AIDS TREATMENT NEWS No. 113 - October 19, 1991
John S. James

This phase II, unblinded, "pilot" study enrolled a total of 67 volunteers, all of whom had symptomatic HIV infection, but not AIDS. All had T-helper counts of 200 to 500, and were either p24 positive or had plasma viremia, when they began the trial. (For the viremia measure, this study used a quantitative test for the amount of virus present, not the older viral cultures which were only positive or negative but did not indicate an amount.)

Those randomly assigned to the 300-mg dose had the greatest T-helper improvement, from an average of 321 to 412 during the first 12 weeks of treatment. Several other measurements -- the proportion who became p24 negative, the decrease in p24 levels in the others, and the reduction in plasma viremia -- were the same in all dosage groups. Clinical improvement, measured by weight gain, Karnofsky performance scores, and reduced fatigue, was better in the low and medium doses (300 and 600 mg) than in the 1500-mg dose.

After the 12th week, patients continued in a second phase of the trial for a median of 28 additional weeks. None of the 22 who were p24 positive at the 12th week became p24 negative later -- suggesting the limited effectiveness of AZT. In fact, the p24 levels increased 14 percent during this second phase (the median of 28 weeks after the 12th week of treatment). This increase was comparable in all three dosage groups.

As an additional test to see whether the different doses worked equally well, some patients were crossed over from 300 or 600 mg to 1500, or from 1500 to 300. This change in the dose of AZT had no effect on p24 levels.

This study also tested acyclovir (Zovirax) in combination with AZT, by randomly assigning some of the patients in each of the AZT dosage groups to 4.8 grams of acyclovir per day. There was no evidence that the combination had any more antiretroviral effect than AZT alone. But the authors pointed out that their study could not rule out the possibility that acyclovir might increase survival, as one study(2) suggested. Only additional trials could determine if suppressing certain herpes viruses with acyclovir would have clinical benefit. No toxicity was seen from the acyclovir, when combined with any dose of AZT.

The researchers concluded, "The consistency of the clinical and laboratory data ... suggests that 300 mg of zidovudine a day has antiviral and CD4-lymphocyte-enhancing effects similar to those of a 600-mg dose, with less toxicity than higher doses." However, "Our findings must be corroborated before this dosage is routinely adopted." They also conclude that "The minimal effective dose of zidovudine for the treatment of HIV infection has yet to be determined, and further studies of very low daily doses are warranted."

This study was supported by grants from the National Institutes of Health and the AIDS Clinical Trials Group (ACTG) of the National Institute of Allergy and Infectious Diseases. The principal investigator was Lawrence Corey, M. D., of the University of Washington in Seattle.

Comment

The fact that a small study was finding that 300 mg of AZT seemed to work as well as 600 mg had become widely known in the AIDS community. But formal publication provides the details which make the result more useful.

At this time the usual dose of AZT is 500 or 600 mg per day. It is unlikely that this standard will change just because of one relatively small study. But the new results should make physicians and patients more confident about lowering the dose when necessary, or when they are already inclined to do so.

This trial was well designed, in several ways. It used relatively few patients, and therefore could be conducted quickly, cleanly, and economically. It made good use of laboratory endpoints, including quantitative plasma viremia, and also used clinical endpoints such as weight gain and fatigue scores. While none of these measurements is by itself definitive, the consistency between them is convincing. The researchers tabulated results at 12 weeks (known to be long enough for AZT to show benefits), but then continued the study to obtain longer-term data. These aspects of this trial illustrate current developments in clinical-trial design.

References

1. Collier AC, Bozzette S, Coombs RW, and others. A pilot study of low-dose zidovudine in human immunodeficiency virus infection. The New England Journal of Medicine, October 11, 1990, volume 323, number 15, pages 1015-1021.

2. Fiddian AP. [Wellcome Research Laboratories, Beckenhham, Kent, U.K.] Preliminary report of a multicentre study of zidovudine plus or minus acyclovir in patients with acquired immune deficiency syndrome or acquired immune deficiency syndrome-related complex. J. Infect., January 1989, volume 18 [supplement 1], pages 79-80.

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