Zidovudine: Five Years Later

Abstract

Zidovudine, a nucleoside analog, was the first agent proved to be effective in the management of human immunodeficiency virus type 1 (HIV-1) infection. After demonstration of zidovudine's in-vitro activity against HIV-1 in 1985, the drug was rapidly evaluated in phase I and phase II clinical trials and was found to be effective in decreasing both mortality and the incidence of opportunistic infections in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex; the drug was also found to have a substantial but tolerable toxicity profile. Since the licensure of zidovudine in 1987, an intensive clinical research effort has established the drug's efficacy in the prevention of disease progression in asymptomatic and mildly symptomatic HIV-infected persons and has established the success of lower-dose therapy in patients at all stages of disease. The current recommendation is to use zidovudine at a dose of 500 to 600 mg/d in both symptomatic and asymptomatic persons with CD4 counts of less than 500/mm3. The major toxicities of anemia and neutropenia are less frequent at the lower doses presently used and can be managed by dose reduction or by use of hematopoietic growth factors. The inexorable disease progression seen despite zidovudine therapy and the isolation of clinical strains of HIV-1 resistant to zidovudine in vitro highlight the limitations of prolonged monotherapy with this agent. Although alternative dideoxynucleoside agents (for example, didanosine [dideoxyinosine and zalcitabine dideoxycytidine]) are available for the management of HIV-infected persons, zidovudine remains the cornerstone of antiretroviral therapy. Current research efforts are directed at elucidating the clinical relevance of zidovudine resistance and studying regimens in which zidovudine is used in combination with other agents. This latter approach holds great promise for improving efficacy, limiting toxicity, and perhaps preventing the emergence of viral resistance. For the forseeable future, zidovudine will continue to play a role in the development and in our understanding of antiretroviral therapy.

Optimal control of the chemotherapy of HIV

“…Rather, if treatment is strong at the outset, and then gradually lessens in strength over time (whether because of a change in dosage or other effects), it is still effective in balancing the benefit to T cells and systemic costs. This is seen, in particular, with drug treatments such as with AZT and DDT [25].…”

“…There are many data available on the treatment of HIV infection (cf., [25,18]) and many laboratories and clinics are keeping close accounts of patient treatment courses with respect to effectiveness and results. Of interest here is the fact that there are conflicting results as to whether treatment is better at the early stage of disease (when the CD4> T cell count is between 200/mm and 500/mm of blood), (see [13,15]) or at the later stage (when the count is below 200/mm ) [16,11].…”

Swainsonine protects both murine and human haematopoietic systems from chemotherapeutic toxicity

“…We focused on AZT because it is one of the most commonly used drugs in the treatment of AIDS and because its limiting toxicity is haematopoietic (Yarchoan et al, 1989;McLeod and Hammer, 1992).…”

“…Epithelial linings, such as the oropharynx and the gastrointestinal tract, and the bone marrow are among the most sensitive tissues (Dorr and Fritz, 1980;Hoagland, 1992;Perry, 1992;Pratt et al, 1994). In fact, myelosuppression is often the dose-limiting feature in chemotherapy regimens for a number of diseases, including cancer (Hoagland, 1992) and acquired immune deficiency syndrome (AIDS) (Richman et al, 1987;Shaunak and Bartlett, 1989;Walker et al, 1987;McLeod and Hammer, 1992). Supporting patients through a period of myelosuppression or decreased resistance to infection has become a significant part of a chemotherapeutic regimen (Vose and Armitage, 1992).…”

Decline in the HIV‐1 Isolation Rate in Japan: A 12‐Year Observation

“…During the initial period of single RTI therapy, many physicians experienced patients whose adherence to AZT was not regular: high doses of AZT were administered, causing many adverse side effects. A few years later, the dosage of AZT was reduced, and around 1991-1992, it was reported by many researchers that double RTI therapy was effective to suppress viral replication in vivo, resulting in prolongation of the patient's life (6,7). Promising reports on the results of double RTI therapy probably encouraged the physicians as well as the patients.…”