New uses for old drugs in HIV infection: the role of hydroxyurea, cyclosporin and thalidomide.

The tenacious effort to develop new, specific agents to treat HIV infection is currently accompanied by a reconsideration of existing drugs on the basis of their known or putative effects on the retroviral life cycle and/or the tuning of immune mechanisms. Three specific 'older' compounds that interfere with HIV infection by both a direct antiviral activity, and a modulation of T-cell activation and proliferation have received the most attention. Hydroxurea, a classical chemotherapeutic agent, inhibits retroviral reverse transcription by targeting a cellular enzyme responsible for the synthesis of deoxynucleoside triphosphates. It may also have a role in reducing viral load while maintaining low numbers of potential target T cells. Beneficial effects of hydroxyurea in combination with didanosine and/or stavudine on viral load have been shown in a number of clinical trials. Cyclosporin, a known immunosuppressant, blocks the activation of T cells, hence reducing the permissivity to HIV, and also prevents proper HIV virion maturation. However, clinical studies have produced conflicting results in HIV-infected patients with regard to immunological and disease effects and toxicity. Thalidomide may have antiretroviral effects as a result of its primarily inhibitory effects on the production of tumour necrosis factor alpha (TNFalpha). TNFalpha induces expression of HIV from chronically infected cell lines by stimulating a cellular transcription factor, and blocking of TNFalpha-stimulated HIV replication by thalidomide has been shown in vitro and ex vivo. However, the effects on TNFalpha production in vivo have been inconsistent. Thalidomide has shown potential in treating some AIDS-related conditions [cachexia (weight loss and muscle wasting), and aphtous oral, oesophageal or genital ulcers]. However, because of its numerous and major adverse effects, thalidomide should always be used cautiously. In summary, some older drugs have potential as anti-HIV agents and offer the advantage of extensive clinical experience in other therapeutic areas. They should be considered as potential partners for the products emerging from more recent research and development.