Issues in the testing of drug combinations

Article Abstract:

The use of a combination of drugs in the treatment of AIDS may be more effective and less toxic than the use of a single agent. Administration of a combination of drugs allows AIDS patients to be treated for various aspects of AIDS at the same time, including treatment against the virus, therapy to prevent opportunistic infections, and treatment to stimulate the immune system. Three issues are discussed pertaining to the testing of combinations of drugs. These issues are: the design of clinical trials of combination therapies to answer multiple questions; the comparison of combinations of drugs to single agents; and the clinical significance of drug synergy (greater activity when drugs are used together than if their effects were just added together). Clinical trials can be designed to answer two or more questions, with the same number of patients as it would take to answer one question (factorial design). Often, more information is revealed in a factorial trial because comparisons can be made with identical groups, while in separate trials the groups would be different. A clinical trial that combines two drugs is designed so that drug A, drug B, and the combination of the two drugs are tested against each other. Each agent must be tested at a dose that gives the maximum response. This dose can be determined in separate trials, or in a study that tests each single agent and the combination of agents at several different dose levels. A strategy has been worked out to determine the maximum tolerated dose by giving the drugs at increasing concentrations until toxicity is reached. For drugs to be synergistic, the response to both drugs must increase with dose. However, a combination can be better than each single drug, without being synergistic. If two drugs have different types of toxicities, the combination of the drugs may be effective against the virus while the toxicity levels are not reached. (Consumer Summary produced by Reliance Medical Information, Inc.)

HIV infection, HIV infections, Drug interactions, Chemotherapy, Combination, Combination chemotherapy

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Insights from monitoring the CPCRA didanosine/zalcitabine trial

Article Abstract:

It may be advisable to avoid releasing preliminary results from research studies on life-threatening diseases, such as acquired immunodeficiency syndrome (AIDS). It may also be advisable to reevaluate the use of CD4 cell counts as an indicator of AIDS progression and to carefully adjust for even small irregularities in important patient risk factors. Researchers analyzed the design of a research study comparing the effectiveness of didanosine (ddI) and zalcitabine (ddC) drug therapies in patients with AIDS and suggested changes for future drug studies. The final results indicated that ddC may be somewhat more effective than ddI. However, preliminary results favored ddI as being significantly more effective than ddC. CD4 cell counts, as an indicator of disease progression, did not correlate with the results of this study. A small imbalance in the participants' functional status, as measured by Karnofsky scores, between the two treatment groups may have biased the study's results.

Analysis of variance, Didanosine, Zalcitabine

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