Improved Treatments : Prognosis on AIDS Grows Less Gloomy
Just a few years ago, many physicians felt that diagnosing a new case of acquired immune deficiency syndrome was similar to pronouncing a death sentence.
“Not in recent memory have so many relatively young, previously healthy people died so quickly with care-givers seemingly powerless to influence the eventual outcome,” Dr. Robert M. Wachter of UC San Francisco wrote in the New England Journal of Medicine in January, 1986.
“Our major role as physicians was comforting the dying,” said Dr. Richard Chaisson, director of the AIDS service at the Johns Hopkins Hospital in Baltimore. “It was very discouraging.”
But with the advent of new therapies, the mood of many physicians who have cared for AIDS patients since early in the epidemic is starting to change. Specialists say the advances against AIDS are a result of new medications such as AZT and aerosol pentamidine, steady improvements in the quality of medical care and heightened patient awareness.
As a result, while a cure for AIDS is nowhere near, physicians are much more confident about their ability to treat the disease. Now “we have something to offer” that may prolong survival and improve the quality of life for many AIDS patients, Chaisson said.
“There is a general diminution in the amount of hopelessness,” said Wachter, who is program chairman for the 1990 International Conference on AIDS in San Francisco. Physicians sense that eventually “there may be a light at the end of the tunnel.”
Dr. Harry Hollander, chief AIDS physician at UCSF’s Moffitt-Long Hospital, said that while there “are still bad days and notable failures of therapy,” he is “thrilled to see patients do much better than they did at the beginning of the epidemic.”
The median survival time for patients diagnosed with Pneumocystis carinii pneumonia, the most common life-threatening infection seen in AIDS patients, has nearly doubled--from about 11 months in the early 1980s to an estimated 18 to 24 months in recent years.
In addition to treatment improvements, physicians also have a better ability to predict which individuals infected with the human immunodeficiency virus, the cause of AIDS, will develop serious symptoms and greater skill at anticipating and managing life-threatening complications, such as central nervous system infections.
As a result, they have broadened their focus--from attending to the needs of severely ill HIV-infected patients to trying to forestall symptoms in those who have yet to become ill.
Blood tests for infection with the HIV, despite lingering concerns about confidentiality and potential discrimination, have become a routine part of medical practice.
“The person who is not aware of their health status with respect to HIV is not making decisions with all possible information,” said Dr. Michael Gottlieb of Sherman Oaks Community Hospital, the Los Angeles AIDS physician who was one of the first to describe cases of the mysterious disease in 1981. “Denial is crumbling because of the increased hope that constructive interventions are available.”
As AIDS is gradually transformed from an acute illness into a chronic process, the debilitating ailment no longer seems in a class by itself. More internal medicine specialists view it is as akin to other serious diseases that they are trained to take care of, such as cancer and heart disease.
To UCLA oncologist John Glaspy, the “slow plodding progress” against AIDS is reminiscent of the progress that has been made over the last decade against acute myelogenous leukemia, a devastating blood tumor that primarily strikes young adults.
Median Survival Increases
In 1976, the median survival after diagnosis of this leukemia was fewer than six months. Now, median survivals of two years or more are achieved, and some patients who can receive bone marrow transplants may be cured. “Viewed in historical perspective, AIDS is not atypical,” Glaspy said.
But at the same time, improved therapies for some AIDS complications have “unleashed sides of the disease that are not yet treatable,” according to Hollander. As certain infections are thwarted and patients survive longer, their weakened immune systems can still fall prey to other infections and tumors.
These potentially untreatable complications include resistant viral illnesses and a germ known as Mycobacterium avium, a cousin of the tuberculosis bacteria. Lymph node tumors known as lymphomas, malnutrition, cytomegalovirus infections and gastrointestinal maladies caused by a protozoa known as cryptosporidium are also daunting problems.
“The big deficiency is the lack of of immune (system) restorative drugs of any potency,” Gottlieb said. He compared the use of available immunotherapy to “fighting a war with a toy pistol.”
There is also concern that progress against the nervous system complications of HIV will lag behind progress in other areas. This is because damage to brain and nerve cells may be more difficult to either treat or reverse. As a result, as AIDS patients survive longer, more may eventually develop severe confusion and lethargy.
“Rapid drug development for me . . . may seem horribly slow for a patient with HIV,” Dr. Paul Volberding, the director of the division of AIDS activities at San Francisco General Hospital, said at a medical meeting last December. The issue for many patients, he said, is “what am I going to do now to save my life.”
Destroys Immune System
HIV progressively destroys the immune system, leading to symptoms such as fevers, weight loss, mouth sores, mental deterioration and a variety of potentially devastating infections and tumors.
For an HIV-infected individual, the most important risk factor for progression to AIDS is the time that has elapsed since the initial infection. Current data suggests that 50% to 75% of infected individuals will develop AIDS or AIDS-related symptoms within 10 years of infection.
Five years ago, AIDS was usually not diagnosed until a patient was already in the advanced stages of the disease. A gay man who had felt fine weeks previously would show up in a hospital emergency room unable to breathe. A chest X-ray would reveal the characteristic abnormalities of pneumocystis.
Then everything in his world would fall apart at once. AIDS would be confirmed. His sexual identity would be unmasked. In the midst of an acute illness, he would learn that he would probably die within months.
But now the disease is usually being detected earlier.
One possibility to explain this change is that patients who died from AIDS early in the epidemic had a more virulent form of the virus or diminished immune responses, contrasted to the individuals who are getting sick now, according to Volberding.
A more likely possibility, however, is that greater patient and physician awareness and improved interventions are paying off in earlier diagnoses and improved survival. Better medical management has had a “major effect,” Volberding said.
Through the efforts of public health officials, physicians and organizations such as the American Foundation for AIDS Research and Project Inform, a San Francisco-based clearinghouse for treatment information, gay men, intravenous drug addicts and others at risk for HIV infection often seek out HIV testing and obtain medical care before they become ill.
Dr. Stephen Becker, who practices in the Potrero Hill section of San Francisco, said people “are coming in a lot more educated (about AIDS)” and “more accepting of the concept of prophylaxis.” He added: “There is a lot more participation in decisions by patients and a lot more planning. That makes caring for people easier.”
Even patients who develop significant AIDS symptoms can sometimes be treated outside the hospital. AIDS specialists believe that outpatient treatment can diminish costs and minimize the disruption of their patients’ lives.
Pneumocystis pneumonia, for example, is frequently diagnosed through the examination of sputum specimens, and mild cases are treated with oral medicines.
By comparison, in the early 1980s pneumocystis diagnosis usually required bronchoscopy, an examination of the lungs with a flexible fiber-optic tube inserted through the mouth. And even mild cases were treated in the hospital with several weeks of intravenous antibiotics.
AIDS patients who require months of intravenous antibiotics to treat fungal diseases or cytomegalovirus retinitis, an eye infection that can lead to blindness, may also be able to benefit from outpatient therapy. In a minor surgical procedure, a permanent intravenous catheter can be inserted into a large vein in the chest. Patients can then receive most of their therapy outside the hospital by returning to a clinic or a doctor’s office on a regular basis.
When patients come into the hospital, they may be “just as sick as they ever were both psychologically and medically, but they tend to be much better prepared for it,” said Dr. Molly Cooke, an assistant professor of medicine at San Francisco General. As a result, she said caring for AIDS patients seems “much more like regular medicine” than in years past.
But Dr. Neil Schram, an internist at the Kaiser Permanente Medical Center in Harbor City, said that newly diagnosed HIV-infected individuals still come to his office “feeling like they are about to die.”
As a result, while not playing down the seriousness of the diagnosis, Schram said he “carefully expressed” cautious optimism. I “try to make them realize that (dying) is not necessarily something they have to worry about now,” he said.
The cornerstones of progress against AIDS are the antiviral drug AZT, which has been shown to prolong the lives of some AIDS patients, and preventive treatments for pneumocystis pneumonia, such as aerosol pentamidine. Both of these drugs are used by thousands of AIDS patients. There are also smaller steps, such as better management of HIV-infected individuals with recurrent herpes infections, syphilis or tuberculosis and a wider range of alternative antibiotics to use when first-line treatments falter.
Other highly touted AIDS drugs, such as the genetically engineered molecule CD4 and an AZT-like drug known as dideoxyinosine, are in the early stages of human testing. They have yet to be proven safe and effective.
The U.S. Food and Drug Administration approved AZT for prescription sales in March, 1987. According to the FDA, AZT is indicated for AIDS patients who have already had a bout of pneumocystis as well as ‘symptomatic” HIV-infected individuals with T-4 white blood cells counts of 200 per cubic millimeter or less. (Healthy individuals usually have T-4 white blood cell counts of 800 to 1,000 or more).
Ongoing studies in the United States and other nations are designed to assess the risks and benefits of using AZT in individuals who have yet to develop HIV symptoms and symptomatic individuals with higher T-4 white blood cell counts. Results are not expected until next year at the earliest, according to Volberding of San Francisco General.
Volberding chairs the largest of these studies, AIDS Clinical Trials Group protocol 019, which is sponsored by the National Institute of Allergy and Infectious Diseases. As of mid-March, the study had enrolled about 2,800 out of a projected 3,500 patients.
Pending the completion of the studies, Volberding said a “very common practice” among AIDS specialists is to prescribe AZT for any patient who is “convincingly symptomatic from HIV infection,” irrespective of their T-4 count, as well as asymptomatic patients with low T-4 counts. He added that “the vast majority of patients who are believably symptomatic” will have low T-4 counts.
Given the grim prognosis of AIDS, some physicians believe that it is wrong to withhold AZT until HIV-infected individuals become physically sick. For example, if left untreated, more than 50% of asymptomatic HIV-infected individuals with T-4 counts of below 200 will develop AIDS within two years and many others will develop HIV-related symptoms, according to Andrew R. Moss, an AIDS epidemiologist at San Francisco General.
But deploying AZT too early could have undesirable consequences. For example, some researchers have already found resistant strains of HIV in AIDS patients who have received AZT for more than six months. Side effects, such as severe anemia can develop, as well as heretofore unrecognized long-term toxicities. As a result, some patients might not be able to benefit from the drug when they really need it.
In addition, infected individuals without symptoms, depressed T-4 counts or other HIV-related laboratory abnormalities are at low risk of progressing to AIDS within the next year or two. Thus, they may be in a position to wait until the ongoing AZT studies are completed or more effective drugs becomes available.
According to Cooke, the varying temperaments of both physicians and patients play a key role in resolving these dilemmas. “For some people, it is virtually intolerable to sit around, letting the virus do what it wants,” she explained. But other patients “mistrust medicines” and feel “that untested drugs have the potential to actually do very bad things.”
Cooke added: “I have patients who have 70 T-4 cells and don’t want to take anything. . . . (There are also patients) who are taking everything they can get their hands on.”
Last month, the FDA approved expanded distribution of aerosol pentamidine. The FDA based its decision on a review of still unpublished data showing that a monthly breathing treatment with the investigational drug can frequently prevent initial or repeated bouts of pneumocystis pneumonia. The drug is not a treatment for HIV itself.
The FDA’s recommendations for when aerosol pentamidine should be used are similar to its recommendations for when AZT should be used. A key difference is that all HIV-infected individuals with T-4 counts less than 200 are included, regardless of whether they have symptoms.
When inhaled, aerosol pentamidine sometimes causes wheezing and coughing. But, unlike AZT, it appears to have no serious side effects throughout the body. Therefore, many AIDS specialists believe that it is easy to use with AZT.
On the other hand, aerosol pentamidine is not foolproof and some high-risk patients will still develop pneumocystis, according to Dr. Fred R. Sattler, coordinator of the interdisciplinary AIDS Clinic at County-USC Medical Center in Los Angeles. Sattler said aerosol pentamidine “will have a marked impact on the incidence of pneumocystis, but it is not going to wipe it out.”
As a result, AIDS specialists are already trying to improve on aerosol pentamidine. Some physicians, for example, recommend other medicines to prevent pneumocystis, such as trimethoprim-sulfamethozazole or the anti-leprosy agent dapsone. Unlike aerosol pentamidine, these medicines are more likely to have severe side effects. Studies comparing these pneumocystis preventives to aerosol pentamidine are in progress at many medical centers, including County-USC, UCLA and UC San Diego.
UC San Francisco’s Hollander said the need for further progress was most evident when he cares for an “occasional patient” who is diagnosed with AIDS and dies quickly, despite optimal therapy. He explained: “There is just an incredibly frustrating sense of deja vu, of what treating AIDS patients was like before AZT and aerosol pentamidine.”
PRESCRIPTION AND EXPERIMENTAL DRUGS
The “AIDS/HIV Experimental Treatment Directory,” published by the American Foundation for AIDS Research, lists about 40 experimental agents against the AIDS virus as well as numerous additional drugs for AIDS-related infections and tumors.
These are some of the drugs currently in widespread use.
AZT--The only drug that has been shown to prolong the lives of some AIDS patients. Also known as azidothymidine or zidovudine. Blocks the replication of the human immunodeficiency virus (HIV) but does not rid the body of the infection. May cause serious side-effects, such as anemia, requiring blood transfusions or discontinuation of the medicine. Undergoing extensive testing, particularly to determine if it is safe and effective in the early stages of HIV infection. Manufactured by Burroughs Wellcome Co., Research Triangle Park, N.C. Approved for prescription sales in March, 1987.
Pentamidine--In intravenous dosage form, commonly used to treat Pneumocystis carinii pneumonia, the most common life-threatening infection seen in AIDS patients. In aerosol form, used as a preventive treatment for the pneumonia and being tested as a treatment. Intravenous pentamidine can cause severe side-effects. Aerosol pentamidine is minimally absorbed into the circulation and has significantly fewer side-effects. Aerosol pentamidine was given “Treatment IND” status by the U.S. Food and Drug Administration in February 1989, a designation that allows widespread distribution while scientific studies of safety and effectiveness continue. Manufactured by LyphoMed, Inc. of Rosemont, Ill.
Trimethoprim-sulfamethoxazole--In intravenous or oral dosage form, commonly used to treat Pneumocystis pneumonia. Pills are also being used by some physicians as a preventive treatment for the pneumonia. Has a higher incidence of toxicity in AIDS patients than in non-AIDS patients, such as fever, allergic drug reactions and low white blood cell or red blood cell counts.
Alpha interferon--Hormone-like protein made in small amounts in the body and in large amounts in the laboratory through recombinant DNA techniques. Approved by the FDA in November, 1988, for treatment of Kaposi’s sarcoma, the most common tumor seen in AIDS patients. Has beneficial effects on the tumor but ability to prolong survival not known. Manufactured in competing forms by Hoffman-La Roche of Nutley, N.J. and Schering Corp of Kenilworth, N.J.
These are some of the experimental agents, now being tested in humans, that have attracted widespread interest.
Dextran sulfate--Popular underground drug that is imported from Japan. In the laboratory, prevents HIV from infecting immune system cells and interferes with the ability of the virus to kill these cells. Preliminary studies in healthy individuals and animals suggest that when taken by mouth, dextran is not significantly absorbed into the bloodstream. As a result, will be tested via intravenous and other dosage routes. Proponents say that further research on oral dextran is also needed.
Dideoxyinosine (DDI)--One of a number of experimental drugs that are chemically related to AZT. In the laboratory, blocks the replication of the AIDS virus. Initial human tests in progress. Manufactured by Bristol-Myers Co., Wallingford, Conn. Another related drug in human tests is dideoxycytidine (DDC), made by Hoffman-La Roche Inc., of Nutley, N.J.
Ganciclovir--Experimental therapy for AIDS patients with Cytomegalovirus retinitis, an eye infection that can lead to blindness. Given Treatment IND status by the FDA in November, 1988. Can cause low white blood cell and platelet counts. Manufactured by Syntex Corp., Palo Alto. Another experimental drug for the eye infection is Foscarnet, manufactured by Astra Lakemedel, of Hopkinton, Mass.
HIV-Immunogen--Immunization treatment developed by Dr. Jonas Salk, the polio vaccine pioneer. Inactivated HIV particles are injected into HIV-infected individuals in an attempt to boost their immune systems. Initial tests being conducted at USC’s Kenneth Norris Jr. Cancer Hospital. Manufactured by Immune Response Corp. of San Diego.
Soluble CD4--Experimental agent made by recombinant DNA technology. Modeled on a protein that allows HIV to attach to white blood cells. The theory is that soluble CD4 will act as a decoy that will sponge up HIV and, as a result, protect white blood cells. Preliminary tests in the laboratory and in monkeys suggest that CD4 blocks HIV from infecting white blood cells and reproducing. Initial human tests in progress. Companies involved in developing competing versions of CD4 are Biogen Inc., Cambridge, Mass., Genentech Inc., South San Francisco, and Smith Kline & French Laboratories, Philadelphia.