Leflunomide (Arava®), an immunomodulatory drug used for rheumatoid arthritis, may be able to boost the anti-HIV acitvity of AZT in a similar way to hydroxyurea’s effect on ddI and mycophenolic acid’s effect on abacavir, according to a study published in the July 25th issue of AIDS.
Researchers from the University Hospital of Zürich, Switzerland looked at peripheral blood mononuclear cells to assess the anti-HIV acitivity of leflunomide, and tonsillar lymphocytes to look at CD4 cell survival in the presence of the drug, and also compared it with various doses of hydroxyurea and mycophenolic acid. All tests were done in vitro.
Leflunomide decreased HIV replication by about 75% at the usual dose given for rheumatic disease (10-20 mg/day). This was similar to hydroxyurea but superior to mycophenolic acid. They also found that together leflunomide and mycophenolic acid have modest additive anti-HIV effects.
The researchers discovered that leflunomide reduces HIV replication in several ways. First of all, it lowers the amount of nucleotides available for HIV to use. Secondly, it also reduces the number of CD4 and CCR5 receptors, which are essential for HIV to bind to CD4 cells.
Even though, like hydroxyurea and mycophenolic acid, leflunomide is a cytostatic drug, this is not necessarily a barrier for use in people with CD4 cell counts well above 200 cells/mm3. This is because loss of CD4 cells is also linked to immune activation and immunomodulatory drugs may actually be beneficial by keeping the amount of activated CD4 cells at a lower level so that there are less CD4 cells for HIV to infect when it is replicating.
Leflunomide has the advantage of being cheap, at £46.50 for a month’s supply at either dose. There are some potential major drawbacks to using the drug for HIV disease, however. It is linked to often severe liver toxicity in the first six months of use in people using it for rheumatic disease. The likely additive burden on the liver of other antiretrovirals, particularly protease inhibitors, is a concern.
Although this is potentially exciting news, the authors conclude: “The challenges will be to determine whether leflunomide has in vivo anti-HIV activity and to identify clinical settings where it may be indicated. As suggested, leflunomide may serve as adjunct to AZT in patients with AZT-resistant HIV strains.”
Further information on this website
Hydroxyurea - overview
Discredited hydroxyurea back on the agenda - news story
Schläpfer E et al. Anti-HIV-1 activity of leflunomide: a comparison with mycophenolic acid and hydroxyurea. AIDS; 17(11):1613-1620, 2003