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Antiretroviral Therapy in AIDS
- Samuel Broder, MD;
- Hiroaki Mitsuya, MD;
- Robert Yarchoan, MD; and
- George N. Pavlakis, MD, PhD
Abstract
Objective: To review recent developments of antiretroviral therapy for the acquired immunodeficiency syndrome (AIDS) and related disorders.
Data Sources, Study Selection, and Data Extraction: An edited and updated summary of a Clinical Staff Conference held 26 October 1988 at the National Institutes of Health. The speakers discussed their own work as well as related work from other groups.
Data Synthesis: The discovery that human immunodeficiency virus (HIV) causes AIDS has permitted the development of rational antiviral therapy for this disease. Various steps in the replicative cycle of HIV can be targeted for intervention. More basic research into the life cycle of HIV is therefore likely to yield new therapeutic approaches. In 1985, nucleoside analogues called dideoxynucleosides were discovered to be potent inhibitors of HIV replication in vitro. Dideoxynucleosides selectively inhibit HIV reverse transcriptase after they are phosphorylated intracellular to 5′-triphosphates. One dideoxynucleoside, 3′-azido-2′, 3′-dideoxythymidine (AZT or zidovudine) has been found to prolong the life of patients with AIDS. This drug can partially reverse HIV dementia and decrease short-term progression to AIDS; it has been approved for treating HIV-infected patients with fewer than 500 CD4+ cells/mm3. AZT is only a first step in developing new therapy for AIDS. Its use is associated with toxicities, particularly bone marrow suppression. Several groups have reported the development of AZT-resistant strains of HIV. Other dideoxynucleosides whose toxicity profiles differ from that of AZT have also shown activity against HIV in early clinical studies. Large-scale, randomized trials of these drugs are now under way. Studies have shown that the binding of HIV to CD4 may be blocked by genetically engineered forms of CD4 and that HIV protease may be inhibited by substrate analogues. Protease inhibitors are an excellent area for further study in patients. Antisense oligonucleotide therapy may target the regulatory genes of HIV and is also being considered.
Conclusion: With these advances, AIDS is gradually changing from an imminently fatal disease to one that can be managed with the judicious use of drugs and biologies. Progress against AIDS will continue, provided that researchers adhere to the principles of controlled trials.
Article and Author Information
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An edited summary of a Clinical Staff Conference held 26 October 1988 at the Amphitheater, Building 10, Bethesda, Maryland. The conference was sponsored by the National Institutes of Health, U.S. Department of Health and Human Services.
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Authors who wish to cite a section of the conference and specifically indicate its author may use this example for the form of reference:
Yarchoan R. Taking anti-AIDS drugs from the test tube to patients, pp 607-611. In: Broder S, moderator. Antiretroviral therapy in AIDS.Ann Intern Med. 1990;113:604-618.
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Grant Support: In part by the National Cancer Institute, DHHS, under contract ♯N01-CO-74101 with ABL.
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Requests for Reprints: Samuel Broder, MD, National Cancer Institute, 9000 Rockville Pike, Building 31, Room 11A48, Bethesda, MD 20892.
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Current Author Addresses: Dr. Broder: National Cancer Institute, 9000 Rockville Pike, Building 31, Room 11A48, Bethesda, MD 20892.
Drs. Mitsuya and Yarchoan: National Cancer Institute, 9000 Rockville Pike, Building 10, Room 13N248, Bethesda, MD 20892.
Dr. Pavlakis: Human Retrovirus Section, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Building 539, Room 121, Frederick, MD 21701.
