AIDS TREATMENT NEWS No. 115 - November 27, 1990
John S. James
The Federally sponsored trial, ACTG 106, is being conducted in Miami and San Diego; principal investigators are Margaret A. Fischl, M. D., and Douglas D. Richman, M. D. The 48 volunteers all had AIDS or advanced ARC, with T-helper counts under 200 when they entered the study. Six different treatment regimens are being compared; the 48 volunteers are divided into six groups of eight each. Five of the six treatment arms combine ddC and AZT; the sixth uses a very low dose of AZT alone. The doses (in milligrams, given every eight hours) are:
AZT ddC 200 0.750 200 0.375 100 0.750 100 0.375 50 0.750 50 none
Since these amounts are given three times a day, the total AZT doses are 600, 300, and 150 mg per day. The high ddC dose is the same as that now being used in the major ddC vs. AZT comparison trials, and the low ddC dose is half that amount. Volunteers were first assigned to the four arms with the higher AZT doses (600 or 300 mg per day). Some groups have been on the treatment for over a year, others for less time.
We have not seen the data, which will of course change as the study progresses. The following overview comes from a recent Project Inform fact sheet, and other published sources cited in the references below.
Results
Large T-helper increases were found. The Project Inform report cited a median peak increase of 164; the exact figure will change as the study progresses. After reaching this peak, T- helper counts began to decline. We have heard conflicting reports about how far the counts declined, but it is clear that they are above the starting value after one year of the treatment. Both the size of the increase, and the time it was sustained, are much better than with AZT treatment alone -- especially for this group of patients, whose median starting T- helper count was under 100. Also, 100 percent of patients in the four treatment arms with the higher AZT doses (600 or 300 mg per day) combined with ddC had increases of at least 50, measured on at least two consecutive tests. These results strongly suggest that the combination treatment has a greater antiviral effect than AZT alone.
What about clinical improvement? Few opportunistic infections have occurred in the study, and all of them occurred within the first few weeks of treatment -- none within the remaining time, about 50 weeks for many patients. This clustering of infections early in the study strongly suggests that the regimen was helpful, since with no treatment, the rate of infections would, if anything, have increased. The early infections may have been developing before the treatment's benefit had time to begin. Other clinical improvement was also reported, with median weight gain of about 9 pounds.
Tests will soon be run to look for changes in plasma viral levels, and to see if drug resistance develops during the combination treatment. The researchers do not yet have this information.
What Should Be Done?
The results already known from ACTG 106 suggest that the combination treatment with ddC and AZT may be substantially better than any standard therapy (i.e., AZT alone), for many patients at least. We do not have conclusive proof, however, because of the relatively small number of volunteers in this study, and because the combination was not directly compared to a standard dose of AZT. Also, this study does not answer the question of how best to use ddC for patients now failing AZT.
What will happen now? The usual procedure would be to run more studies, after finishing this one; with luck, conclusive proof might be available in two years. The problem, of course, is that many people do not have that time to wait. Note that this study applies most directly to those whose HIV infection is relatively advanced.
What should be done is to convene a panel of experts, give them access to all the existing data on ddC and ddI, from all completed and ongoing studies, along with the technical support staff necessary so that they can analyze it. They should be asked whether physicians could provide better care for persons with AIDS or HIV if they had these drugs available, than if they continue to have only AZT. If the answer is yes, for ddC or ddI or both, then the drug(s) should quickly be approved for prescription use, with appropriate labeling, including an explanation of the available evidence which led to approval, and the panel's recommendations to physicians concerning use of the drugs. After approval, postmarketing studies should answer the remaining questions, such as how to best use the drugs for particular patient populations. (Is it better, for example, for patients who have used AZT but are now failing it to switch to ddC or ddI alone, to one of those drugs in combination with AZT, or to alternating use of the drug and AZT?)
Comment
A number of other studies of human use of ddC are either published, in press, or in process. ddC is being tested alone, in comparison with AZT, and in alternation with AZT. In addition, there are similar studies with ddI; however, the ddI-AZT combination study started later than ACTG 106, so little information is now available. (There is more information now about ddI as a single agent, however, than about ddC; for a review of a recent ddI report, see AIDS TREATMENT NEWS #110, September 7, 1990.)
Currently, the open-access programs for ddI and ddC have made these drugs available to many patients who cannot use AZT. But these programs are limited because their strict entry criteria exclude many patients who could benefit, without taking individual circumstances into account. Also, they do not allow combination use with AZT -- which now seems to be emerging as the best way to use these drugs. And the paperwork required of physicians effectively makes these drugs unavailable to many patients.
The largest ddC and ddI studies are usually set up to compare each of these drugs with AZT. These trials were designed this way because it would have been unethical to test ddC or ddI in a placebo trial, when the standard of care is now AZT. But how these drugs compare to AZT is usually the wrong question, since generally the new drugs will be used for patients who cannot benefit from AZT, or in combination with that drug. The right question is whether physicians can give better care if they have these drugs available in addition to AZT.
The references below list many papers which have already been published on human use of ddC in HIV treatment. But the most important studies are now ongoing. It is urgent that the existing information be brought together and evaluated now, leading to drug approval if appropriate. It would be tragic to wait a year, two years, or more for approval of ddC and ddI, when people need treatment options now.
References
Note: This list is not complete. Only the more relevant articles on human use of ddC -- especially together with AZT -- are included.
American Foundation for AIDS Research. AIDS/HIV Treatment Directory. September, 1990; pages 18-19, 43. Also see June, 1990; pages 28-29.
Bozzette SA and Richman DD. Salvage therapy for zidovudine- intolerant HIV-infected patients with alternating and intermittent regimens of zidovudine and dideoxycytidine. American Journal of Medicine. May 21, 1990; volume 88, supplement 5B, pages 24S-26S.
Bozzette S, Skowron G, Arrezo J, Spector SA, Pettinelli C, and Richman DD. Alternating and intermittent ddC and AZT in the treatment of persons with advanced HIV infection and hematologic intolerance to AZT [abstract S. B. 425]. Sixth International Conference on AIDS, San Francisco, June 20-24, 1990.
Broder S. Pharmacodynamics of 2',3'-dideoxycytidine: an inhibitor of human immunodeficiency virus. American Journal of Medicine. May 21, 1990; volume 88, supplement 5B, pages 2S-7S.
Broder S, and Yarchoan R. Dideoxycytidine: Current clinical experience and future prospects -- A summary. American Journal of Medicine. May 21, 1990; volume 88, supplement 5B, pages 31S- 33S.
Dubinsky RM, Yarchoan R, Dalakas M, and Broder S. Reversible axonal neuropathy from the treatment of AIDS and related disorders with 2',3'-dideoxycytidine (ddC). Muscle and Nerve. October, 1989; volume 12, number 10, pages 856-860.
Kolata, Gina. Interest grows in licensing shortcut for 2 AIDS drugs. The New York Times, Medical Science section, September 25, 1990.
Meng TC, Boota A, Fischl MA, Spector SA, McCaan M, and Richman DD. Phase I/II dose finding study of concurrently administered dideoxycytidine and zidovudine [abstract S. B. 426]. Sixth International Conference on AIDS, San Francisco, June 20- 24, 1990.
Meng TC, Fischl MA, and Richman DD. AIDS Clinical Trials Group: phase I/II study of combination 2',3'-dideoxycytidine and zidovudine in patients with acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex. American Journal of Medicine. May 21, 1990; volume 88, supplement 5B, pages 27S-30S.
Merrigan TC, Skowron G, Bozzette SA, and others. Circulating p24 antigen levels and responses to dideoxycytidine in human immunodeficiency virus (HIV) infections. Annals of Internal Medicine. February 1,1989; volume 110, pages 189-194.
Merrigan TC and Skowron G. Safety and tolerance of dideoxycytidine as a single agent. Results of early-phase studies in patients with acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex. American Journal of Medicine. May 21, 1990; volume 88, supplement 5B, pages 11S- 15S.
Pizzo PA. Treatment of human immunodeficiency virus-infected infants and young children with dideoxynucleosides. American Journal of Medicine. May 21, 1990; volume 88, supplement 5B, pages 16S-19S.
Project Inform, San Francisco. News bulletin, "Combination Therapy," November, 1990.
Richman DD. Susceptibility to nucleoside analogues of zidovudine-resistant isolates of human immunodeficiency virus. American Journal of Medicine. May 21, 1990; volume 88, supplement 5B, pages 8S-10S.
Shirasaka T, Yarchoan R, Aoki S, and others. In vitro study of drug-sensitivity of HIV strains isolated from patients with AIDS or ARC before and after therapy with AZT and/or 2',3'- dideoxycytidine (ddC) [abstract Th.A. 263]. Sixth International Conference on AIDS, San Francisco, June 20-24, 1990.
Skowron G, and Merrigan TC. Phase II trial of alternating and intermittent regimens of zidovudine and 2',3'-dideoxycytidine in ARC and AIDS [abstract Th.B. 23]. Sixth International Conference on AIDS, San Francisco, June 20-24, 1990.
Skowron G, and Merrigan TC. Alternating and intermittent regimens of zidovudine and dideoxycytidine in the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. American Journal of Medicine. May 21, 1990; volume 88, supplement 5B, pages 20S-23S.
Yarchoan R, Pluda JM, Thomas RV, Pemo CF, McAtee N, and Broder S. Long-term (18 month) treatment of severe HIV infection with an alternating regimen of AZT and 2',3'- dideoxycytidine (ddC) [abstract W. B. P. 327]. Fifth International Conference on AIDS, Montreal, June 4-9, 1989.
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