Nucleoside Analoguess in Combination


Nucleoside Analoguess in Combination

Seattle Treatment Education Project (STEP) Perspective, Vol. 5, No. 2 - July 1993 * 127 Broadway E. Ste 200 Seattle, WA 98102
Joel Gibson M.S

Margaret Fischl announced the results of ACTG 155 which looked at the safety and efficacy of AZT & ddC alone and in combination. The 901 participants who had a mean duration of prior AZT usage of 18 months were divided into two groups: symptomatic with less than 300 CD4 cells, asymptomatic with less than 200 CD4 cells. Individuals in each group were further divided up into one of three treatment arms: AZT (200 mg three times/day), ddC (0.75 mg three times/day), or a combination of the two drugs at the same dosages as the monotherapy arms. The main group of individuals enrolled in this trial were symptomatic with less than 300 CD4 cells. The mean duration of follow up was greater than 17 months. In initial analyses, no difference between the three treatment arms could be found with regard to disease progression or survival. However, in an analysis done after the trial by stratifying participants by initial CD4 counts of less than 50 CD4 cells, 50-150 CD4 cells, and 150-300 CD4 cells, the results are as follows. Combination therapy with AZT and ddC was significantly favored over either of the monotherapies in people with greater than 150 CD4 cells at the beginning of the trial. In people with less than 150 CD4 cells, combination therapy did not significantly increase survival as compared with monotherapy, although there was a trend in that direction. And in all people, one monotherapy was not any better than the other (all individuals had had at least six months of prior AZT usage). Criticism has been leveled at this analysis because this was not how the trial was originally stratified or designed, i.e. to answer the question of optimal therapy based on initial CD4 count. With regard to toxicity, there was severe neuropathy seen with equal frequency (albeit rare) in all groups (therefore, probably not ddC related). Moderate neuropathy was seen with increased frequency in the groups taking ddC vs. the AZT monotherapy group. Neutropenia was present in the groups taking AZT but not ddC, and anemia was present in all three treatment groups.

In vitro work presented by the famed "convergent, combination therapy" group at Harvard, showed that this type of therapy may prevent the emergence of multi-drug resistance to HIV. This is based on the theory that attacking the virus at the same site by differnt agents may render it non-viable. (See related articles in this issue of the Perspective on Nevirapine Use in Clinical Trials & Convergent Combination Therapy). These analyses were done using clinical isolates in activated and resting lymphocytes and monocytes/macrophages. Researchers at Harvard have since tested a variety of drug combinations, all having the same results: inhibition of viral replication and infection of new cells. These drug combinations include: AZT & ddI & Nevirapine, AZT & ddI & pyridinones (e.g. Merck's "L" drug), AZT & ddI & Foscarnet, AZT & ddC & Nevirapine, and AZT & ddC & pyridinones. These effects were seen whether AZT-resistant virus was used in the experiments, or whether AZT-resistant and ddI- resistant virus was used, or whether Nevirapine-resistant virus was used. The investigators also looked at drug combinations that affected different points in the viral life cycle and did not see the same effect. Examples of these combinations include AZT & protease inhibitor & interferon alpha and AZT & protease inhibitor & tat inhibitor. Researchers at other institutions which have attempted to duplicate the results achieved by the Harvard group, have not had the same success. Some found that the virus was able to "breakthrough" even with the three drug combination used by the Harvard investigators. Still, it will be very interesting to see how these multi-drug combinations pan out in clinical trials.

In a small study in people who were rapidly progressing in their illness, either AZT & ddI was given or AZT & ddC. To be included, one had to have had prior AZT therapy for greater than 24 weeks. The dose of AZT was 500 mg/day, for ddI was 400 mg/day, and for ddC was 2.25 mg/day. In people with less than 200 CD4 cells, a significant mean increase in CD4 cells was seen in the AZT & ddI group over the mean level of CD4 cells in those taking AZT & ddC. The reduction of p24 antigen was the same for both combinations. And with regard to disease progression or death, there was a trend for a more favorable outcome with AZT & ddC as compared with AZT & ddI, but this was not statistically significant.

References:

1.WS B25 (1,5,6). 1993. IX International Conference on AIDS. Berlin, Germany. June 1993.
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This information is designed to support, not replace, the relationship that exists between you and your doctor.
©1993. AEGIS.