Pharmacokinetics of Saquinavir, Atazanavir, and Ritonavir in a Twice-Daily Boosted Double-Protease Inhibitor Regimen

The objective of this study was to evaluate the pharmacokinetics of atazanavir (ATV), saquinavir (SQV), and ritonavir (RTV) in a boosted double-protease inhibitor (PI) therapy regimen without reverse transcriptase inhibitors (RTIs). The study design was as follows. Patients with limited RTI options received a PI combination of 300/100 mg ATV/RTV once daily and 1,000 mg SQV twice daily (group 1; n = 49) without RTI comedication. The results were compared to the plasma concentrations of PIs of patients taking either 300 mg ATV/100 mg RTV once daily plus RTIs (group 2; n = 72) or patients taking 1,000 mg SQV/100 mg RTV plus RTIs (group 3; n = 90). The study methods were as follows. Patients were given a 12/24-h pharmacokinetic assessment at steady state. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry. The minimum and maximum concentrations (C(min) and C(max)), area under the concentration-time curve under steady-state conditions (AUC(ss)), elimination half-life, time of maximum concentration and lag time were subject to statistical analysis. The results show that patients treated with ATV/SQV/RTV exhibited significantly high SQV concentrations and moderate enhancement of the AUC(ss) of ATV in comparison to those of patients of the control groups: for SQV in groups 1 and 3, the geometric mean (GM) of the AUC(ss) was 22,794 versus 15,759 ng·h/ml (GM ratio [GMR] = 1.45; P < 0.05), the GM of the C(max) was 3,257 versus 2,331 ng/ml (GMR = 1.40; P < 0.05), and the GM of the C(min) was 438 versus 437 ng/ml (GMR = 1.00); for ATV in groups 1 and 2, the GM of the AUC(ss) was 39,154 versus 33,626 ng·h/ml (GMR = 1.16), the GM of the C(max) was 3,488 versus 2,924 ng/ml (GMR = 1.20), and the GM of the C(min) was 515 versus 428 ng/ml (GMR = 1.21). RTV levels were comparable for all groups. A subgroup analysis detected only marginal differences in ATV plasma exposure if combined with tenofovir-disoproxilfumarate and without it. We conclude that our pharmacokinetic results support the use of a boosted double-PI regimen of ATV/SQV/RTV as a treatment option for patients who need antiretroviral therapy without RTIs

Mortality of HIV-infected patients starting potent antiretroviral therapy: comparison with the general population in nine industrialized countries

BACKGROUND: Mortality in HIV-infected patients has declined substantially with combination antiretroviral therapy (ART), but it is unclear whether it has reached that of the general population. We compared mortality in patients starting ART in nine countries of Europe and North America with the corresponding general population, taking into account their response to ART. METHODS: Eligible patients were enrolled in prospective cohort studies participating in the ART Cohort Collaboration. We calculated the ratio of observed to expected deaths from all causes [standardized mortality ratio (SMR)], measuring time from 6 months after starting ART, according to risk group, clinical stage at the start of ART and CD4 cell count and viral load at 6 months. Expected numbers of deaths were obtained from age-, sex- and country-specific mortality rates. RESULTS: Among 29 935 eligible patients, 1134 deaths were recorded in 131 510 person-years of follow-up. The median age was 37 years, 8162 (27%) patients were females, 4400 (15%) were injecting drug users (IDUs) and 6738 (23%) had AIDS when starting ART. At 6 months, 23 539 patients (79%) had viral load measurements or=350 cells/microL and suppressed viral replication to 10 were 4, 14 and 47%. CONCLUSIONS: In industrialized countries, the mortality experience of HIV-infected patients who start ART and survive the first 6 months continues to be higher than in the general population, but for many patients excess mortality is moderate and comparable with patients having other chronic conditions. Much of the excess mortality might be prevented by earlier diagnosis of HIV followed by timely initiation of ART

Importance of Baseline Prognostic Factors With Increasing Time Since Initiation of Highly Active Antiretroviral Therapy: Collaborative Analysis of Cohorts of HIV-1-Infected Patients

Background: The extent to which the prognosis for AIDS and death of patients initiating highly active antiretroviral therapy (HAART) continues to be affected by their characteristics at the time of initiation (baseline) is unclear. Methods: We analyzed data on 20,379 treatment-naive HIV-1- infected adults who started HAART in 1 of 12 cohort studies in Europe and North America (61,798 person-years of follow-up, 1844 AIDS events, and 1005 deaths). Results: Although baseline CD4 cell count became less prognostic with time, individuals with a baseline CD4 count 350 cells/μL (hazard ratio for AIDS = 2.3, 95% confidence interval [CI]: 1.0 to 2.3; mortality hazard ratio = 2.5, 95% CI: 1.2 to 5.5, 4 to 6 years after starting HAART). Rates of AIDS were persistently higher in individuals who had experienced an AIDS event before starting HAART. Individuals with presumed transmission by means of injection drug use experienced substantially higher rates of AIDS and death than other individuals throughout follow-up (AIDS hazard ratio = 1.6, 95% CI: 0.8 to 3.0; mortality hazard ratio = 3.5, 95% CI: 2.2 to 5.5, 4 to 6 years after starting HAART). Conclusions: Compared with other patient groups, injection drug users and patients with advanced immunodeficiency at baseline experience substantially increased rates of AIDS and death up to 6 years after starting HAART

A Controlled Clinical Trial of E5 Murine Monoclonal IgM Antibody to Endotoxin in the Treatment of Gram-Negative Sepsis

Objective. —To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with gram-negative sepsis. Design. —Double-blind, randomized, placebo-controlled trial. Setting. —Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals. Patients. —Hospitalized adults with signs of gram-negative infection and a systemic septic response. Intervention. —Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against gram-negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later. Main Outcome Measures. —Mortality over the 30-day study period, resolution of organ failures, and safety. Results. —Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed gram-negative sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with gram-negative sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P =.01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group (P =.05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified. Conclusions. —Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with gram-negative sepsis who are not in shock when treated.(JAMA. 1991;266:1097-110

A Controlled Clinical Trial of E5 Murine Monoclonal IgM Antibody to Endotoxin in the Treatment of Gram-Negative Sepsis

Objective. —To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with gram-negative sepsis. Design. —Double-blind, randomized, placebo-controlled trial. Setting. —Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals. Patients. —Hospitalized adults with signs of gram-negative infection and a systemic septic response. Intervention. —Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against gram-negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later. Main Outcome Measures. —Mortality over the 30-day study period, resolution of organ failures, and safety. Results. —Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed gram-negative sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with gram-negative sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P =.01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group (P =.05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified. Conclusions. —Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with gram-negative sepsis who are not in shock when treated.(JAMA. 1991;266:1097-110

Importance of Baseline Prognostic Factors With Increasing Time Since Initiation of Highly Active Antiretroviral Therapy: Collaborative Analysis of Cohorts of HIV-1-Infected Patients

Background: The extent to which the prognosis for AIDS and death of patients initiating highly active antiretroviral therapy (HAART) continues to be affected by their characteristics at the time of initiation (baseline) is unclear. Methods: We analyzed data on 20,379 treatment-naive HIV-1- infected adults who started HAART in 1 of 12 cohort studies in Europe and North America (61,798 person-years of follow-up, 1844 AIDS events, and 1005 deaths). Results: Although baseline CD4 cell count became less prognostic with time, individuals with a baseline CD4 count 350 cells/μL (hazard ratio for AIDS = 2.3, 95% confidence interval [CI]: 1.0 to 2.3; mortality hazard ratio = 2.5, 95% CI: 1.2 to 5.5, 4 to 6 years after starting HAART). Rates of AIDS were persistently higher in individuals who had experienced an AIDS event before starting HAART. Individuals with presumed transmission by means of injection drug use experienced substantially higher rates of AIDS and death than other individuals throughout follow-up (AIDS hazard ratio = 1.6, 95% CI: 0.8 to 3.0; mortality hazard ratio = 3.5, 95% CI: 2.2 to 5.5, 4 to 6 years after starting HAART). Conclusions: Compared with other patient groups, injection drug users and patients with advanced immunodeficiency at baseline experience substantially increased rates of AIDS and death up to 6 years after starting HAART