June 29 and July 2, 1998
Hydroxyurea continues to fascinate, tease and titillate the HIV research world. It is relatively inexpensive, and is not an antiviral in its own right. It clearly enhances the activity of ddI and of ddI/d4T, at the cost of some anemia and decreased white blood cell count. However, does it have some unique properties due to enhancing activity of other nucleosides? Does it have unique effects on HIV disease because it decreases activation of CD4 cells? Clear answers are not in. There was neither enough data to deflate the hype, nor to answer the above questions. Two of the most interesting abstracts are below.
Poster Session 12371: Suppression of HIV replication and cell proliferation leads to minimal levels of proviral DNA and to immune recovery
This is a fascinating study by Franco Lori's group in Pavia, Italy (one of the major hydroxyurea proponents), in collaboration with some prominent groups elsewhere, notably Bruce Walker's lab at Harvard, and Bob Siliciano's lab at Hopkins. They treated 24 patients with a combination of HU, ddI and protease inhibitors for an average of 11.3 months. These patients were started on therapy soon after infection -- 10 treated before, 6 within 1 year and 8 after 1 year of seroconversion. Average baseline values were: plasma viremia 455,700 copies/ml, CD4 499/ml. Plasma RNA became undetectable in all patients within 16 weeks and remained undetectable for up to 21 months. HIV RNA became undetectable in the semen of 6/6 patients. In the lymph nodes, HIV RNA was undetectable in 6/7 patients (<1 cell/4.4 ? 107), as was HIV DNA in 2/6 patients (<1 cell/3 ? 105). Using the Siliciano assays for hidden reservoir virus, replication competent HIV was recovered with an unusually low frequency (<1 cell/1 ? 107) in 3/3 patients. Most interestingly, the patients had very strong T helper responses to HIV antigens. Bruce Walker has hypothesized that the specific T helper response is key in controlling viremia in long term non progressors. In one patient, despite very low levels of latent provirus that could be recovered from resting lymphocytes, HIV did not rebound 1 year after interrupting the treatment. It is not clear whether the preserved T helper responses were simply due to starting early after seroconversion, or whether hydroxyurea had a unique effect in this setting.
Poster Session 42262: Enhanced activation of nucleoside analogues in the presence of hydroxyurea in vitro
In light of the continued interest in hydroxyurea and the accumulation of evidence on its effectiveness, the question is often asked if hydroxyurea enhances the activity of any drug besides ddI. The proposed mechanism by which hydroxyurea (HYDREA) enhances the activity of ddI is by decreasing the amount of intracellular dATP (the natural nucleoside) and increasing the ratio of ddATP to dATP, making it more likely the reverse transcriptase will use a ddATP (the active form of ddI), which stops the growing RNA chain. This effect should not enhance the activity of thymidine analogues (d4T, AZT) or cytosine analogues (3TC). There has been some evidence that hydroxyurea may lead to increased phosphorylation of d4T, which would increase the activity of d4T. This has not been confirmed. This study looked at intracellular levels of AZT and 3TC triphosphate with and without hydroxyurea. The investigators found that HU increased the levels of intracellular AZT and 3TC triphosphate by more than 100 percent. This suggests than hydroxyurea may enhance the activity of AZT, 3TC, and probably d4T. This would probably be most important in the setting of salvage therapy where low level resistance might be overcome by higher levels of the active drug.