CURDLAN SULFATE (CRDS) IN A 21-DAY INTRAVENOUS TOLERANCE STUDY IN HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) AND CYTOMEGALOVIRUS (CMV) INFECTED PATIENTS - ANTI-CMV ACTIVITY WITH LOW TOXICITY

This study evaluated tolerance (and possible efficacy) for 21 days of i.v. administration at three dose levels of curdlan sulfate (CRDS) (a semisynthetic sulfated polysaccharide), administered over 30 minutes, in HIV and CMV (in some cases) infected individual with CD4 levels < 5 00 cells/mm(3). Half of the subjects were previously treated with reve rse transcriptase inhibitors (RTI) (which were continued during the CR DS administration) and half the patients had no prior RTI treatment. E valuation of other sulfated polysaccharides in HIV had been discontinu ed due to side effects and lack of activity. Three groups of HIV patie nts (also including subsets with CMV infection) were treated separatel y with 50 mg/70 Kg, 100 mg/70 Kg and 200 mg/70 Kg of CRDS infused i.v. over thirty minutes daily for 21 days. In each dose group, half of th e patients selected were being treated with a RTI and half were on no RTI. Patients were monitored for CD4 cell levels, viral load in some c ases, and safety parameters in blood. Samples of urine and semen were additionally taken for CMV by culture and for PCR assay in subsets of participants. CRDS in this 21 day study was well-tolerated and produce d few reportable side effects. Systematic decreases in platelets and i ncreases in p24 antigen previously seen with dextran sulfate were not observed in this study with CRDS. In the 21 patients testing positive for CMV at the start of the study, 12 were CMV negative at the end of 21 days. In an untreated historical control group, 0/36 went from CMV positive to negative over a period of 13-15 years. The anti-CMV activi ty of CRDS in this study, therefore, had a p value < 0.001, based on t hese historical controls. The marked temporary increases in CD4 levels seen in the single dose and the seven-day CRDS studies on HIV patient s were also seen for 21 days in the current study (p = 0.0001). Treatm ent with CRDS seems promising against CMV in HIV infected patients, ev en with once daily dosing of this two-hour half-life drug. CRDS was we ll tolerated and its lack of toxicity makes it an attractive candidate for CMV-infected HIV patients. Multiple daily dosing, or the continuo us infusion of CRDS, could lead to increased effectiveness against bot h HIV and CMV, especially in combination with other agents. Given the toxicity of existing anti-CMV agents, and considering the emerging imp ortance of CMV in atherosclerotic disease, further studies on CRDS are warranted.