Hydroxyurea (HU) was first proposed for the treatment of HIV disease when it was shown that this compound could act synergistically with ddI to block HIV replication in tissue culture. The explanation for this effect was that HU was a known antagonist of the cellular enzyme ribonucleotide reductase, and that an important consequence of this inhibitory activity was to diminish pool sizes of cellular nucleoside triphosphates. Moreover, this effect was most pronounced in regard to intracellular levels of deoxyadenosine triphosphate (dATP). Since the latter is directly competed with by ddA triphosphate, the active form of ddI, for incorporation into growing viral DNA chains, it follows that the chain-terminating effects of ddI during viral reverse transcription could be augmented in the presence of HU.

Following the formulation of these concepts about six years ago, HU has been tested as an adjunct to NRTI therapy in a number of clinical trials. Most of the results have indeed confirmed that patients who received combinations of HU and NRTI experienced more profound drops in viral burden than if HU was omitted from these regimens. Furthermore, tissue culture data have shown that the synergy between HU and ddI is not restricted to wild-type viral isolates but applies as well to HIV variants that display resistance to ddI and that possess relevant resistance-conferring mutations in their RT genes (i.e. mostly L74V). While these resistant viruses are not as sensitive to the combination of ddI/HU as are corresponding pre-treatment isolates, the fact remains that the presence of HU can restore a significant measure of susceptibility to ddI in this circumstance. By contrast, HU is devoid of anti-HIV activity on its own.

The benefits of HU may not be restricted to combination regimens that include ddI. First, pre-clinical data have shown that at least one other NRTI, PMPA, which also competes with dATP for incorporation into viral DNA, can act synergistically with HU to block HIV replication. Second, accumulating evidence from clinical trials suggests that the benefits of HU can be extended to regimes that include a variety other RT inhibitors, e.g. d4T, 3TC.

Although early work had suggested that the benefits of HU might be realized in patients undergoing an initial course of treatment, more recent data indicate that HU may also have an important role as part of salvage and/or intensification regimens in patients who have experienced rebounds in plasma viremia levels.

These findings have led to speculation that other factors besides synergy between HU and NRTI might be responsible, at least in part, for the encouraging clinical data that have been obtained with HU-containing drug combinations. Some scientists feel that the well-described myelosuppressive effects of HU may actually be of benefit in the context of HIV disease, by limiting the rate at which CD4 cell levels are restored in HIV-infected patients. Slower replenishment of CD4 numbers may limit the relative size of the potential target reservoir for reinfection by HIV, while providing an opportunity to establish a functional anti-HIV cellular immune response that may help to keep viral replication in check.

Finally, it is of considerable importance that HU is a very inexpensive drug, in comparison with all other compounds used in treatment of HIV disease. This means that HIV-infected patients in poor countries can at long last hope to be treated with at least the combination of HU and ddI. This provides a small note of optimism for the future treatment of HIV disease in the developing world.