Reduction of the viral load of HIV-1 after the intraperitoneal administration of dextrin 2-sulphate in patients with AIDS.
OBJECTIVE
To determine the safety and efficacy of the sulphated polysaccharide, dextrin 2-sulphate, when delivered to the lymphatic circulation by the peritoneal route.


METHODS
An open Phase I/II dose-escalation clinical study in which six patients with AIDS were treated with seven courses of dextrin 2-sulphate each lasting 1 month.


METHODS
During each course of treatment, the drug was administered daily for 28 days using an intraperitoneal catheter. Viral load was measured at frequent intervals using a plasma tissue culture infectious dose (TCID) assay, a cellular TCID assay, p24 antigenaemia, HIV-1 RNA and HIV-1 DNA. Plasma beta-chemokine levels were also measured.


RESULTS
Dose escalation was completed without toxicity. A total of 7 patient-months of treatment were completed. With increasing doses of dextrin 2-sulphate, the infectious plasma viraemia, cellular viraemia and p24 antigenaemia all fell during the period of drug administration, but with no significant change in HIV-1 RNA. This was associated with increased plasma levels of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. Dextrin 2-sulphate accumulated in peritoneal macrophages and induced the release of MIP-1alpha and MIP-1beta from these cells in vitro. These beta-chemokines could have augmented the cell surface-mediated anti-HIV-1 effect of dextrin 2-sulphate in vivo by binding to and blocking the CC-chemokine receptor-5. A second fall in infectious plasma viraemia, cellular viraemia, p24 antigenaemia and HIV-1 RNA was seen at day 100 which was then sustained for several months. A clinical improvement in Kaposi's sarcoma was also seen.


CONCLUSIONS
Our results suggest that the intraperitoneal administration of dextrin 2-sulphate can reduce the replication of HIV-1 in patients with AIDS. With increasing doses of dextrin 2-sulphate, the fall in viral load was seen during the period of drug administration and again 2 months after completing treatment.
Shaunak
S
S
Department of Infectious Diseases, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Thornton
M
M
John
S
S
Teo
I
I
Peers
E
E
Mason
P
P
Krausz
T
T
Davies
D S
DS
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy; D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology*; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003912:Dextrins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D007263:Infusions, Parenteral; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D012367:RNA, Viral / Q000097:blood; D012514:Sarcoma, Kaposi / Q000188:drug therapy; D016896:Treatment Outcome; D019562:Viral Load; D014766:Viremia
D019380:Anti-HIV Agents; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003912:Dextrins; D019402:Macrophage Inflammatory Proteins; D012367:RNA, Viral; C091377:dextrin 2-sulfate