Gay Men's Health Crisis "Treatment Issues", Vol. 8, No. 5 - July 1994
Dave Gilden

Benefits vs. Side Effects

Recommendations that AZT be used by people with HIV who are symptom-free but have CD4 cell counts depressed below 500 per cubic millimeter of blood were based largely on a trial conducted by the U.S. government's AIDS Clinical Trials Group (Protocol 019).[1]

Over the course of a relatively short time - about a year - the incidence of illnesses indicative of declining immune function (i.e., of disease progression) was significantly lower among those taking AZT than in those who were not. It is noteworthy, though, that this incidence did not differ between the group receiving high-dose AZT (1,500 mg per day) and lower dose AZT (500 mg per day).

A new reanalysis of the 019 study that takes into consideration AZT's serious side effects[2] has found that the initial conclusion is flawed. The greater rate of disease in the non-AZT group is balanced out by the increased rate of severe and life-threatening toxicities in those receiving AZT. Such side effects include vomiting that requires intravenous feeding, anemia that requires blood transfusions and debilitating fatigue. Average time from the start of the study to an adverse event (stemming from either drug toxicity or disease progression) was about 15.5 months for either the placebo or lower dose AZT group and about 15 months for the high-dose AZT group.

Early vs. Late

The 019 reanalysis extended the period of follow-up out to eighteen months, but the finally published conclusions of the lengthy and massive Anglo-French "Concorde" study[3] indicate that eighteen months is still far too short to identify AZT's benefits for those with early HIV infections. Concorde documented the experience of almost 1,800 initially asymptomatic HIV-positive individuals over four years. The participants, 40 percent of whom started the trials with near-normal CD4 cell counts of over 500, were divided into an immediate treatment group which began AZT at once and a deferred treatment group which was supposed to wait until ARC or AIDS symptoms appeared.

The initial results of the Concorde study were released a year ago[4] and did not encourage early treatment with AZT. The full description of the study data confirms the original impression, backing it up with a fuller description of the overall effect of AZT on disease progression and on long-term survival, which after all is the ultimate test of a therapy's worth.

It should be stressed that Concorde did not prove that AZT is useless. Quite the contrary, the trial found an immediate benefit from AZT even in the symptom-free population under study. For the first year of the trial, development of AIDS or ARC symptoms was significantly lower for those on AZT, but this difference shrank rapidly by the end of year two, and in the succeeding years the cumulative number of people who had ARC or AIDS symptoms was essentially the same in each group.

As for survival, using AZT early or late seemed to make no difference at any time. By the end of one year, almost no one had died in either group. At the four year cut-off point, the cumulative death rate in the early AZT group (11 percent) was actually a little higher than in the late AZT group (9 percent), although this difference was judged not statistically significant.

Just before the Concorde trial article, a group of European and Australian investigators published the data from an AZT trial in symptom-free, HIV-positive individuals that seemed at first glance much more positive about the use of AZT as early intervention.[5] This trial, which incidentally was funded by AZT's manufacturer, Burroughs Wellcome, is representative of the older trials of early AZT use. It reveals the same insufficiencies, the same emphasis on short-term "disease progression," as defined by new symptoms, while ignoring long-term, overall survival rates.

The Euro-Australian researchers found that early AZT did seem to reduce the rate of development of AIDS or ARC symptoms, but only for the first year. This was the period that the trial was designed to cover, and the researchers concluded that AZT "is effective in delaying progression to symptomatic HIV disease in high-risk, asymptomatic HIV-infected subjects." But in the relatively small number of trial participants followed for a second year, the results were not so hopeful. After the first year was over, the rate of symptom occurrence was greater for those receiving AZT than for those receiving placebo. This result, and the Concorde long-term data on survival as well, may reflect the accumulation of AZT's toxic effects, particularly suppression of the bone marrow's ability to produce red and white blood cells.

Real World Experience

It seems that AZT has an impact on health and survival that lasts for a year or so and then fades, no matter at what stage of immune deficiency the drug is started: A seventeen-country European study that tracked the experience of almost 4,500 people diagnosed with AIDS from 1979 to 1989 and treated with AZT only after that diagnosis also reported its data this spring.[6] The authors found that administering AZT immediately after AIDS diagnosis reduced the death rate by half in the first year compared to people who were never treated with AZT (24 percent versus 50 percent). Once again, that advantage vanished in the course of the second year. People with AIDS who were treated with AZT for more than two years died at a faster rate than people who had survived AIDS for the same length of time without AZT.

Published alongside the European report was a paper from San Francisco on the survival time of a group of gay men with CD4 counts below 200 per cubic millimeter of blood.[7] This level now confers on one an official AIDS diagnosis regardless of physical symptoms. Median survival time, the point at which only half those with a CD4 cell count of below 200 remain alive, increased after 1986 by about a year (from 28 months to 38-40 months) and has remained constant since then. Although use of AZT may have had some influence, that influence could not be distinguished in the study's statistical analysis. Gains from using prophylaxis for Pneumocystis carinii pneumonia (PCP) together with AZT were large enough to be statistically significant, though. This finding once again reflects the narrow boundaries of AZT's utility and confusion about when to use the drug.

The use of AZT in early intervention, which may shorten survival later on, could have affected the San Francisco results. More importantly, the San Francisco study further serves as a strong reminder that survival gains for people with HIV have been largely accomplished by altering the environment in which AIDS occurs - in this case by better management of opportunistic infections, PCP in particular.

Changing to a Different Antiviral

One big problem with relying on a single chemical agent to combat any pathogen, especially a rapidly mutating one like HIV, is the development of resistance to that agent. AZT is especially vulnerable to the emergence of genetic mutations that produce resistance because it belongs to a class of drugs known as reverse transcriptase inhibitors. These drugs block HIV's reverse transcriptase enzyme, which the virus uses to help insert its genes into the genetic material of healthy, uninfected cells. The reverse transcriptase inhibitors in this way impede the spread of HIV into new cells, but they do nothing to stop the production of new virus in cells that already harbor viral genes. It is now clear that there are large numbers of HIV-containing cells at nearly every stage of infection, especially in the lymph nodes. There is a steady production of new HIV particles, some of which inevitably contain mutations conferring resistance to AZT.

A common criticism of the Concorde trial and other AZT-only studies is that there are other available drugs - ddI and ddC (both also reverse transcriptase inhibitors) - and still others will be available soon. People with HIV could perhaps get their benefit from AZT and after a year or so change to another drug. Unfortunately, the experience has been that people do poorly on their second drug. CD4 counts rise only briefly and then resume their downward trend while new symptoms develop, according to two recently published studies on switching to ddI or ddC.[8,9] d4T, the AZT-related drug now nearing approval, seems to perform no better than ddI or ddC as a second drug.[10]

The reason why the drugs that replace AZT perform comparatively poorly is not clear. The continued toll of HIV and opportunistic infections plus AZT's accumulating side effects may leave the immune system less functional than before AZT therapy regardless of a person's actual CD4 count. Also, AZT-resistant HIV may be more mutable than AZT-sensitive strains of the virus, making resistance to new drugs emerge more quickly.

Another Alternative

One therapy that may strengthen the reverse transcriptase inhibitors is high-dose acyclovir. In a trial reported last month,[11] individuals taking 3,200 mg of acyclovir a day in addition to their choice of anti-HIV therapy (mostly AZT) and PCP prophylaxis were 40 percent less likely to die over the course of the next year than those following similar regimens minus the acyclovir. (It should be noted that this is another trial funded by Burroughs Wellcome, which owns the rights to acyclovir as well as AZT.)

Although CD4 counts were not greater, the incidence of herpes virus infection (although not CMV) was reduced considerably in the acyclovir group. This may be a clue as to why acyclovir prolonged survival in the trial participants, all of whom had very advanced HIV infections. Acyclovir may improve health by suppressing herpes or other opportunistic viral infections that either weaken the body's defenses directly or act as a cofactor that promotes HIV. Either way, acyclovir could represent an additional strategy for buttressing the current weak anti-HIV medications by improving the body's overall microbial environment.

1 Volberding PA, et al. New England Journal of Medicine. 1990; 322(14): 941-9.

2 Lenderking WR, et al. New England Journal of Medicine. 1994; 330(11): 738-43.

3 Seligmann M, et al. Lancet. 1994; 343(8902): 871-81.

4 AboulkerJ-P et al. Lancet, 1993; 341(8849):889-90.

5 Mulder JW, et al. AIDS. 1994; 8(3):313-21.

6 Lundgren JD, et al. Journal of the American Medical Association. 1994; 271(14):1088-92.

7 Osmond D, et al. Journal of the American Medical Association. 1994; 271(14):1083-7.

8 Spruance SL, et al. Annals of Internal Medicine. 1994; 120(5):360-8.

9 Abrams DI, et al. New England Journal of Medicine. March 10 1994; 330(10):657-62.

10 Bristol-Myers Squibb Corp. unpublished data submitted to the Food and Drug Administration. May 1994.

11 Youle MS, et al. AIDS. 1994; 8(5):641-9.

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