Bulletin of Experimental Treatments for AIDS, No. 1; June, 1988
Jim Palazzolo and Ron Baker
"AZT is working better than many had even hoped. We're seeing fewer side effects, particularly when we can initiate therapy before a life-threatening infection sets in."
-- Marcus Conant, MD1
"The toxicity* of AZT is probably greater than reported, and it can be expected that reports will continue to appear demonstrating the harmful effects of the drug. There is no justification for its use in groups other than that in which a survival benefit was claimed, that is, in patients with fewer than 200 T-helper cells."*
-- Joseph Sonnabend, MD2
These quotations reflect the controversy among physicians and researchers about the appropriate use of AZT (zidovudine, Retrovir). The drug is the only FDA-approved antiviral* for people with AIDS and severe ARC. AZT is not a cure for AIDs, and it does not prevent PWAs or PWARCs from developing new infections. However, for some PWAs and PWARCs, it slows down progression of the disease. And for some individuals who can tolerate its toxicity, AZT reduces symptoms of HIV infection.
Despite FDA approval for limited use, AZT is considered an experimental drug for HIV-infected individuals who show no symptoms of infection. Studies are now underway to determine the most effective dosage, long-term effects, how it works with other drugs and how beneficial it is at various stages of HIV infection3.
In studies of AZT, many of the AIDS and severe ARC patients had increases in infection-fighting T-helper cells during the first three months of therapy. The T-helper cells also worked better after therapy. Later, however, the number of T-helper cells decreased, although these cells continued to work better. In time, many of the individuals eventually developed new infections. This suggests that AZT only slows down, rather than stops, the progression of the disease in severely affected individuals. However, AZT may work better in individuals who start the drug in an earlier stage of infection (see p.6).
AZT works by stopping the replication of HIV. When HIV replicates, it builds a DNA* chain which is incorporated into the DNA of the T-helper cell. AZT attaches itself to HIV's DNA chain and terminates it before it can be completed and inserted into the DNA of the T-helper cell. Therefore, AZT helps block the spread of HIV to uninfected cells, but does not affect T-helper cells already infected with HIV. These infected cells allow HIV to spread if therapy is stopped. This is why AZT is not a cure for AIDS.
Unfortunately, AZT also attaches to the DNA of cells of the bone marrow and blocks the bone marrow's ability to produce red and white blood cells. This is one cause of the drug's toxicity.
AZT crosses the blood-brain barrier* and reaches the brain, where HIV infection can cause dementia.* There are anecdotal reports of dementia improving in some individuals on AZT. Studies of the effects of AZT on HIV-related dementia are currently underway4.
Researchers are now studying the use of AZT with other drugs. Some of these drugs (acyclovir, alpha interferon, ampligen and dextran sulfate) appear to increase the antiviral effect of AZT in test tube studies. Some physicians have been prescribing acyclovir, an anti-herpes drug, with AZT.
Acyclovir is an anti-viral for herpes simplex virus (HSV) that may also work against Epstein-Barr virus (EBV). Some scientists suspect that these infections may speed up the development of AIDS in HIV-infected individuals.
According to Conant, while acyclovir may not make the AZT work better, it is effective against the herpes simplex virus: "We know from laboratory work that reproduction of the herpes simplex virus makes HIV reproduce more frequently. Therefore, if I were on AZT and having episodes of herpes, I would use 800 mg of acyclovir every day to suppress the herpes." By keeping HSV under control, HIV-infected individuals may stay healthier.
Immune-boosting drugs are also being studied with AZT, in the hope that these drugs can help repair damaged immune systems. Studies are also underway using erythropoietin* to treat the anemia* caused by AZT and using GM-CSF* to alleviate lowered white blood counts caused by AZT.
The most effective therapeutic dosage of AZT is still being studied. The "full" dose chosen for use in early studies of AZT is 200 mg every four hours. Physicians sometimes prescribe a "half" dose for patients, but it is unknown whether a half dose is sufficient to stop HIV replication. To help determine whether AZT is stopping replication of the virus, Conant tests for the p24 antigen.* (The p24 antigen test has not yet been approved by the FDA.) Conant may put patients on a full dose if the test shows signs of viral replication. According to Robert Gorter, MD5], the most effective dose may be two 100 mg capsules every four hours, "but it is really still unclear, and that's why it is still being studied."
The short half-life* of AZT requires people to take it every four hours, including a middle-of-the night dose. Larger, less frequent doses are being studied. A more convenient dosage schedule of 250 mg every six hours and 500 mg every 12 hours was used in a study recently published in The Lancet6. These schedules eliminate the middle-of-the night dose. The results of the study indicate that it may not be necessary to take AZT every four hours in order to stop HIV replication.
Research conducted at Johns Hopkins University suggests that probenicid, an anti-gout drug, can double the half-life of AZT by slowing the loss of AZT from the blood7. There is a danger, however, that at a full dose of AZT, probenicid could increase the toxicity of the drug.
William Reiter, MD8, has been prescribing probenicid with a reduced dose of AZT in certain circumstances. His opinion is that this combination maintains the same blood levels of AZT as a full dose without increasing toxicity. His patients take 200 mg of AZT every six to eight hours. Reiter stated that "probenicid can reduce the dose of AZT, so it significantly reduces the cost of the drug. It also makes the drug more convenient to use by eliminating the need for a middle-of-the-night dose." He has been following patients and their blood levels of AZT on this drug combination for about one year.
AZT is very toxic. Bad reactions to AZT may include nausea, muscle fatigue and aches, difficulty in sleeping, moderate-to-severe headache, and, in extreme cases, confusion. Gorter has observed that "some patients on AZT who are demented cleared, yet it's been the other way around with other patients: they were doing well and within a week of starting AZT they really got confused."
AZT may make the symptoms of AIDS and ARC worse in the first six to eight weeks of use. These side effects go away in most patients after this time. According to Barbara Newlin9: "People who have had bad side effects can sometimes go back and start AZT at a very low dose, slowly building up to a full dose. Then they may be able to get past the early side effects and do well on the drug."
The main dangers in taking AZT are that the drug causes anemia and neutropenia* by suppressing the bone marrow. People who have low hemoglobin*, low neutrophil* counts and low vitamin B12 levels in the blood before beginning AZT are more likely to develop anemia and neutropenia. These problems can appear very quickly after starting AZT or many months later. This is why anyone taking the drug needs twice-monthly monitoring of their blood counts by a knowledgeable physician. If anemia appears, the individual and doctor have three options: stop the drug, lower the dose, or receive blood transfusions. When the neutropenia appears, either the dosage must be reduced or the drug must be stopped. This toxicity almost always goes away when the drug is stopped.
Gorter has found that most people at a later stage of AIDS who cannot tolerate AZT at a full dose also cannot tolerate it at a half dose; some ARC patients do better on a half dose, he said. In Reiter's opinion, an individual's ability to tolerate AZT depends not on the stage of HIV infection, but on pre-treatment blood counts. However, some individuals with normal red blood counts have become anemic within two months after starting AZT.
Some scientists have noted that 40 to 50% of patients with AIDS or severe ARC taking AZT experience bone marrow suppression severe enough to require blood transfusions. This decreases to 10 to 15% for individuals in earlier stages of HIV infection10. In the Lancet study of 18 men at an early stage of HIV infection, only two developed anemia and none developed neutropenia11.
Because it is a new, experimental drug, the long-term effects of AZT are not known.
Individuals on AZT should consult with an AIDS-knowledgeable physician before taking other drugs. Acetaminophen (Tylenol, Datril and others) should NOT be taken with AZT because it may increase the drug's bad side effects. Aspirin is thought to be a safe alternative to these drugs. Other drugs that should NOT be taken with AZT include probenicid (unless part of a research protocol)12, cimetidine, lorazepam and indomethacin.
Ribavirin, an antiviral drug used by many individuals infected with HIV, should NOT be taken with AZT. Ribavirin competes for the cellular enzymes that make AZT work, causing both drugs to become less effective. No studies have been done to determine whether AL-721 is safe in combination with AZT, but most physicians interviewed by BETA said the two drugs can probably be taken together safely.
Other drugs which suppress the bone marrow, such as IV chemotherapies for KS, may not be advisable with AZT because they increase bone marrow suppression. Before taking ANY drug with AZT, talk with your physician.
DHPG (gancyclovir) an experimental treatment for CMV retinitis*, also causes bone marrow suppression. Most physicians recommend against taking the two drugs together. CMV retinitis can cause blindness. People with this condition and their physicians must face the difficult choice of treating AIDS or ARC with AZT or CMV retinitis with DHPG.
Should an asymptomatic seropositive (someone with a positive AIDS antibody test but no symptoms of AIDS or ARC) take AZT? This is a difficult question to answer, because the drug is so toxic. Studies sponsored by the NIH are now underway in medical centers in the San Francisco Bay Area and across the country to determine the possible benefits and toxicity of AZT for asymptomatic seropositives.
Because of the harmful effect of the drug, some physicians, such as Sonnabend, believe that the use of AZT is only justified in those groups where its effects have already been thoroughly studied -- severe ARC patients with low numbers of T-helper cells and AIDS patients who have recovered from one bout of PCP. But many physicians are prescribing AZT for patients with T-helper cells in the range of 200 to 400, even when no symptoms are present.
James Campbell, MD13, urges caution in prescribing AZT for asymptomatic patients because of the drug's toxicity. Campbell reports that some of his patients who were at the 400 T-helper cell level with no symptoms developed severe anemia on AZT.
Conant suggests that individuals with T-helper cell counts above 400 NOT take AZT. He advises others with counts below 200 to go on a full dose. In the range of 200 to 400, he advises patients to take AZT if the T-helper cells are falling rapidly or the p24 antigen test indicates HIV replication.
Reiter has been following 22 asymptomatic seropositives for six months to one year. He determines whether or not an asymptomatic seropositive should start AZT by looking for signs of HIV replication -- a consistently falling T-helper cell count for abnormal T-helper cell function14. He also uses the p24 antigen test to see if viral protein is circulating, which indicates a high degree of viral replication. Reiter also uses the beta-2 microglobulin test* as an indication of viral replication. He does NOT use AZT in asymptomatic seropositives if there is no sign of viral replication.
According to Reiter, it is better to treat HIV infection while the immune system is still relatively intact. As mentioned above, Reiter is currently following 22 asymptomatic seropositives. He reports that these patients all had normal blood counts (CBC)*. All had approximately 400 T-helper cells before beginning AZT. According to Reiter, they all take 200 mg ever six hours, and all have shown improvements in T-helper cell number and function15. He stopped the drug three months after T-helper cell counts normalized. He believes that this type of early intervention can be well tolerated with minimal toxicity. Reiter reports that none of these patients have experienced toxic side effects from AZT. As promising as Reiter's results appear, they are anecdotal and have not been proven by clinical trials.
In the recent Lancet16 study, 18 HIV-infected men (5 without symptoms and 13 with persistently swollen lymph nodes) received AZT or AZT and acyclovir for 24 weeks. All 18 were antigen positive*, indicating that HIV was actively replicating. At the end of 24 weeks antigen levels had decreased significantly in 15 men. Nine had become antigen negative. The antigen level rose in only one person. The swollen lymph nodes returned to normal size in 9 of the 13 men; they became smaller in the other 5. T-helper cells increased in 14 of the 18 men. The results from using acyclovir with AZT were the same as when AZT was used alone.
Although no disease progression was seen in any of the 18 men, larger, longer-term studies of AZT for asymptomatic seropositives and people with persistently swollen lymph nodes will be necessary. Further studies will also be needed to determine whether acyclovir makes AZT work better.
The experiences of five individuals on AZT are summarized below. Two individuals have AIDS, to have ARC and one is HIV-positive, but asymptomatic. Their experiences show that reactions to AZT vary widely.
John (AIDS diagnosis, November, 1986)
John has been taking AZT for 18 months. He was in the original AZT study at San Francisco General Hospital for PWAs with one bout of PCP. After a year and a half on AZT, John is still working. During the first year he had no adverse reactions, but six months ago he developed anemia, and has required five blood transfusions.
Kevin (ARC diagnosis, May, 1987)
Before beginning AZT, Kevin's symptoms included a persistent fever, diarrhea, chronic fatigue and stomach problems. These symptoms continued from May to July, 1987.
In July Kevin started AZT. He expected a "horrible reaction" and took time off from work. But during the first eight weeks, he experienced no bad side effects, even though he was on a full dose of the drug. After four weeks on AZT, all Kevin's symptoms cleared.
Nine weeks after beginning the drug, however, his hemoglobin count started dropping and he felt increasingly fatigued. He developed severe anemia and required a blood transfusion in September. His physician then put him on a half dose (one 100 mg capsule every four hours). Following the transfusion, his energy returned. In November his hemoglobin count started falling again and his doctor cut his dose even further, to a quarter dose (one 100 mg capsule every eight hours). His ARC symptoms have not reappeared, but he is still anemic and will probably need further transfusions if he keeps taking AZT.
Bill (ARC diagnosis, September, 1982)
Bill's symptoms began with a year of fevers and night sweats that occurred five years ago. His lymph glands have remained swollen for five years. He also developed shingles*, hairy leukoplakia*, and thrush*. When his health took a turn for the worse, Bill started himself on ribavarin*. The symptoms continued and in addition he became irritable and insomniac.
In July, 1987 he stopped the ribavirin and began taking a combination of acyclovir and AZT. During the first six weeks on this combination his fatigue worsened and he lost his appetite and more weight. After six weeks these side effects went away, and the ARC symptoms also disappeared. His white and red blood cell counts remain normal after six months on AZT. He has regained the weight lost during the previous months and feels well.
Roger (AIDS diagnosis, September, 1986)
Roger was recovering from his second bout of PCP when he started AZT. He had lost a lot of weight and after beginning the drug he lost even more weight. He became confused and developed severe headaches. Two months later he became anemic and decided to stop taking the drug.
Karl (Asymptomatic Seropositive)
Karl found out he had an abnormal T-helper count in 1984, and since then his physician has monitored his count every three months. Karl took ribavirin from February, 1986 to March, 1987. He developed anemia and his T-helper count continued to drop. He stopped the ribavirin and began AZT in April, 1987. During the first four weeks, he experienced mild headaches, nausea, and insomnia. After starting AZT, his T-helper count steadily increased from 100 to 470, and he has not experienced any other side effects.
Physicians have varying opinions and experiences in following patients on AZT. Here are some of them:
Paul Volberding, MD (Director, SF General Hospital AIDS Division):
"Clear guidelines [about prescribing AZT for HIV infection] are needed but none is possible, given our lack of controlled experience with the drug. This author would generally advise that asymptomatic HIV infection not be treated with zidovudine outside the context of a controlled clinical trial. Particularly if prognostic testing of an asymptomatic patient suggests a very early infection, i.e., normal numbers of CD4+ cells and low or nondetectable HIV p24 antigen or beta-2 microglobulin, therapy should be deferred until information is available from the clinical trials in progress." (From AIDSFILE, March, 1988)
Barbara Newlin, Adult Nurse-Practitioner, MSN:
"AZT is not a miracle drug, it's not a cure for AIDS. However, people who begin taking it before they are ill -- when they are asymptomatic -- are doing very, very well. Furthermore, they tend to tolerate the drug better than people who start taking it when they are sick."
Robert Gorter, MD:
"If patients are interested in taking AZT, I say give the drug the benefit of the doubt. If they can tolerate it, then there is probably some benefit -- at least for a while. But I'm not extremely convinced of recommending it to everyone. However, if people want to give it a try, then I always support it."
James Campbell, MD:
"There are some people who are terribly sensitive to AZT who will sustain significant damage to the bone marrow. That's one of the reasons I've been more cautious recently about recommending it."
William Reiter, MD:
"If you don't have a spontaneous recovery of the immune system in AIDS patients taking AZT, then the benefits of treatment with AZT are limited. On the other hand, if you're treating patients early in the course of their illness and you're treating the HIV infection itself, before it has caused widespread damage to the immune system, it's a much more optimistic situation."
1 Professor of Dermatology, University of California at San Francisco. Wall Street Journal (September 11, 1987), p. 24.
2 Independent AIDS researcher, New York City. Review of AZT multi-center trial data (obtained under the Freedom of Information Act by Project Inform and ACT-UP, October 1, 1987), p. 11.
3 During the early stages of HIV infection individuals show no outward symptoms of the disease, but their immune systems may be under attack by the virus. This is indirectly indicated by falling T-helper cell numbers. In the later stages (from a few months to many years after infection) more T-helper cells are destroyed. This causes further damage to the immune system. This is the stage when people develop ARC and AIDS.
4 AmFAR Directory of Experimental Treatments for AIDS and ARC, vol. 1, June, 1987, p. 15.
5 Clinical Instructor of Medicine, UCSF.
6 The Lancet, February 20, 1988, p. 373.
7 AmFAR Directory, vol. 1, October, 1987, p. 17.
8 Director, Center for Special Immunology, Ft. Lauderdale, FL.
9 Adult Nurse-Practitioner for Marcus Conant, MD.
10 AmFAR Directory, vol. 1, October, 1987, p. 10.
11 The Lancet, February 20, 1988, p. 375.
12 Probenicid interferes with the loss of AZT from the body, allowing higher amounts of AZT to remain in the blood. The higher amount of AZT causes higher toxicity. Reiter reduces the dose of AZT when he prescribes probenicid.
13 Associate Clinical Professor of Medicine, UCSF.
14 Reiter measures how effectively T-cells work by measuring their response to mitogens. Mitogens are substances which cause normal T-helper cells to multiply. When T-helper cells are infected with HIV they do not respond normally to the mitogens.
15 The normal range for T-helper cells is from 480 to 1800, but this may vary according to where the test is given.
16 The Lancet, February 20, 1988, p. 373.
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Copyright © 1988 - Bulletin of Experimental Treatments for AIDS (BETA). Reproduced with permission. BETA is published four times a year by the San Francisco AIDS Foundation. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. Call 415.487.8060; FAX: 415.487.8069. Mailing Address: P.O. Box 426182, San Francisco, CA 94142-6182. beta@sfaf.org http://www.sfaf.org/beta.html
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