Ro 24-7429 is a drug related to valium which is thought to inhibit the action of an HIV gene called tat.

The HIV tat gene produces a protein (also called Tat) which greatly increases the growth efficiency of the virus; when that tat gene is inhibited in the test-tube, HIV essentially ceases to produce new virus or infect other cells. Researchers therefore believe that drugs that block this gene product may be effective treatments for people with HIV. There is also evidence that the tat protein stimulates the growth of Kaposi's sarcoma cells; tat-inhibitors may therefore also help people with KS. Tat may also be implicated in the development of progressive multifocal leukoencephalopathy (PML).

Preliminary tests have suggested that it may be more difficult for HIV to develop resistance to an anti-tat drug in the same way it can become resistant to drugs like AZT, ddI and non-nucleoside anti-virals. This may be because a mutation which could get around the drug's effect could well be lethal to the virus.

Ro 24-7429 was developed by Roche Products Ltd.

Current use

Test-tube studies produced promising results; Ro 24-7429 was active against a wide range of HIV strains, including AZT-resistant virus. HIV strains that were resistant to the drug did not develop despite over 2 years of repeated exposure to the drug.

However, in the first human study of Ro 24-7429, no antiviral effects were seen at doses up to 300 mg/day. At higher doses the drug accumulates in the body and causes unacceptable side-effects. In August 1993 Roche announced that it was therefore abandoning the development of Ro 24-7429. The drugs lack of activity appears to have been due to it being bound to protein in the blood and therefore not entering infected cells at doses high enough to be effective.

More recent research showed that in the test-tube the effects of Ro 24-7429 were greatly enhanced when used in combination with oxpentifylline.

Current developments

Enthusiasm for tat inhibitors waned in the light of research presented at the Ninth International Conference on AIDS in Berlin in 1993. This suggested that the tat protein may not in fact be essential for HIV replication.

Key research

Lietman reported the results of a double-blind placebo-controlled dose-escalating safety and pharmacokinetics study of Ro 24-7429 in asymptomatic or mildly symptomatic HIV-positive men. Patients were randomized into three groups; 6 patients in each group received active drug and 3 received placebo. Patients received Ro 24-7429 15, 50 or 150 mg every 6 hours for 5 days. Nonlinear pharmacokinetics were observed at these doses. The apparent half-life ranged from 3.6 to 6.8 hours. Discoloured urine was observed in the patients receiving Ro 24-7429; no other adverse reactions attributable to the drug were observed.

Haubrich enrolled 96 participants with CD4 counts between 50-500 in a study comparing three doses of Ro 24-7429 (75 mg/day, 150 mg/day or 300 mg/day) to standard dose AZT or ddI (ACTG 213). After 12 weeks the study was terminated due to lack of antiviral activity of Ro 24-7429 at the doses studied, as reflected in falling CD4 count and increasing p24 antigen. Roche consequently discontinued the development of Ro 24-7429.

Georges reported that Ro 24-7429 is highly protein-bound and not likely to achieve active intracellular concentrations. The concept of Tat inhibition as treatment for HIV infection has therefore not yet been tested.

Hsu reported that after 2 years of repeated weekly passage of HIV in fresh CEM cells in the presence of Ro 24-7429, the virus did not develop resistance to the drug.

Serious side-effects (anorexia and malaise) were observed in some female monkeys receiving oral Ro 24-7429.

Biswas reported that in vitro the combination of Ro 24-7429 and oxpentifylline was synergistic, with maximal HIV inhibitory effects seen at concentrations low enough to avoid cytotoxicity.

References

Biswas DK et al. Co-operative inhibition of NF-kB and Tat-induced superactivation of human immunodeficiency virus type 1 long terminal repeat. PNAS USA 90:11044-11048, 1993.

Georges DL et al. The HIV-1 Tat antagonist Ro 24-7429 is highly protein bound and relatively inactive at physiological serum concentrations. 2nd National Conference on Human Retroviruses, Washington, abstract 480, 1995.

Haubrich RH et al. A randomised trial of the activity and safety of Ro 24-7429 (Tat antagonist) versus nucleoside for human immunodeficiency virus infection. J Inf Dis 172:1246-1252, 1995.

Hsu MC et al. Inhibition of type 1 human immunodeficiency virus replication by a tat antagonist to which the virus remains sensitive after prolonged exposure in vitro. PNAS USA 90(14):6395-6399, 1993.

Lietman PS et al. Pharmacokinetics, safety, and tolerance of a TAT antagonist. 8th International Conference AIDS, Amsterdam, abstract MoB 0021, 1992.

Nelbock P et al. A cDNA for a protein that interacts with the human immunodeficiency virus tat transactivator. Science 248(4963):1650-1653, 1990.

Witvrouwa M et al. Cell type-specific anti-human immunodeficiency virus type 1 activity of the transactivation inhibitor Ro5-3335. Antimicrobial Agents & Chemotherapy 36:2628-2633, 1992.