Discredited hydroxyurea back on the agenda

Hydroxyurea was back in the limelight at a meeting of scientists convened in Stresa, Italy, last week for a two day conference on Immune Reconstitution and Control of HIV.

Franco Lori, of RIGHT at Policlinico San Matteo, Pavia, Italy and Washington, DC, who has been at the forefront of using the old anti-cancer drug as part of cutting-edge antiretroviral therapy, presented new evidence that hydroxyurea alone does not cause mitochondrial toxicity-related pancreatitis, and that lower doses (300 mg BID) of hydroxyurea are the most effective yet seen.

The use of hydroxyurea as an adjunct therapy alongside ddI alone or combined with d4T, was severely discredited in 2001 when a US study reported three cases of pancreatitis among the 65 people on hydroxyurea, with two deaths from complications of pancreatitis (Havlir). At the same time, a review of over 2,000 patients from the Johns Hopkins HIV Clinic found a four-fold increased risk of pancreatitis when hydroxyurea was taken with d4T or ddI (Moore). Since then, doctors have generally shied away from prescribing hydroxyurea, and it was thought that use of this potentially useful drug was too limited by its side-effects.

However, Lori presented evidence that the toxicity of hydroxyurea combined with ddI is not only dose-related but also depends on which version of ddI is used, and how often it is given. By measuring in vitro the amount of mitochondrial toxicity caused by each drug alone, he has discovered that hydroxyurea alone causes no mitochondrial toxicity at any of the usual doses (300 mg - 600 mg BID).

When hydroxyurea is added to ddI 400 mg, either as one pill of ddI EC(enteric-coated) once a day, or two doses of 200 mg ddI chewable tablets twice daily, some mitochondrial toxicity is seen but not enough to cause severe side effects like pancreatitis.

However, when the 400 mg dose of ddI is given as chewable tablets in a once daily dose, hydroxyurea has an additive effect, causing the highest levels of mitochondrial toxicity which could lead to severe side effects like fatal pancreatitis.

Lori says that the study deaths from the combination of hydroxyurea and ddI/d4T occurred using the highest dose of hydroxyurea (600 mg BID) and once-daily administration of ddI 400 mg.

Lori added that his lab’s latest unpublished studies have shown that use of the lower dose of hydroxyurea (300 mg BID) alongside 400 mg ddI EC, is associated with the greater increase of CD4 cells compared with higher doses of hydroxyurea - unsurprising given that hydroxyurea is known to blunt CD4 increases. What was surprising however, was that the lowest dose of hydroxyurea was also associated with the highest reduction in viral load.

Lori cannot explain these findings and further studies are ongoing.

But perhaps the most exciting application of hydroxyurea is the use of the drug during structured treatment interruption (STI), in order to reduce the pool of activated lymphocytes that could be infected and therefore keep viral load down. This is known as the prey-predator hypothesis. Lori and others are planning on doing further studies based on the findings of Garcia, who used hydroxyurea during five cycles of STI in 20 patients with a viral load < 20 copies/ml. They were randomized either to continue HAART or HAART plus hydroxyurea for 24 weeks followed by five STI cycles. Hydroxyurea was also stopped in cycles 1-3 but continued in cycles 4 and 5. Viral load remained below 5000 copies/ml in eight out of nine patients in the hydroxyurea group and in four out of ten patients in the HAART group after a median 48 weeks of follow-up after the fifth interruption ( P=0.039). Lori believes this could also be acheived with another cytostatic drug, mycophenolate (CellCept), an anti-rejection drug used after transplant therapy, which also boosts abacavir.