Effect of a four-week course of interleukin-10 on cytokine production in a placebo-controlled study of HIV-1-infected subjects.

Interleukin (IL)-10 suppresses synthesis of the pro-inflammatory cytokines tumor necrosis factor (TNF)alpha, IL-1beta, and interferon (IFN)gamma. Since pro-inflammatory cytokines have been implicated in the production of human immunodeficiency virus type 1 (HIV-1), cytokine synthesis in whole blood cultures were determined during a 4-week course of subcutaneous IL-10 injections in 33 HIV-1-infected patients. Patients were randomized into four groups: placebo (nine), IL-10 at 1 microg/kg/day (nine), IL-10 at 4 microg/kg/day (six) and IL-10 at 8 microg/kg three times per week (nine). Whole blood was obtained at the beginning and conclusion of the study and was stimulated for 24 hours with the combination of IL-18 plus lipopolysaccharide. TNFalpha production in stimulated whole blood was reduced three and six hours after the first injection of IL-10 compared to subjects injected with the placebo. After four weeks of treatment, production of IFNgamma was suppressed in a greater number of patients in the IL-10 treatment groups compared to subjects in the placebo group. Similarly, IL-1beta production was lower in the IL-10 treatment groups compared to subjects receiving placebo. In contrast, after four weeks of IL-10, circulating levels of the anti-inflammatory TNF soluble receptor p55 increased dose-dependently compared to placebo subjects. Patient heterogeneity and small sample size presented difficulties in establishing statistical significance. Although the cytokine changes in our study did not demonstrate statistically significant changes, the data nevertheless reveal that four weeks of IL-10 therapy in HIV-1 infected subjects produced the anticipated suppression of pro-inflammatory cytokines.

High dose oral ganciclovir treatment for cytomegalovirus retinitis.

BACKGROUND: The oral formulation of ganciclovir is approved at a dose of 3.0 g/day for maintenance treatment of cytomegalovirus (CMV) retinitis following an initial induction course of intravenous (IV) anti-CMV therapy. Median time to progression of CMV retinitis is 12-20 days shorter with oral compared to IV ganciclovir maintenance, likely due to the limited oral bioavailability of ganciclovir. OBJECTIVES: We hypothesized that higher systemic drug exposures associated with increased doses of oral ganciclovir would be associated with increased efficacy. STUDY DESIGN: Maintenance treatment of CMV retinitis with higher than standard doses of oral ganciclovir (>3.0 g/day) was studied in 281 AIDS patients with previously treated, stable retinitis randomized to 3.0, 4.5 or 6.0 g/day oral, or 5 m/kg/day IV ganciclovir. Graders unaware of treatment assignments determined retinitis progression using fundus photographs. Vision, other ophthalmic measures and safety were assessed open-label. RESULTS: Median days to photographic progression were 41, 50, 57 and 70, respectively (P=0.052; 3.0 g vs. IV). Hazard ratios for progression relative to IV were 1.66, 1.28 and 1.19 (P=0.016 for 3.0 g). NONMEM-modeled estimates of average serum ganciclovir concentration area under the curve (AUC(0-24)) correlated best with time to progression (P=0.0019). Six grams per day oral ganciclovir was most similar in efficacy to IV, although broad confidence intervals prevented a conclusive comparison. Patients receiving oral ganciclovir had a lower frequency of sepsis and IV catheter events. CONCLUSIONS: This study suggests that the efficacy of ganciclovir for the maintenance treatment of CMV retinitis improves with increasing total drug exposure (measured as average serum concentration AUC(0-24)). All four regimens of ganciclovir were reasonably well tolerated, with safety profiles similar to what has been reported in prior work.