Hydroxyurea is active in vitro against multidrug-resistant HIV
16 July 2000. Related: Conference reports, Drug resistance, Intl Drug Resistance Workshop 4 Sitges 2000.
The in vitro activity of hydroxyurea alone and in combination with ddI against multidrug resistant recombinant HIV constructed from patient isolates was reported by Esther Race from INSERM, Paris [1].
Wild type HIV and recombinants resistant to 3TC only, ZDV only and 2 recombinants displaying multiple NRTI resistance were measured for infectivity in the presence of HU and ddI using log fold dilutions of ddI (from 0.01 to 100 mM) and half log dilutions of HU (from 1 to 300 mM).
In wild type HIV and the two isolates resistant to either ZDV or 3TC, HU significantly reduced the IC50 of ddI, with maximum decreases of 8.6, 10.7 and 9.6 fold respectively. However, in the two multidrug-resistant HIV variants the enhancing effect of HU was less pronounced, with maximum decreases in the IC50 of ddI of 3.4 and 2.6 fold.
Noticing that in the multidrug-resistant viruses hydroxyurea appeared to exert an antiviral activity by itself (IC50 of 62 and 67 mM) it was decided to investigate the effect of HU alone on a wider panel of HIV. A total of 49 recombinant viruses (n=4 sensitive, n=14 resistant to 1 to 3 NRTIs, n=31 multi-NRTI resistant) were tested.
- In the NRTI sensitive viruses HU exerted no antiviral effect at concentrations up to 500 mM.
- In viruses resistant to between 1 and 3 NRTIs a limited antiviral effect was seen with a median IC50 of 156.5 mM.
- In viruses resistant to 4 to 5 NRTIs HU was significantly more active with a median IC50 of 73.5 mM. (28/31 of these viruses carried the double insert at codon 69 in RT).
The investigators concluded that hydroxyurea significantly reduces the infectivity of some multidrug-resistant HIV variants and hypothesise that the reduction in the intracellular pool of dNTP caused by HU selectively alters DNA polymerisation by HIV with poorly processive mutant reverse transcriptase. This finding could constitute the basis for a rational and targeted use of hydroxyurea in antiretroviral salvage therapy where multi-NRTI resistance is demonstrated.
Comment
It would appear that HU may be better used for patients with extensive NRTI resistant HIV. It is unfortunate that these advanced patients are less likely to tolerate hydroxyurea.
Reference:
- Paulous S, Race E & Clavel F. Activity of hydroxyurea on multidrug-resistant HIV-1 variants. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 13.