Dextran sulphate is a drug that was developed as an anti-coagulant to delay clotting of blood in people who had heart disease or strokes. It has been used orally in Japan and intravenously in Britain as a treatment for hyperlipidemia (excess fat in the blood). Coincidentally, it was also found to prevent the formation of syncytia in the test-tube. Syncytia are clumps of T-cells which form when uninfected cells gather around one or more HIV-infected cell.

Other drugs which belong to the same chemical family as dextran sulphate are the sulphated polysaccharides. These include heparin sulphate, pentosan polysulphate, chondroitin sulphate and sulphated polyvinyl alcohol. The sulphated polysaccharides, particularly dextrin 2-sulphate, have been shown to bind with the HIV 'tat' protein in vitro, thus inhibiting HIV replication (Watson

Effectiveness and side-effects

Because it was available over the counter in Japan, orally-taken dextran sulphate was a popular underground drug in the USA. Two formal trials found that very little dextran sulphate was absorbed into the body orally and the drug therefore had no effect against HIV (except possibly in the gut).

Researchers therefore tested an intravenous version of the drug. However, no antiviral effects were seen; if anything, p24 antigen levels increased. The emergence of resistance mutations may explain the lack of anti-HIV activity (Este).

The drug caused serious thrombocytopenia, a shortage of platelets in the blood which can cause potentially fatal bleeding problems.

Current developments

A trial of a closely related drug, dextrin-2-sulphate, is currently under way in London and Brighton. This is being studied in the form of an infusion delivered into the body cavity. In a small pilot study, it seemed to lead to reductions in the amount of infectious HIV in the blood.

Key research

Dextran sulphate's anti-HIV activity in two T-lymphocyte cell lines was reported by Ueno and confirmed by Mitsuya.

Abrams conducted a phase I trial of oral dextran sulphate in people with AIDS/ARC followed by an ACTG phase I/II trial. Laboratory study indicated the drug was poorly absorbed and no overall antiviral effect or improvement in immune function was observed. A study by Lorentsen comparing oral with IV administration further supported the findings of Abrams.

Hiebert, however, reported that after oral dosing (4 g/day for 5 days), dextran sulphate could be found in plasma and in 7/20 lymphocyte samples. When dextran sulphate was administered orally to HIV-positive persons (1 g four times daily) for up to 4 months, the drug was detected in plasma, lymphocytes and urine when examined at monthly intervals.

Flexner administered the maximally tolerated dose of dextran sulphate by continuous intravenous infusion to 10 people with symptomatic HIV infection for up to 14 days. Drug concentrations were up to 200-fold greater than the IC₅₀ for free HIV infectivity in vitro. Circulating p24 antigen levels increased in 8/8 people treated for longer than 3 days (median proportional increase 73.5%; range 32-130%). This increase was highly significant when compared with a large cohort of untreated historical controls. Continuous intravenous infusion was toxic, producing profound but reversible thrombocytopenia in 8/8 people treated for longer than 3 days and extensive but reversible alopecia in 5/8.

Shaunak treated six people with AIDS with seven 1-month dose-escalating courses of dextrin 2-sulphate, delivered to the lymphatic circulation using a peritoneal catheter. At increasing doses, infectious HIV plasma viraemia and p24 antigenaemia fell, but there was no change in HIV RNA levels.

Watson reported in vitro research which showed the interaction of recombinant HIV proteins with sulphated polysaccharides. Dextrin 2-sulphate (D2S) bound strongly to HIV-1 tat (EC50 = 0.10 microg/ml), less strongly to CD4 (EC50 = 0.33 microg/ml), weakly to HIV vif and gp160, and not at all to HIV gp120 or p24.

Este reported mutations in the gp120 glycoprotein which led to resistance to dextran sulfate and cross-resistance to other polyanionic compounds.

References

Abrams D I et al. Oral dextran sulphate (UA001) in the treatment of AIDS and AIDS-related complex. Annals of Internal Medicine 110: 183-188, 1989.

Este JA et al. Development of resistance of human immunodeficiency virus type 1 to dextran sulfate associated with the emergence of specific mutations in the envelope gp120 glycoprotein. Molecular Pharmacology 52(1): 98-104, 1997.

Flexner C et al. Pharmacokinetics, toxicity and activity of intravenous dextran sulfate in human immunodeficiency virus infection. Antimicrobial Agents & Chemotherapy 35(12): 2544-2550, 1991.

Hiebert L et al. Orally administered dextran sulphate is absorbed in HIV-positive individuals. Journal of Laboratory and Clinical Medicine 133(2): 161-170, 1999.

Lorentsen K J et al. Dextran sulphate is poorly absorbed after oral administration. Annals of Internal Medicine 111(7): 561-566, 1989.

Mitsuya H et al. Dextran sulphate suppression of viruses in the HIV family: inhibition of virion binding to CD4+ cells. Science 240(4852): 646-649, 1988.

Shaunak S et al. Reduction of the viral load of HIV-1 after the intraperitoneal administration of dextrin 2-sulphate in patients with AIDS. AIDS 12: 399-409, 1998.

Ueno R et al. Dextran sulphate, a potent anti-HIV agent in vitro having synergism with zidovudine. Lancet i(8546):1379, 1987.

Watson K et al. Interaction of the transactivating protein HIV-1 tat with sulphated polysaccharides. Biochemical Pharmacology 57(7): 775-83, 1999.