Pharmacokinetics and tolerability of intravenous trecovirsen (GEM 91), an antisense phosphorothioate oligonucleotide, in HIV-positive subjects.

Trecovirsen, a 25-mer antisense phosphorothioate oligonucleotide targeted at the gag site of the HIV gene, was administered to HIV-positive volunteers as an i.v. infusion. Single doses ranged from 0.1 to 2.5 mg/kg in an ascending escalation in cohorts of 6 to 12 subjects. Plasma trecovirsen concentrations and pharmacokinetic parameters could be assessed at doses > or = 0.3 mg/kg. Peak plasma concentrations and AUC values increased disproportionately with increasing dose while elimination half-life increased and plasma clearance decreased, indicating a saturable process over this dose range. The only significant adverse event observed was an isolated, transitory increase in activated partial thromboplastin time at doses > or = 2.0 mg/kg that was related to plasma trecovirsen concentrations and is attributed to the polyanionic character of the molecule. Thus, trecovirsen administration was well tolerated in single i.v. doses up to 2.5 mg/kg.

Toxoplasma gondii infection in advanced HIV infection.

OBJECTIVE: To study Toxoplasma encephalitis (TE) in advanced HIV infection, including predictive factors, possible prophylactic regimens and impact on survival. DESIGN: Epidemiological analysis of data collected prospectively during the Alpha study, a double-blind, randomized clinical trial, comparing two doses of dideoxyinosine in patients with advanced HIV disease. PATIENTS: First episode of TE occurred in 75 out of 499 patients participating in the trial. METHODS: Kaplan-Meier estimates and semi-parametric Cox's model were used. RESULTS: A low CD4 cell count and a positive Toxoplasma serology were strongly predictive of the occurrence of TE. In patients with CD4 counts < 100 x 10(6)/l and a positive Toxoplasma serology at entry to the study, the 12-month TE incidence was 25.4%. Patients who were receiving at entry any of the following potentially antitoxoplasmic drugs: trimethoprim-sulphamethoxazole, pyrimethamine, dapsone, pyrimethamine-sulphadoxine or sulphadiazine, had a lower TE incidence than those who were not; 6.2 versus 18.8%, respectively (P < 0.001). The rate of survival 12 months after TE was 29.6%. Even after adjusting the major prognostic covariates, TE was predictive of death (P < 0.001; relative risk, 1.8). CONCLUSIONS: The high HIV incidence, morbidity and mortality in high-prevalence areas suggests that primary prophylaxis should be given in patients at high risk for toxoplasmic reactivation.

Long-term follow-up of patients with AIDS on maintenance therapy for toxoplasmosis.

To assess potential interactions of multiple drug regimens administered to patients with AIDS for toxicity and efficacy, we reviewed the charts of 35 patients on maintenance therapy for toxoplasmosis. Seven relapses of toxoplasmosis occurred in 6 of 35 (17%) patients, and seven episodes of pneumocystosis occurred in 6 of 35 (17%) patients. Four relapses of toxoplasmosis and 5 relapses of pneumocystosis were seen in 20 patients treated with pyrimethamine/clindamycin; 2 relapses of toxoplasmosis and 2 relapses of pneumocystosis were seen in 11 patients treated with pyrimethamine alone, and 1 relapse of toxoplasmosis was seen in 13 patients treated with pyrimethamine/sulfadiazine. Adverse effects were related to pyrimethamine in 10 patients, to clindamycin in 7 patients, and to sulfadiazine in 8 patients. These results must be compared with those of prospective trials to determine the efficacy and safety of various maintenance regimens.