leisure time, occasionally taking a weekday off with his new lover, a young man who is HIV-negative, shopping together for furniture and curios.

Yet Mr. Bloom clearly would like to return to work. When friends talk about career accomplishments and goals, he grows wistful. "For me, work has always been enjoyable," says Mr. Bloom, who got his entrepreneurial start in college selling 5,000 copies of a Stevie Wonder album at the student co-op in a single day, then eventually going on to open several audio-video stores. "When I'm running a meeting I'm in my element. I never felt: Oh God, I have to go to work today."

But his medical history prevents him from qualifying for a new disability policy as an independent worker. His only hope of coverage would be to join a large company that offers generous disability benefits to all its employees.

Like many people who have battled a mortal illness, Mr. Bloom says he would be hard-pressed to go back to his old line of work, selling video cameras, tape editors and other electronics. He and his former boss parted company on strained terms, partly because of a disagreement over Mr. Bloom's final commission checks, partly because of indignation on his boss's part that Mr. Bloom hadn't explained his health problems more candidly as they unfolded.

"Jeff was a very good salesman, but toward the end, I couldn't count on him to come to work," recalls his former boss, Robert Levin, head of an audio-video equipment store in Wheaton, Md. "Not knowing the complete story, I thought he was just sicklier than most." For his part, Mr. Bloom says: "I could do that kind of sales again, but it would be tedious. If I have a finite amount of time left, I'd like to do something more fulfilling."

For the past two years, his volunteer AIDS work has taught him how to capably maneuver through the machinations of Washington politics. This past summer, he helped lead a patient-group coalition that lobbied against Republican efforts to overhaul the Food and Drug Administration, and successfully pressed Congress to increase subsidies to people unable to afford costly AIDS drugs.

Those skills might serve Mr. Bloom well if he pursued a career as a professional lobbyist -- which he would like to do, if only the disability rules would let him. He also worries that the staying power of his drug-cocktail therapy is unknown: it could last for years; it might fail at any time.

"It would make sense, in pure business terms, to let people with AIDS try to work," he adds. "But there has been this expectation that people are just going to die."

© 1996, Dow Jones & Company

He Wants to Test a 'Cure,' But Others Are Critical; A Talent for Sound Bites

Irene Diamond's Dream Lab

By Michael Waldholz

NEW YORK -- Twenty-one men infected with the AIDS virus -- test subjects in a controversial experiment -- have been able to stave off illness for the past year by gulping down about 20 pills a day. Now researchers are asking them to do the unthinkable: halt the multidrug "cocktail" regimen that has quelled the growth of the deadly virus inside them.

It is an audacious gamble. But lead researcher David Ho argues it is the only way to test whether the cocktail approach, which has boosted the health of thousands of patients this year, could become an outright cure for AIDS if used early and intensively enough. So far, though, none of the patients have agreed to stop treatment.

"Would you?" asks Scott, a health-care worker and test subject who refused researchers' request two weeks ago. Scott has gone almost a year without any sign of the virus in his bloodstream, but he frets: "I think the virus is probably still in there somewhere, waiting. Someone else is going to have to go first."

Some rival scientists say Dr. Ho's bold gambit amounts to scientific grandstanding, a tactic to generate publicity for himself and raise funding for the laboratory he runs, the Aaron Diamond AIDS Research Center. Critics worry that Dr. Ho's experiment, in addition to possibly endangering his patients, will falsely raise hopes.

"It's going to mislead people into thinking there is a cure," says Mark Harrington, a veteran patient advocate with the New York-based Treatment Action Group. "And, of course, that's crazy." A skeptical Robert Gallo, the co-discoverer of the AIDS virus and director of a rival research center in Baltimore, bluntly asks: "Why are there so many press releases" emanating from Dr. Ho's lab?

Dr. Ho rejects such criticism. He says he avoids using the word "cure" because "it's way too premature." But he argues: "We are asking critical questions that need to be asked, pushing the virus as hard as we can, probably harder than anyone else. . . . We want to find out what's achievable, and the only way to conduct this kind of experiment is in people. And that creates all sorts of commotion.

"People say I'm a news hound," adds Dr. Ho, who has been cited in several hundred articles during the past two years, "but it's actually making it harder for me to get my work done."

The star researcher has, however, developed an undeniable knack for the easy-to-swallow soundbite. While other scientists typically wait to discuss their work until after publishing the results in scholarly journals, Dr. Ho this year has grabbed headlines by making bold claims at scientific conferences months before publishing his findings. Recently he has, in so many words, predicted how long it may take for the virus in some patients to be completely eradicated: perhaps after six months to three years of cocktail therapy, if treatment begins soon after infection.

"It's mostly speculation right now," counters Jerome Groopman, an AIDS researcher at Beth Israel Deaconness Medical Center in Boston, who cites a dearth of hard evidence supporting such lofty speculation. Like others, he wonders about the ethics of asking the patients doing well on the drugs to stop therapy. "We don't know enough right now to predict how long we'll have to treat them," Dr. Groopman says.

The Diamond Center has been the object of much acclaim this year -- as well as criticism and jealousy -- for discovering important new details about the behavior of the AIDS virus and promoting a new class of drugs known as protease inhibitors. Founded just six years ago, the lab has rapidly become one of the world's foremost AIDS research institutes.

It is the passion of a most unlikely duo: Dr. Ho, 43 years old, a subdued yet disarmingly self-assured scientist born in Taiwan and schooled in California; and his wealthy New York benefactor, Irene Diamond, an 86-year-old widow who has spent the past 10 years in a late-life odyssey "to make a real difference," as she puts it.

Mrs. Diamond was a script reader on some of Hollywood's most famous movies in the 1940s and '50s, working for producer Hal Wallis, whose credits include "Casablanca." In 1942 she married Aaron Diamond, who later built a fortune as a New York real-estate developer. In 1984, while they were vacationing in Florida, her husband broached the idea of placing $150 million of assets into a foundation to support the arts, medicine and minority education in New York. One day later, Aaron Diamond died of a heart attack.

"I was determined to carry out his dream," Mrs. Diamond says.

Thus the Aaron Diamond Foundation was endowed in 1986. In 1990 it created the Aaron Diamond AIDS Research Center, donating $11 million, matched by a city contribution of $3.4 million, to set up the lab in an abandoned floor of an old public-health building. Some of the world's most acclaimed AIDS scientists applied for the top job. Against the advice of some prominent medical experts, Mrs. Diamond chose a relative unknown -- David Ho.

"I didn't want a diva, a prima donna," she says. "I wanted someone young and ambitious, with new ideas. Once I met David, I knew we had our man."

Flush with cash, Dr. Ho outfitted the new research center with expensive, state-of-the-art equipment and lured away leading scientists from bigger-name labs. Soon, it will have to survive financially on its own. On Dec. 31, Mrs. Diamond plans to shut down the Aaron Diamond Foundation because it will have finished handing out all of the wealth that she and her husband had set aside for good causes. Attracting funds from other sources to keep the center financially stable, critics argue, is one motive behind Dr. Ho's propensity for publicity.

Still, Dr. Ho and his team have earned justifiable accolades for challenging long-held assumptions about how the AIDS virus works and, by inference, how it can be controlled. "David's work in the past few years has helped to completely transform our understanding of HIV," says Joep Lange, a leading AIDS researcher at the University of Amsterdam. "It is one of the most important contributions of the past decade."

For most of the past 15 years, researchers and doctors believed that after an initial infection, the virus goes into hiding, lying dormant for years before reawakening and ravaging a patient's disease-fighting immune system. So any drugs for attacking HIV, the AIDS virus, were withheld until a patient developed visible symptoms of full-blown AIDS, usually three to eight years after infection. That way, researchers argued, HIV had less time to spin off new copies that were resistant to the therapy.

But Dr. Ho had believed, for years before he could actually produce any proof, that HIV didn't sit idle at all, but instead started reproducing itself in massive quantities almost immediately. This implied such a significant reversal in long-held precepts of AIDS research and treatment that, for several years, Dr. Ho couldn't raise federal grant money to explore his theory; backed by the Diamond Center, he was able to pursue his hunch.

Dr. Ho and his team published a startling set of findings in support of his theory early last year. They found that the virus is a constant dynamo of activity from the first moment of infection, reproducing perhaps a billion copies every day. These offspring wage a nonstop, ferocious battle against the immune system, eventually overwhelming it. Waiting years to begin attacking HIV, Dr. Ho now asserts, can put the patient too far behind to ever fully recover.

Then Dr. Ho galvanized the AIDS community with a more disturbing disclosure in January of this year. At a crowded science meeting in Washington, D.C., he revealed, in advance of publication, new findings showing that the virus's rapid growth rate was 10 times as great as estimated a year earlier. By analyzing test patients' blood every few hours instead of just every few days, he discovered that the rampaging virus produces an unfathomable 10 billion to 30 billion viral offspring every day.

That meant that new mutant copies of HIV, some of them possibly drug resistant, were being produced every few minutes -- and that the only chance of subduing the virus was a combination of several drugs attacking different parts of the virus, all at once. At the same session, Diamond researchers reported preliminary findings showing that a three-drug attack had shut down 99.9% of this rampant viral presence in the blood of test patients, something never accomplished before.

Since then, Dr. Ho has become evangelical in arguing that the drug cocktails should be used much more aggressively and earlier than ever before. That stance rankles many colleagues, who say such early use of the complicated and costly new medicines is impractical, unaffordable and just plain risky. Early and wider use of the drugs, health-policy experts warn, would require already-strapped federal and state programs to spend an additional $5 billion a year. Broader distribution also could hasten the emergence of HIV strains resistant to the newest drugs, allowing them to spread.

"That's a pretty frightening concern," says Eve Slater, a clinical-research executive at Merck & Co., which developed and markets one of the powerful new protease inhibitors. "The drugs we have now have to last as long as possible, because we really don't know when we'll develop new drugs to replace them."

By now Dr. Ho has become accustomed to getting caught in the crossfire. His outward style -- soft-spoken and unfailingly polite -- masks an aggressive maverick streak. At recent AIDS conferences, he has been accorded celebrity status, yet "he is one of the nicest guys you'll meet in the high-pressure field of competitive science," says Henry Chang, a researcher at Healthcare Foundation of Los Angeles who worked for Dr. Ho in the late 1980s.

Dr. Ho came to America from Taiwan at age 12, arriving in Los Angeles with his mother and a younger brother to join his father, who had immigrated to the U.S. several years earlier to study electrical engineering. Although he couldn't yet speak English, young David soon excelled in school, especially in math and science. He attended the California Institute of Technology and earned a medical degree at the University of California at Los Angeles.

As a young doctor training at a Los Angeles hospital in 1981, he began treating some of the first patients in the U.S. complaining of strange skin cancers and unusual infections. Many experts believed the problems were caused by hard living -- too much sex and drugs -- but Dr. Ho believed otherwise.

"From the start I thought some type of infectious agent, maybe a virus, was at work," he recalls. He was eager "to try to figure out what was going on."

In 1982 he headed east to Harvard University, joining Martin Hirsch, a leading virologist at Massachusetts General Hospital and Harvard School of Medicine, who was trying to track down the cause of the strange symptoms. About a year later, scientists in France and the U.S. isolated HIV.

Most early research efforts were aimed at looking for a vaccine and finding new treatments. Dr. Ho, drawing on his training as a doctor instead of just as a biologist, wanted to understand the enemy -- where it lurks, how it behaves. He therefore embarked on a prodigious portfolio of experiments aimed at unraveling how the newly discovered virus works.

He was the first, for instance, to isolate HIV in semen, proving that it could be transmitted sexually; and he proved it wasn't active in saliva, indicating it couldn't be transmitted in a kiss. He also found the virus in spinal fluid, indicating it endangered the central nervous system and the brain.

"David was asking the kind of questions that made you say, `Gee, why didn't I ask that?'" says Harvard's Dr. Hirsch. "From his earliest days as a researcher in my laboratory, David has consistently shown a unique ability to cut to the heart of the chase, to solve difficult problems in a simple and elegant way."

Dr. Ho left Harvard in 1986 to run a laboratory at UCLA, continuing his research. A few years later, he helped expose one of the first major failures in AIDS treatment, involving a genetically engineered protein called CD4. But in failure he found hope, figuring the flop had to be caused by HIV's heretofore unrecognized reproductive prowess.

"CD4's failure led some of us to believe the amount of virus circulating [in the body] must be much greater than previously thought," he says. Only by gaining new insight into how aggressively HIV spreads through the body "could we ever hope to come up with a rational treatment. But that kind of research required more resources than I had" at UCLA.

When word spread in 1990 about the plum research job up for grabs at the New York's first and only AIDS research lab, Dr. Ho joined a lengthy list of applicants. He won the top job by presenting his interviewers with an unusually clear goal: He wanted to quantify the precise size of the viral attack and test ways to subdue it. "I couldn't believe my good fortune," he says, adding, "Irene has been supportive, inspiring and very generous. If this place is unique, it's because of her."

Most young scientists scrape by on elusive funding from federal grants or drug companies and work in university labs where resources are scarce, offices are cramped and staffing depends on grant renewals. To the envy of rivals, the Diamond Center started out with ample seed money to hire talent, acquire new gear and begin research that would help secure grants later on.

Developers gutted and rebuilt the lab, housed on the seventh floor of a city-owned building across First Avenue from New York's famed Bellevue Hospital. The Diamond Center has dark tiled floors and hallways lined in blond oak paneling illuminated by frosted-glass sconces. Nine shiny, spacious labs hold specially designed virus-containment units and advanced genetics equipment; benches and walls glisten with stainless steel.

Last month, the center opened a second floor of lab space, conference rooms and offices, courtesy of a new $10 million grant from Mrs. Diamond's foundation. She also has given the AIDS lab real-estate assets worth another $5 million, which eventually will be sold.

"The place is very impressive looking," says Richard Koup, an infectious-disease researcher who was Dr. Ho's first hire at Diamond. "It helps us recruit good people. It shows them right away that this place is different." David Baltimore, a Nobel Prize laureate at the Massachusetts Institute of Technology, adds: "A major reason for David's success is that he's put together a group of very solid scientists, about the best group you'll see anywhere. No other AIDS lab can boast so many accomplished people."

Dr. Koup, for example, has pursued work that many researchers believe may contribute to developing the next generation of AIDS drugs, perhaps even a preventive vaccine. For almost two years, he had been monitoring a small group of New York subjects who claimed they had been repeatedly exposed to HIV but for some strange reason weren't infected. Something about their biology must be different. Identify it, and it could become a new weapon, scientists figured.

Then last spring, several rival research groups reported that they had identified an important chemical gateway in immune-system cells that acts as an entryway for HIV. Dr. Koup immediately examined that chemical in the blood of his AIDS-defying subjects. In August, he reported a surprise: These people had an inborn defect in the entryway chemical that protected them from getting infected. Several giant drug companies are racing to discover drugs that can mimic that lifesaving defect.

"There's no way I could have done this work at a university lab," Dr. Koup says; the collection of top-notch researchers at Diamond was the key. "When I need a solution, a lab technique or insight I just walk across the hallway. We have a critical mass here."

That critical mass similarly contributed to Dr. Ho's much-hailed findings about the surprisingly prodigious reproductive power of the AIDS virus. (Although he got most of the credit, a team at the University of Alabama at Birmingham had made a similar discovery.)

The Alabama team had been using a powerful drug from Merck and, when HIV overwhelmed the new remedy so quickly, concluded it must be because of the virus's particularly explosive growth. "David gets a lot of credit because he quantified what we saw, he proved what we knew," says Emilio Emini, Merck's top AIDS scientist. "If anything, his talent is for describing things better than others, and for doing the experiments others simply overlook."

And so it is that Dr. Ho, testing his early-treatment thesis, has embarked on the controversial experiment involving the 21 New York patients. All of them began the multidrug therapy within just six months of being infected. Many of the patients have gone a year without detectable virus in the blood. Although none have agreed to stop taking the drugs yet, the Diamond researchers will continue following them, asking them periodically to go off therapy. Dr. Ho hopes to prove that the drug cocktail can entirely eradicate all HIV in these patients.

Other researchers say more realistic goals should be pursued, such as discovering new targets in the virus for attack and testing which combinations of drugs work best. They note that, while doctors regularly eliminate illness-causing bacteria with antibiotics, no drug therapy has ever been able to vanquish any virus, let alone one as pernicious as HIV.

"We simply don't know enough about the virus, about whether you can reach all the places where it hides in the body," says Dr. Gallo, director of the Institute of Human Virology in Baltimore. Douglas Richman, a leading researcher at the University of California, San Diego, who is trying a limited eradication test of his own, says: "I think [Dr. Ho's] chances of success are, at best, 50-50."

Dr. Ho is betting his odds are better. Because the patients started the therapy so soon, their immune systems haven't been beaten down by the virus, and HIV hasn't had much time to turn out drug-resistant clones or to advance into the brain, spleen and other difficult-to-reach organs and tissues.

Doubters say those inaccessible "sanctuary" sites probably harbor lingering viral particles that can emerge months and years after the drug cocktail has cleared HIV from the bloodstream. But Dr. Ho argues that the virus may simply burn itself out after six months to three years of drug bombardment. He believes that the lingering HIV copies in these sanctuary sites will disappear when the cells that host them die a natural death and are replaced by new, uninfected cells.

The patients, then, would be cured.

"That's a pretty extraordinary claim," says Jay Levy, a leading virus researcher at University of California, San Francisco. "What's it based on?"

Answer: Theory and mathematics, actually, rather than hard evidence. Dr. Ho bases his prediction on a mathematical calculation that even he has trouble explaining but which is based on the speed with which virus levels in the bloodstream decay during the first few months of treatment. The only way to know for sure, however, is to follow the 21 test patients subjects and persuade some of them to drop the cocktail therapy to see what happens. In recent weeks, the Diamond center has recruited 30 patients into two additional eradication experiments, one of which uses two drugs not yet on the market that may attack virus lodged in brain tissue.

Dr. Ho and his clinical director, Martin Markowitz, argue that if HIV reappears they can resume the cocktail attack. So far, none of the patients is ready to risk it.

In coming months, the Diamond researchers will begin removing tissue from several potential sanctuary sites in the patients' bodies, searching for the presence of hidden virus. If they find that HIV has so securely inhabited these tissues, eluding even the "early and hard" attack of the protease cocktails, it will mean the virus has prevailed once again.

"Then we will know a lot more, even if what we've learned is upsetting," Dr. Ho says. He acknowledges he is feeling the pressure of the public glare and says that proceeding is like conducting "a biochemistry experiment with the whole world looking over your shoulder."

But "the only way we'll find out is to do the experiment. Only with data can we move ahead," he says. Is it possible he is wrong? "Absolutely," he allows, then adds: "I don't think I am."

© 1996, Dow Jones & Company