Optimum hydroxyurea dose determined

Use of hydroxyurea seems to have reduced over the last two years despite promise when used in salvage therapy to enhance phosphorylation to thymidine (d4T) or cytidine (3TC) analogues, and to potentiate ddI activity and possibly compensate for ddI resistance by re-establishing the nucleotide ratio in favour of ddI.

Of note, hydroxyurea is included in both the Montaner and Katlama multiple drug rescue protocols using > 7 drug regimens, and is likely to still remain an important option in multiply drug experienced patients.

In practice, in these and other studies, ddI has been dosed at 500mg BID (twice daily) and toxicity (neutropenia, nausea, skin and nail discolouration, hair-loss and mouth ulcers together with increased risk of ddI side effects of neuropathy and pancreatitis) at this dose has also limited its use in clinical practice.

Franco Lori has led much of the research into HU, including as an ARV adjunct with ddI in reduced ARV combinations and as an immune modulator with treatment interruptions. Lori presented results from the RIGHT 702 study, which randomised 115 HIV-positive patients in a 3×3 factorial design to 600mg, 800-900mg and 1200mg in once, twice or three-times daily dosing, together with d4T/ddI background therapy.

The abstract reports that pairwise comparisons between the 600mg and 800-900mg daily dosing were statistically significant in favour of the 600mg arms at all dosing regimens for proportion of patients < 400 and < 50 copies/ml at both 24 and 48 weeks, although the actual percentages were not reported. BID dosing was reported as superior to QD dosing for virological but not immunological endpoints.

The most effective daily dose for the primary endpoint (% BLQ < 400 copies/ml at week 24) was the 300mg BID arms (p=0.017).

The seriousness of higher doses, and the use of hydroxyurea with ddI in general was highlighted by a fatal case of pancreatitis in the 1200mg QD arm – clearly the wrong study for this patient. The practical use of HU is likely to remain in a salvage setting, when other options are limited, supported by close monitoring.

F Lori, R Pollard, P Shalit et al. A low hydroxyurea dose (600mg daily) is found optimal in a randomised, controlled trial (RIGHT 702). XIV International AIDS Conference, Barcelona, 7-12 July. Abstract TuPeB4465.