AIDS TREATMENT NEWS No. 110 - September 7, 1990
John S. James
A total of 58 patients were involved in the study, 22 with AIDS and 36 with related conditions; their median T-helper count when they started ddI was 47 (range 4 to 267). The survival rate after 21 months was 80 percent for patients with AIDS and 93 percent for those with symptomatic HIV infection who did not meet the definition of AIDS. (Many patients were on the study for less than 21 months, but survival to that time was estimated by the Kaplan-Meier statistical method, which is well accepted for this purpose.) The paper was published in The Lancet, September 1, 1990[1]; additional information from interviews with scientists involved in the study appeared in The Wall Street Journal, August 31, and in other newspapers through a United Press International story.
How does this survival compare with that of AZT or no treatment? The Lancet article cautions that this data may not be comparable with past experience because most patients were stable when they began the study, many received pneumocystis prophylaxis, and 10 were treated with AZT while their ddI was temporarily stopped. News stories reported that earlier studies with similar patients had found about a 50 percent survival at 21 months among those treated with AZT, and 25 percent survival with no treatment; but we do not know if those figures reflect pneumocystis prophylaxis.
Other highlights of the Lancet paper:
* Of the 13 patients who received long-term (median 17 months) treatment with well-tolerated doses of ddI (no more than 9.6 mg/kg per day), mean T-helper count started at 157 and increased by 50 percent (at the time of maximum increase, after nine months of treatment). T-helper cell and p24 antigen improvements continued for some patients for up to 15 months, after which there were too few patients to draw firm conclusions.
* Patients with little or no prior treatment with AZT (no more than four months) showed much better T-helper improvements than those who had used AZT for much longer. But p24 antigen, a measure of viral activity, decreased substantially in both groups during ddI treatment. The article does not speculate on why the T-helper count increased less in patients who had had long-term use of AZT, but lead investigator Dr. Robert Yarchoan, interviewed in The Wall Street Journal, suggested that the reason may have been the effect of AZT on the bone marrow, which produces T-helper as well as other blood cells. (The AZT doses of these patients were not reported, but presumably they would have taken the "high" dose, 1200 mg, which was standard at that time, and which causes much more toxicity than the lower doses now in use.)
* Of five patients in the study who had dementia or other cognitive dysfunction, all had improved cognitive measurements after six to 12 weeks of ddI.
* Toxicities were severe at high doses of ddI, with most patients developing neuropathy, pancreatitis, or hepatitis within six months; no one died of drug effects in this study. But at doses of 3.2 to 9.6 mg/kg per day, only three of 35 patients developed any of these serious toxicities. Many patients had less severe side effects, such as insomnia, irritability, abdominal pains, and headache; we do not know what doses these patients used. To reduce pancreatitis, the most serious toxicity of ddI, the researchers now "measure serum amylase and triglyceride and temporarily stop ddI when the amylase rises to 1.5-2 times the upper limit of normal or when the triglyceride concentration rises above 7 g/l; ddI is then re-instituted when the levels approach normal."
Comment
This small study does not prove that ddI is better than AZT, although the good survival rate for patients with AIDS or serious symptoms, and low T-helper counts when they began the study, suggests that it might be. The important question, however, is not whether ddI is better on the average, but whether it is better for some patients. It seems clear that the answer is yes, and that the drug should be approved as a treatment option.
References
1. Yarchoan R, Pluda JM, Thomas RV, and others. Long-term toxicity/activity profile of 2',3'-dideoxyinosine in AIDS or AIDS- related complex. The Lancet. September 1, 1990; volume 336, pages 526-529.
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