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The safety and efficacy of cidofovir gel for treatment of acyclovir-unresponsive herpes simplex virus infections in AIDS patients was evaluated in a randomized, double-blind, multicenter trial. Cidofovir (0.3% or 1%) or placebo gel was applied once daily for 5 days. Ten of 20 cidofovir-treated and none of 10 placebo-treated patients had complete healing or >50% decreased area (P = .008); 30% of cidofovir-treated patients versus 0 placebo recipients had complete healing (P = .031). Viral shedding ceased in 13 (87%) of 15 cidofovir-treated and 0 of 9 placebo-treated patients (P = .00004). For cidofovir-treated patients, median time to complete or good response was 21 days, and median time to negative viral culture was 2 days (P = .025, P = .0001, respectively). Median lesion area decreases were 58% for cidofovir-treated versus 0 for placebo-treated patients (P = .005), and mean pain score changes were -1.84 versus -0.34 (P = .042). Application site reactions occurred in 25% of cidofovir-treated and 20% of placebo-treated patients; none was dose-limiting. Cidofovir therapy provided significant benefits in lesion healing, virologic effect, and pain reduction. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether supplementation with alpha-lipoic acid (ALA), a glutathione-replenishing disulfide, modulates whole blood total glutathione (GSH + GSSG) levels and improves lymphocyte function in human immunodeficiency virus (HIV)-infected subjects with history of unresponsiveness to highly active antiretroviral treatment (HAART). Design and setting: Randomized, double-blinded, placebo-controlled trial conducted at two study sites: an eye clinic at a county hospital in San Jose and a research clinic in San Francisco, California. Subjects: A total of 33 HIV-infected men and women with viral load > 10,000 copies/cm(3), despite HAART, aged 44-47 years, approximately 36% nonwhite, were enrolled. Intervention: Patients were randomly assigned to receive either ALA (300 mg three times a day) or matching placebo for 6 months. Main outcome measures: The change over 6 months in blood total glutathione status, lymphocyte proliferation response to T-cell mitogens, CD4 cell count, and viral load in patients receiving ALA compared to placebo. Results: The mean blood total glutathione level in ALA-supplemented subjects was significantly elevated after 6 months (1.34 +/- 0.79 vs. 0.81 +/- 0.18 mmol/L) compared to insignificant change (0.76 +/- 0.34 vs. 0.76 +/- 0.22 mmol/L) in the placebo group (ALA vs. placebo: p = 0.04). The lymphocyte proliferation response was significantly enhanced or stabilized after 6 months of ALA supplementation compared to progressive decline in the placebo group (ALA vs. placebo: p < 0.001 with phytohemagglutinin; p = 0.02 with anti-CD3 monoclonal antibody). A positive correlation was seen between blood total glutathione level and lymphocyte response to anti-CD3 stimulation (R(2) = 0.889). There was no significant change in either HIV RNA level or CD4 count over 6 months in the ALA-supplemented compared to the control group. Conclusion: Supplementation with alpha-lipoic acid may positively impact patients with HIV and acquired immune deficiency syndrome by restoring blood total glutathione level and improving functional reactivity of lymphocytes to T-cell mitogens. [ABSTRACT FROM AUTHOR]

BACKGROUND: HGS004 is a fully human immunoglobulin (Ig) G4 monoclonal antibody against CC chemokine receptor 5 (CCR5) with robust in vitro activity against a diverse panel of CCR5-tropic human immunodeficiency virus type 1 (HIV-1) isolates. METHODS: A single-blind, randomized, placebo-controlled study was conducted in patients infected with CCR5-tropic HIV-1 to evaluate the safety, pharmacokinetics, and antiviral activity of HGS004. Sixty-three subjects were randomized into 5 dose cohorts (0.4, 2, 8, 20, and 40 mg/kg) and received a single intravenous dose of HGS004 or placebo. RESULTS: HGS004 was well tolerated, and no dose-limiting toxicities were observed. Pharmacokinetics were nonlinear across the 0.4-40-mg/kg dose range, with dose-proportional increases in maximum concentration, although the area under the curve increased more than proportionally to dose. High levels of receptor occupancy were observed for up to 28 days in the higher-dose cohorts. Plasma HIV-1 RNA reductions of >1 log(10) at day 14 were observed in 14 (54%) of 26 subjects in the 8-, 20-, and 40-mg/kg cohorts. In the 40-mg/kg cohort, 4 of 10 subjects had a >1 log(10) HIV-1 RNA reduction at day 28. Drug concentrations relative to isolate sensitivity (the ratio of the concentration at day 14 to IC(90)) predicted antiviral response on day 14. CONCLUSIONS: HGS004 is safe and well tolerated and demonstrates meaningful antiviral activity when administered to patients infected with CCR5-tropic HIV-1. Copyright © 2008 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety and efficacy of zalcitabine (also known as dideoxycytidine [ddC]) in patients with advanced human immunodeficiency virus (HIV) infection.Design: Open-label, randomized study.Setting: AIDS Clinical Trials Units, university-affiliated medical centers, and private practice groups.Patients: Patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex who had tolerated zidovudine for 48 weeks or more.Intervention: Fifty-nine patients received zidovudine (500 to 1200 mg/d) and 52 patients received zalcitabine (2.25 mg/d).Measurements: The primary end points were survival and time to an AIDS-defining event or death.Results: Because significantly more patients withdrew from zidovudine therapy, the median duration of treatment was greater in the zalcitabine group than in the zidovudine group (279.0 days compared with 174.5 days; P = 0.001). The estimated 12-month, event-free probabilities were 53% for the zalcitabine group and 57% for the zidovudine group (relative risk, 1.02; 95% CI, 0.5 to 2.2). The estimated 12-month survival rates were 81% for the zalcitabine group and 75% for the zidovudine group (relative risk, 1.39; CI, 0.5 to 3.8). The rate of decline in CD4 lymphocyte counts was significantly slower in the zalcitabine group than in the zidovudine group (-0.08 cells/day compared with -0.17 cells/day). Patients in the zalcitabine group had gained an average of 0.5 kg at week 20 and 0.4 kg at week 24, whereas patients in the zidovudine group had lost an average of 1.8 kg at week 20 and 2.4 kg at week 24 (P = 0.04 and P = 0.05, respectively). Moderate to severe peripheral neuropathy and ulcerative stomatitis occurred in 10 and 9 patients, respectively, in the zalcitabine group.Conclusions: The sample size for this study was smaller than planned, and no differences in survival and clinical end points were found. Slower rates of decline in CD4 lymphocyte counts and weight, however, were noted for the zalcitabine group. [ABSTRACT FROM AUTHOR]

Blood culture isolates from patients receiving first-(peripheral retinitis) or second-line (relapsing retinitis) therapy with intravenous cidofovir were obtained from three clinical trials for in vitro antiviral susceptibility analyses. Isolates from 6 patients obtained after 14.3 weeks (mean) of first-line cidofovir therapy showed complete susceptibility to cidofovir, ganciclovir, and foscarnet. Isolates from 20 patients were obtained after 17.3 weeks (mean) of second-line cidofovir therapy. Ten showed complete susceptibility to all inhibitors, 3 showed low-level ganciclovir resistance (< 6-fold) but were sensitive to cidofovir and foscarnet, and 7 showed moderately reduced susceptibility (< 8-fold) to cidofovir and high-level resistance (8- to 23-fold) to ganciclovir in vitro. Four of these 7 isolates showed reduced susceptibility (4-fold) to foscarnet. Notably, there was no difference in time to retinitis progression in patients that were on cidofovir therapy when sensitive isolates were compared with those showing reduced susceptibility to cidofovir in vitro. [ABSTRACT FROM PUBLISHER]

Cidofovir [1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine] susceptibility among 29 paired pre- and post-cidofoVir exposure isolates from 22 patients enrolled in a phase I/II clinical trial, GS-92-101, was determined. This trial was designed to evaluate the safety and antiviral effects of cidofovir in patients with AIDS and asymptomatic shedding of human cytomegalovirus (HCMV) in semen with no evidence of end-organ HCMV disease and no prior anti-HCMV therapy. These patients received a median cumulative dose of 30 mg/kg (range, 3–67) administered over a median of 8 weeks (range, 238). The IC50 values for preexposure isolates ranged from <0.5 to 1.85 and for postexposure isolates from <0.5 to 2 µM. Thus, no significant changes in cidofoVir susceptibilities have been noted for HCMV during the various regimens of cidofovir administrated in this clinical trial. [ABSTRACT FROM PUBLISHER]

Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, is a novel antiviral nucleotide analogue with potent in vitro and in vivo activity against cytomegalovirus (CMV) and other herpesviruses. Thirty-one human immunodeficiency virus-seropositive patients with asymptomatic CMV excretion were evaluated in a phase Ijll study with 2 regimens of cidofovir: cidofovir alone at doses of 0.5, 1.0, 3.0, or 10.0 mg/kg/week (20 patients) and cidofovir at 3.0, 5.0, or 7.5 mg/kg with concomitant oral probenecid, saline prehydration, extended dosing intervals, and drug interruption for proteinuria (19 patients). Prolonged and dose-dependent anti-CMV effect was observed with all cidofovir regimens ⩾3.0 mg/kg. The dose-limiting toxicity of cidofovir was dose- and schedule-dependent nephrotoxicity. Four of20 patients had serum creatinine levels ⩾2.0 mg/dL after a mean cumulative exposure of 14.8 mg/kg cidofovir alone; however, none of 19 patients receiving the modified regimen had elevated creatinine (mean cidofovir exposure, 32.2 rug/kg). The clinical efficacyof cidofovir and its potential for cumulative nephrotoxicity needs further study in patients with end-organ CMV disease. [ABSTRACT FROM PUBLISHER]