Attenuation of the bacterial load in blood by pretreatment with granulocyte-colony-stimulating factor protects rats from fatal outcome and brain damage during Streptococcus pneumoniae meningitis.

A model of pneumococcal meningitis in young adult rats receiving antibiotics once the infection was established was developed. The intent was to mimic clinical and histopathological features of pneumococcal meningitis in humans. The primary aim of the present study was to evaluate whether medical boosting of the peripheral neutrophil count affected the outcome of the meningitis.

Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes.

Background: Treatment strategies for patients in whom HIV replication is not suppressed after exposure to several drug classes remain unclear. We aimed to assess the inter-relations between viral load, CD4-cell count, and clinical outcome in patients who had experienced three-class virological failure.

Methods: We undertook collaborative joint analysis of 13 HIV cohorts from Europe, North America, and Australia, involving patients who had had three-class virological failure (viral load >1000 copies per mL for >4 months).

The changing pattern of Kaposi sarcoma in patients with HIV, 1994-2003: the EuroSIDA Study.

Background: The introduction of highly active antiretroviral therapy (HAART) has radically changed the clinical course of human immunodeficiency virus (HIV) infection. The goals of the current study were to assess the change in the incidence of Kaposi sarcoma (KS) among European patients with HIV since the introduction of HAART and to identify the factors associated with the development of KS among patients receiving HAART.

Methods: The incidence of KS and the factors associated with the development of this malignancy in patients receiving HAART were evaluated using Poisson regression.

Predictors of immunological failure after initial response to highly active antiretroviral therapy in HIV-1-infected adults: a EuroSIDA study.

Background: Factors that determine the immunological response to highly active antiretroviral therapy (HAART) are poorly defined.

Objective: Our aim was to investigate predictors of immunological failure after initial CD4(+) response.

Methods: Data were from EuroSIDA, a prospective, international, observational human immunodeficiency virus (HIV) type 1 cohort.

Starting highly active antiretroviral therapy: why, when and response to HAART.

Highly active antiretroviral therapy (HAART) has dramatically improved the prognosis of patients with HIV, although it remains unclear as to the best time to start treatment to reduce the risk of clinical progression. The initial virological response to HAART, by reducing viral load to below the limit of detection, is essential for reducing the risk of drug resistance, which in the longer term may lead to a deterioration in immune function and an increased risk of clinical disease progression. There has been a switch to more conservative therapy recently, given concerns about toxicities and the difficulties of adhering to a complicated regimen long term.

Clinical trial methodology and clinical cohorts: the importance of complete follow-up in trials evaluating the virological efficacy of anti-HIV medicines.

Purpose Of Review: It has been common practice in randomized trials of HIV medicines to classify switches away from the original therapy as failures in analyses of virological effect, in line with an HIV-RNA measurement above a given level of quantification. This approach precludes the ability to identify the possible effects of a given therapy on those of a subsequent therapy. This review explores whether there have been changes in the reporting of randomized trials since the importance of continuous follow-up throughout the study period was initially raised 2 years ago.

Soluble urokinase receptor is elevated in cerebrospinal fluid from patients with purulent meningitis and is associated with fatal outcome.

The urokinase-type plasminogen activator system has been suggested to play a pathophysiological role in brain damage. The aim of this study was to evaluate CSF levels of suPAR in 183 patients clinically suspected of having meningitis on admission. Of these, 54 patients were found to have purulent meningitis, 63 had lymphocytic meningitis, 12 had encephalitis, and 54 patients were suspected of, but had no evidence of, meningitis.

Changing incidence of central nervous system diseases in the EuroSIDA cohort.

A drastic decrease in incidence has been observed for most human immunodeficiency virus (HIV)-related opportunistic manifestations after use of highly active antiretroviral therapy (HAART). We assessed the trend of incidence of central nervous system (CNS) diseases in a prospective multicenter observational study involving 9,803 patients across Europe in the period 1994 to 2002 and analyzed patient and treatment variables associated with these conditions. Overall, 568 patients (5.

A randomized trial comparing initial HAART regimens of nelfinavir/nevirapine and ritonavir/saquinavir in combination with two nucleoside reverse transcriptase inhibitors.

Background: A triple-class HAART regimen may be associated with a better virological effect than conventional regimens, but may also lead to toxicity and more profound resistance.

Methods: Randomized, controlled, open-label trial of 233 protease inhibitor- and non-nucleoside reverse transcriptase inhibitor-naive HIV-infected patients allocated to a regimen of nelfinavir and nevirapine (1250/200 mg twice daily; n = 118) or ritonavir and saquinavir (400/400 mg twice daily; n = 115), both in combination with two nucleoside reverse transcriptase inhibitors. The primary end-point was HIV RNA < or = 20 copies/ml after 48 weeks (missing value = failure).

Combination antiretroviral therapy and the risk of myocardial infarction.

Background: It remains controversial whether exposure to combination antiretroviral treatment increases the risk of myocardial infarction.

Methods: In this prospective observational study, we enrolled 23,468 patients from 11 previously established cohorts from December 1999 to April 2001 and collected follow-up data until February 2002. Data were collected on infection with the human immunodeficiency virus and on risk factors for and the incidence of myocardial infarction.

Anemia and survival in human immunodeficiency virus.

The prospective, multicenter cohort study EuroSIDA has previously reported on predictors and outcomes of anemia in patients infected with human immunodeficiency virus. In a Cox proportional-hazards model with serial measures of CD4+ cell count, plasma viral load, and degrees of anemia fitted as time-dependent variables, the relative hazard of death increased markedly for patients with anemia versus no anemia. A clinical scoring system was developed and validated for patients receiving highly active antiretroviral therapy using the most recent laboratory measures.

Low efficacy and high frequency of adverse events in a randomized trial of the triple nucleoside regimen abacavir, stavudine and didanosine.

Background: Highly active antiretroviral therapy containing three nucleoside reverse transcriptase inhibitors has been somewhat successful, but the clinical efficacy is unclear.

Methods: Randomized, controlled, open-label trial of 180 antiretroviral drug-naive HIV-infected patients allocated to a regimen of abacavir, stavudine and didanosine (A/S/D, n = 60), ritonavir and saquinavir (R/S 400/400 mg twice daily; n = 60) or nelfinavir and nevirapine (N/N 1250/200 mg twice daily; n = 60); the latter two in combination with lamivudine and zidovudine. The primary endpoint was HIV plasma RNA < or = 20 copies/ml after 48 weeks.

Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 Trial.

This trial assessed the rate of virological failure at 48 weeks in adult human immunodeficiency virus (HIV) type 1-infected patients assigned indinavir/ritonavir (Idv/Rtv; 800/100 mg 2 times daily) or saquinavir/ritonavir (Sqv/Rtv; 1000/100 mg 2 times daily) in an open-label, randomized (1:1), multicenter, phase 4 design. Three hundred six patients began the assigned treatment. At 48 weeks, virological failure was seen in 43 (27%) of 158 and 37 (25%) of 148 patients in the Idv/Rtv and Sqv/Rtv arms, respectively.

Virological rebound after suppression on highly active antiretroviral therapy.

OBJECTIVE To determine the rate of virological rebound and factors associated with rebound among patients on highly active antiretroviral therapy (HAART) with previously undetectable levels of viraemia. DESIGN An observational cohort study of 2444 patients from the EuroSIDA study. METHODS Patients were followed from their first viral load under 400 copies/ml to the first of two consecutive viral loads above 400 copies/ml.

Cardiovascular disease risk factors in HIV patients--association with antiretroviral therapy. Results from the DAD study.

Objective: To determine the prevalence of risk factors for cardiovascular disease (CVD) among HIV-infected persons, and to investigate any association between such risk factors, stage of HIV disease, and use of antiretroviral therapies.

Design: Baseline data from 17,852 subjects enrolled in DAD, a prospective multinational cohort study initiated in 1999.

Methods: Cross-sectional analyses of CVD risk factors at baseline.

K65R with and without S68: a new resistance profile in vivo detected in most patients failing abacavir, didanosine and stavudine.

Antiretroviral treatment with three nucleoside reverse transcriptase inhibitors (NRTIs) is widely used, but the combination of abacavir, didanosine and stavudine has never been investigated. We describe the surprising and consistent genotypic and phenotypic outcome in patients failing this combination. As part of a Danish multicentre study, 60 antiretroviral-naive patients were randomized to treatment with abacavir, didanosine and stavudine.

Continued indinavir versus switching to indinavir/ritonavir in HIV-infected patients with suppressed viral load.

Objective: To compare continued indinavir (IDV) 8-hourly (q8h) with switching to indinavir/ritonavir (IDV/RTV) 12-hourly (q12h) in HIV-positive patients having suppressed viral load with IDV q8h plus two nucleoside reverse transcriptase inhibitors (NRTI).

Design: Multicentre, international, randomized, open-label study enrolling HIV-1 infected patients on IDV 800 mg q8h plus two NRTI with CD4 cell counts > or = 100 x 106/l and plasma HIV RNA < 500 copies/ml for > or = 3 months.

Methods: Patients were randomized to continue on the same regimen or to switch to IDV plus liquid RTV (IDV/RTV 800 mg/100 mg q12h).

Analysis of virological efficacy in trials of antiretroviral regimens: drawbacks of not including viral load measurements after premature discontinuation of therapy.

Objectives: To compare two analytic approaches to assess the virological effect of HAART according to the intention-to-treat (ITT) principle.

Material: Data from 2318 patients enrolled in 10 randomised clinical trials (RCTs) and from 3091 patients followed in an observation cohort (EuroSIDA) starting their first HAART regimen.

Methods: Two classifications of defining virological response 48 weeks after starting the therapy to be evaluated were compared: 1) only patients remaining on the therapy and having a plasma viral load (pVL) below a given cut-off level at week 48 were classified as responders (ITT/s=f); and 2) patients with a pVL below a given cut-off at week 48 whether they remained on initial assigned therapy or switched therapy were responders (ITT/s incl).

Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunistic pathogens during potent antiretroviral therapy.

Background: The safety of interrupting maintenance therapy for previous opportunistic infections other than Pneumocystis carinii pneumonia among patients with HIV infection who respond to potent antiretroviral therapy has not been well documented.

Objective: To assess the safety of interrupting maintenance therapy for cytomegalovirus (CMV) end-organ disease, disseminated Mycobacterium avium complex (MAC) infection, cerebral toxoplasmosis, and extrapulmonary cryptococcosis in patients receiving antiretroviral therapy.

Design: Observational study.

Association of virus load, CD4 cell count, and treatment with clinical progression in human immunodeficiency virus-infected patients with very low CD4 cell counts.

This study prospectively assessed the impact of treatment modality, virus load, and CD4 cell count of <50 cells/mm(3) on human immunodeficiency virus disease progression. The incidence rate of new AIDS disease or death was 54.8 (95% confidence interval, 48.