AIDS IS 20
The work of many researchers, doctors, patients, activists and family members have contributed to the advances made against HIV/AIDS since its debut 20 years ago.
by Jon Nalick
Birthdays and anniversaries are often cause for celebration—recognizing the accomplishments of the year gone by and expressing hope for the year ahead.
But 2001 marks an anniversary that no one celebrates, a birthday that brings no joy and a milestone that humanity would prefer never existed—the twentieth year of the AIDS epidemic.
The grim anniversary recalls the ever-growing numbers of premature obituaries that hinted at what the years ahead had in store: Ryan White, Rock Hudson, Freddie Mercury, Elizabeth Glaser, Arthur Ashe.
But for USC researchers, the anniversary also serves as a reminder that much has been accomplished in the fight against the disease—and that with perseverance, humanity will someday soon mark the years since AIDS was conquered.
Alexandra Levine, M.D., an expert in hematological cancers and the clinical diagnosis and treatment of HIV-associated lymphomas, has been involved since the earliest known cases in 1981.
Levine has been, and remains, the most visible USC presence on the national level in the fight against AIDS, having been appointed by President Bill Clinton in 1995 to the Presidential HIV/AIDS Advisory Council.
In that capacity, she has helped advise policy-makers at the highest level of the federal government on AIDS education, treatment, prevention and research. She also met with the Bush Administration's Secretary of the Department of Health and Human Services, Tommy Thompson, to discuss the future of U.S. AIDS policy.
"USC has had a very loud voice at the national level and I believe our efforts were extremely powerful in educating President Bill Clinton on the tremendous implications of HIV in sub-Saharan Africa as it relates to our own national security—and the security of the world as a whole. There's no question that President Clinton was listening very carefully—and we put forth a strong argument that it is in the U.S.'s own interests to deal with the international AIDS epidemic," Levine says.
Along with Levine, Parkash Gill, M.D., professor of hematology, has also served at the national level. Both were advisors to the National Cancer Institute in the area of AIDS-related malignancies.
USC's role in the fight against AIDS today stems from its strong involvement since the beginning of the epidemic. Levine says that by 1984, USC was already established as a major center for understanding the new disease, having created one of the first AIDS clinical trials units in the nation.
Such units—of which there are now about 40 nationwide—are National Institutes of Health-sponsored groups that test new therapeutic agents and also existing therapeutic agents in novel fashions. Their goal is to find new treatments not only for AIDS, but also for the secondary infections and disorders the disease promotes.
With the lessons learned in the clinic, USC researchers released a flurry of papers in medical journals from 1984-87 describing various aspects of the disease's progression. For example, Levine says, "We were the first to describe the development of lymphoma in gay men and prove it was related to HIV.
"We went on to define the optimal treatment for AIDS-related lymphoma and to demonstrate that low-dose chemotherapy was more efficacious than standard therapy. Basically, we wrote the book on AIDS-related lymphoma.”
Gill, along with Levine, and Anil Tulpule, M.D., associate professor of clinical medicine, were also instrumental in defining the pathogenesis of AIDS-related Kaposi’s sarcoma, a blood capillary cancer that occurs in as many as 40 percent of all AIDS patients. They pioneered its treatment with a three-drug combination that remained the "gold standard" against which other treatments were compared for years—until the group hit on the use of the drug daunoxone, and then taxol, which is now considered the treatment of choice for advanced disease.
Gill’s work on taxol provided the initial medical data that prompted the U.S. Federal Drug Administration to formally license its use as an effective treatment for Kaposi’s sarcoma.
Since the mid-1980s, "investigators from USC have published extensively on everything from the physical manifestations of the disease to the emotional impact of HIV to child care issues," Levine notes.
Still, USC's contributions are not confined to clinical trials and published articles in medical journals.
In the early days of the epidemic, Levine and Jean L. Richardson, Dr.P.H., professor of prevention research, developed a comprehensive five-week curriculum designed to educate local high school students about AIDS prevention and human sexuality. The program, tested and refined at East Los Angeles schools including Francisco Bravo Medical Magnet High School and Lincoln High School, was later adopted by the Los Angeles Unified School District and remains in use today.
Also, in 1983, USC established a community forum that met twice a month at the USC/Norris Comprehensive Cancer Center to discuss issues related to AIDS and to educate the public. Although the number of attendees waxed and waned over time, in an average week as many as 60 people attended the meetings, which continued for more than a decade. A similar community forum is now held monthly, led by the physician in charge of the HIV/AIDS Clinic at LAC+USC Medical Center.
"It's another example of what USC has done in the community, not just at the national and international level," Levine says.
But while USC has made significant contributions, much hard work remains, says Kathleen Squires, M.D., associate professor of medicine. In 2000, Squires accepted a position as medical director of the LAC+USC Medical Center HIV/AIDS clinic known as "5P21," one of the largest AIDS clinics in the nation.
Squires says that she was eager to begin work at USC and see patients with HIV and AIDS in an academic medical setting.
"I didn't want to work with lab animals or cell cultures. Clinical research satisfied my need. I can ask questions of patients and treat them. You're caring for people, but expanding the knowledge about a disease as well," she says.
"Unfortunately in the U.S. we've grown fairly complacent. The number of new infections each year is stable overall, but that is cause for concern—we want to see a decrease, but it's not happening," she says.
However, the number of people who need care keeps rising. From the start of the AIDS epidemic in June 1981 through December 2000, AIDS claimed more than 21 million lives worldwide, including more than 438,000 in the U.S.
Further, an estimated 900,000 Americans are currently infected with HIV, according to the Centers for Disease Control and Prevention
| POTENT PROTEASE A new protease inhibitor has been shown to be safe, tolerable and effective at warding off HIV in HIV-positive patients with only one dose a day, according to Kathleen Squires, M.D., associate professor of medicine and an infectious diseases researcher. The drug—known as BMS-232632—differs from previous protease inhibitors, she says, in part because those drugs have required patients to adhere to complex dosing schedules. Physicians commonly prescribe one of a variety of protease inhibitors, in partnership with drugs called nucleoside analogs, in a pharmaceutical battle plan to combat HIV. "Our study showed that BMS-232632 is a potent protease inhibitor that is well tolerated and can be used safely in combination with other anti-HIV therapies," says Squires. "This new drug offers patients once-daily dosing, and the additional benefit of a low pill burden." The drug remains active in the bloodstream for longer than other protease inhibitors, making it effective over a longer period and at a lower dose. Squires was among the investigators for the first and second phases of the study, which was conducted at more than two dozen sites in numerous countries on three continents. The double-blind, randomized, 48 week-long study examined the safety and effectiveness of BMS-232632 (paired with two other common anti-HIV drugs known as stavudine and didanosine) compared with a currently available protease inhibitor called nelfinavir (also paired with the same two anti-HIV drugs). Data from 480 patients showed comparable effectiveness of BMS-232632, at doses five to 10 times lower than nelfinavir, Squires says. The drug was just as effective as nelfinavir in reducing the reproduction of the HIV virus and increasing the number of virus-fighting immune cells in the body. Squires and other investigators will take part in phase III clinical trials, in cooperation with the drug's maker, Bristol-Myers Squibb, to further test effectiveness.
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With the advent of highly reactive anti-retroviral therapy, widely hailed in 1996 as a significant turning point in the war against the disease, AIDS fatalities began to plummet. By early 1997, AIDS deaths in the U.S. had declined 75 percent from their 1995 levels.
Squires says that as a result of those clinical successes, some people—especially younger ones who have not seen their peers die from AIDS—often feel less threatened by it, and are less likely to take precautions to prevent infection.
Statistics appear to bear that out: In June 2001, federal health officials released new evidence that infections may be rising in gay men, ages 23 to 29, a sign that the overall downward trend in infections may be reversing.
Squires says that the 5P21 Clinic is an ideal place to study ways to improve AIDS education, treatment and prevention in part because it serves one of the largest and most diverse populations of infected patients in the U.S. Further, the local community matches the demographics of those who are at the greatest risk.
"In the early 1980s, infections affected primarily Caucasian gay men, but since then, the at-risk population has shifted to people of different ethnic backgrounds," now more likely to be black or Hispanic, or female, she says.
"This clinic serves a population that is very disenfranchised and really in need of care," Squires says. "Many of our patients do not speak English and others have serious social and economic barriers to receiving health care, so we have to try and make it easy for them to access our services."
She adds, "The county has made a commitment of providing the multidisciplinary care that HIV-positive patients need — in one building. The physician assistants are the backbone of this clinic, along with the nurses. And the whole mix of physicians makes for a very good model to take care of HIV-positive patients."
USC is the place to be to care for a wide range of people with HIV, she adds. "And USC is a major player in research into women and HIV," noting that Levine leads one of the sites of the NIH-funded Women's Interagency HIV Study.
Squires says she sees USC maintaining a significant contributing role in the medical community's continuing efforts to thwart the disease.
Projects now planned by university clinicians and researchers include studies of effective communication strategies to promote disease prevention and participation in national AIDS vaccine trials—researchers hope that injecting certain DNA particles through a vaccine will help patients' immune systems churn out weapons to fight the virus.
For her own part, Squires says she is interested in looking at possible differences in drugs' effects on HIV in women and men, noting that the HIV drugs used today were mostly tested in male patients.
But there are key differences between the male and female: body fat, enzyme systems that metabolize compounds, hormone systems and the like.
Drugs might be more or less effective or toxic in women than men, but it is up to researchers to shine more light on those differences—possibly leading to more customized treatment regimens.
Squires is also pursuing research into finding new drugs. Since a large proportion of patients have been on their anti-HIV medications for a long time, the virus they harbor may begin to grow resistant to the current regimen of drugs. That makes it critical to find new drugs to keep HIV at bay, says Squires.
Researchers also look for drugs that are easier on patients, produce fewer side effects and require fewer doses.
"There's a lot we don't understand about how HIV works," Squires says. "And there is a long way to go. But we keep learning more and more."
Until the day comes when AIDS researchers put themselves out of work by finding permanent solutions, she adds: "There's a lot to be done."
Still, even though the twentieth anniversary of the AIDS epidemic brings no joy, thanks to continuing research by dedicated physicians and scientists, it does bring something to humanity just as important.
It brings hope.?
Monika Guttman contributed to this article.
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