Higher plasma lopinavir concentrations are associated with a moderate rise in cholestasis markers in HIV-infected patients.

Objectives: The aim of this study was to evaluate the correlation between liver function markers (necrosis and cholestasis) and plasma lopinavir levels in a cohort of HIV-infected patients treated with lopinavir and ritonavir.

Patients And Methods: The blood samples for determining steady-state C(trough) lopinavir levels and analysing liver function were drawn from fasting patients. Steady-state C(trough) lopinavir levels, liver function and immuno-virological markers were assessed on the same day.

Steady-state pharmacokinetics of atazanavir given alone or in combination with saquinavir hard-gel capsules or amprenavir in HIV-1-infected patients.

Objective: The aim of this pilot study was to examine the pharmacokinetics of atazanavir (ATV) when given in combination with amprenavir (APV) or saquinavir hard-gel capsules (SQV) to human immunodeficiency virus (HIV)-positive patients.

Methods: Included in the study were 34 HIV-infected patients enrolled in the ATV Early Access Program, who were treated with unboosted ATV alone (group 1) or with the double protease inhibitor combinations, ATV plus APV (group 2) or ATV plus SQV (group 3). ATV was given at a daily dose of 400 mg q.

Evaluation of atazanavir Ctrough, atazanavir genotypic inhibitory quotient, and baseline HIV genotype as predictors of a 24-week virological response in highly drug-experienced, HIV-infected patients treated with unboosted atazanavir.

The objective of this study was to evaluate virological and pharmacological determinants of a 24-week virological response to unboosted atazanavir (ATV) in highly drug-experienced HIV-infected patients. Among patients enrolled in the ATV Expanded Access Program, those with HIV-RNA >1000 copies/mL, a genotype performed within three months from the baseline (BL), and who completed 24 weeks of treatment, were included. They received at least three antiretrovirals, including ATV 400 mg once daily without boosting.

Study on mutations and antiretroviral therapy (SMART): preliminary results.

Resistance to antiretroviral drugs is believed to be an important cause of treatment failure in human immunodeficiency virus (HIV)-infected patients, however, the role of susceptibility assays in the management of these individuals needs to be defined. SMART (study on mutations and antiretroviral therapy) is an ongoing study on mutations and antiretroviral therapy focused particularly on HIV-infected patients treated with two nucleoside analogue reverse transcriptase inhibitors (NRTIs). Plasma HIV-1 RNA was assessed by NASBA (nucleic acid sequence-based amplifications) (Organon Teknika, Boxtel, The Netherlands) with a detection limit of 80 copies/ml, whereas resistance was assessed by direct sequencing of the RT pol gene in patients with detectable viraemia, and by Antivirogram (Virco) in non-responder patients.

Redistribution of human immunodeficiency virus type 1 variants resistant to protease inhibitors after a protease inhibitor-sparing regimen.

The redistribution of mutations related to protease inhibitor (PI) resistance after a PI-sparing regimen in human immunodeficiency virus (HIV)-infected, highly PI-experienced patients was prospectively assessed. Twenty-five patients failing a PI-including regimen were given PI-sparing antiretroviral therapy, and then followed for 24 weeks after PI resumption. Genotyping was performed by direct sequencing before and during the PI-sparing regimen.

Cost-effectiveness of enfuvirtide for treatment-experienced patients with HIV in Italy.

Background: Enfuvirtide (ENF) plus an optimized background (OB) antiretroviral regimen delays virological failure (VF), reduces HIV-1 viral load, and increases CD4 count compared with OB only in pretreated patients.

Purpose: To forecast long-term outcomes, costs, and cost-effectiveness of ENF+OB vs. OB in the Italian health care system.

TMC114/ritonavir substitution for protease inhibitor(s) in a non-suppressive antiretroviral regimen: a 14-day proof-of-principle trial.

Objective: To evaluate antiviral activity, tolerability, and safety of the protease inhibitor (PI) TMC114 boosted with low-dose ritonavir (RTV).

Design: A randomized, open-label, controlled, phase IIA clinical trial in 15 sites in Europe with 50 HIV-1-infected patients who had taken multiple PIs.

Methods: At entry, PIs in non-suppressive regimens were replaced with TMC114/RTV (300/100 or 600/100 mg twice daily, or 900/100 mg once daily) or left unchanged for 14 days.

The appealing story of HIV entry inhibitors : from discovery of biological mechanisms to drug development.

Current therapeutic intervention in HIV infection relies upon 20 different drugs. Despite the impressive efficacy shown by these drugs, we are confronted with an unexpected frequency of adverse effects, such as mitochondrial toxicity and lipodystrophy, and resistance, not only to individual drugs but to entire drug classes.Thus, there is now a great need for new antiretroviral drugs with reduced toxicity, increased activity against drug-resistant viruses and a greater capacity to reach tissue sanctuaries of the virus.

Induction of murine mucosal CCR5-reactive antibodies as an anti-human immunodeficiency virus strategy.

The genital mucosa is the main site of initial human immunodeficiency virus type 1 (HIV-1) contact with its host. In spite of repeated sexual exposure, some individuals remain seronegative, and a small fraction of them produce immunoglobulin G (IgG) and IgA autoantibodies directed against CCR5, which is probably the cause of the CCR5-minus phenotype observed in the peripheral blood mononuclear cells of these subjects. These antibodies recognize the 89-to-102 extracellular loop of CCR5 in its native conformation.

Osteoprotegerin and bone turnover markers in heavily pretreated HIV-infected patients.

Objectives: To characterize osteoprotegerin (OPG) levels, bone remodelling and bone mineral density (BMD) in heavily pretreated HIV-infected patients on antiretroviral therapy, and to evaluate the clinical factors associated with bone density decline.

Methods: Heavily pretreated (> 5 years) HIV-positive patients were enrolled in this cross-sectional, observational study, which was based on a total body bone densitometry examination and a comprehensive evaluation of bone and mineral parameters.

Results: Sixty-eight patients (55 male and 13 female) with a median age of 41 years (range 25-60 years) were included in the study.

Mutations in the E2-PePHD region of hepatitis C virus type 1b in patients with hepatocellular carcinoma.

An interaction between the protein kinase (PKR)-eIF2-alpha phosphorylation homology domain (PePHD) within the E2 protein of hepatitis C virus (HCV) and cell protein kinase (PKR) may affect the control of protein synthesis and cell growth. In an attempt to investigate the genetic variability of the E2-PePHD domain in hepatocellular carcinoma (HCC), we studied sera and liver tissues from HCC patients. The partial E2-PePHD region was analysed by direct sequencing of the sera of 47 HCCs in cirrhotic livers and 31 cases of chronic active hepatitis (CAH), and tumoral and non-tumoral liver tissues from 13 HCC patients.

Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures.

Objective: To evaluate atazanavir/ritonavir (ATV/RTV) (300/100 mg) once daily, atazanavir/saquinavir (ATV/SQV) (400/1200 mg) once daily, and lopinavir/ritonavir (LPV/RTV) (400/100 mg) twice daily, each with tenofovir (300 mg) once daily and a nucleoside reverse transcriptase inhibitor in treatment-experienced HIV-infected patients.

Methods: Randomized, open-label, 48-week multicenter trial of 358 randomized adult patients who had failed two or more prior HAART regimens with baseline HIV RNA > or = 1000 copies/ml and CD4 cell count > or = 50 x 10(6) cells/l.

Results: The primary efficacy endpoint [plasma HIV RNA reduction assessed by time-averaged difference (TAD)] was similar for ATV/RTV and LPV/RTV [TAD 0.

Enfuvirtide: the first HIV fusion inhibitor.

Highly active antiretroviral therapy, a combination of antiretrovirals to treat HIV-infected individuals, may fail for a number of reasons, including the selection of genetic mutations which confer resistance to the antiretroviral drugs, and poor adherence or treatment discontinuation resulting from drug toxicity. Treatment-experienced patients, who have failed therapy owing to the emergence of drug-resistant virus, have a significant unmet medical need. Enfuvirtide (T-20), the first of a new class of antiretroviral agents known as HIV fusion inhibitors, has a unique mechanism of action involving disruption of HIV entry at the stage of membrane fusion.

Thymidine kinase and deoxycytidine kinase activity in mononuclear cells from antiretroviral-naive HIV-infected patients.

Objective: To evaluate whether an inter-individual variability in the activity of thymidine kinase (TK) and deoxycytidine kinase (dCK), which are involved in the first step of phosphorylation of some nucleoside analogues, exists in antiretroviral-naive, HIV-seropositive patients.

Design: Forty-five randomly selected antiretroviral-naive HIV-infected patients were recruited, together with 26 healthy volunteers with no concurrent infection and under no pharmacological treatment.

Methods: Peripheral blood mononuclear cells (PBMC) were isolated from venous blood and their TK and dCK activities evaluated.

Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy.

Background: Progressive multifocal leukoencephalopathy (PML) remains a frequent and life-threatening complication of human immunodeficiency virus (HIV) infection in the era of highly active antiretroviral therapy (HAART). Although one-half of patients with this disease will survive, the outcome is unpredictable at diagnosis, and prognostic markers are needed.

Methods: JC virus (JCV) DNA levels were measured in cerebrospinal fluid (CSF) samples obtained from 61 HIV-infected patients with PML, including 38 patients who were treated with HAART and 23 patients who did not receive HAART, with use of real-time polymerase chain reaction.

Determination of human papillomavirus (HPV) load and type in high-grade cervical lesions surgically resected from HIV-infected women during follow-up of HPV infection.

Background: The role of human papillomavirus (HPV) load and the importance of multiple-strain HPV infections as biomarkers for the development of cervical disease were evaluated in human immunodeficiency virus (HIV)-positive women.

Methods: A total of 108 samples were analyzed, 64 of which were obtained from 16 HIV-positive women who underwent surgical resection of the cervical cone for treatment of a histologically confirmed high-grade cervical intraepithelial neoplasm (cases) and 44 of which were obtained from 22 HIV-positive women who had high-risk HPV but a negative colposcopy result (controls). Each patient underwent periodic examinations at 6-12-month intervals that included colposcopy, Papanicolaou testing, biopsy (if indicated), and cervical brushing for HPV testing.

Predictive value of anti-cell and anti-human immunodeficiency virus (HIV) humoral responses in HIV-1-exposed seronegative cohorts of European and Asian origin.

Unconventional immune responses have been demonstrated in individuals who, despite repeated exposure to human immunodeficiency virus (HIV) infection, remain seronegative. As environmental exposure to pathogens and genetic background may modulate immune responses differentially, one Italian and two Asian populations of HIV-1-exposed seronegative individuals were studied. In serum samples from each group, IgG to CCR5, IgG to CD4 and IgA to gp41 were measured, which were previously described as markers of unconventional immunity in HIV-exposed seronegative Caucasians.

The role of host immunity in the control of HIV infection: from theory to diagnostic and therapeutic intervention.

Different immune and virological responses to antiretroviral therapy were generally observed in a consistent part of treated patients. The immune reconstitution due to viral decay conseguent to antiretroviral therapy is principally divided in two phases (redistribution and repopulation). Several co-factors (in particular co-receptor and cytokine relationship with HIV infection) can interfere with the response to the antiviral drugs.

A new prospective against HIV infection: induction of murin CCR5-downregulating antibodies.

Natural resistance to HIV is widely growing in humans. An example of an extremely efficacious resistance is represented by exposed seronegative (ESN) subjects, i.e.

Resistance and replicative capacity of HIV-1 strains selected in vivo by long-term enfuvirtide treatment.

Enfuvirtide is the prototype member of a new class of anti HIV-1 agents, the fusion inhibitors (FI). In recent clinical trials, the compound has shown its efficacy in combination with other antiretroviral agents in vivo. However mutant strains resistant to the action of the drug arise quite rapidly in vitro and in vivo.

The introduction of the fusion inhibitors in the HAART-regimens.

Interference with HIV entry into target cells provides a novel approach to the treatment of HIV infection. The inhibition of virus fusion with the co-receptor substrate seems the most specific and potentially best way to interfere with HIV infection and replication. The efficacy of the first compound available (enfuvirtide) is evident after the pre-registrative phase II and III studies showing also that the presence of anti gp 41 antibodies in the plasma of the treated patients does not interfere with drug activity.

Detection of chicken anemia virus in the gonads and in the progeny of broiler breeder hens with high neutralizing antibody titers.

Previous evidence for the presence of chicken anemia virus (CAV) in the gonads of immune specific-pathogen-free chickens raised the question whether this occurs also in commercial breeders. The presence of CAV was investigated by nested PCR in the gonads and spleens of hens from two 55- and 59-week-old, CAV-vaccinated (flocks 2 and 3), and two 48- and 31-week-old non-vaccinated broiler breeder flocks (flocks 1 and 4). In addition, lymphoid tissues of 20-day-old embryos from these hens were also investigated for the presence of CAV.

Expression of the urokinase plasminogen activator and its receptor in HIV-1-associated central nervous system disease.

The urokinase plasminogen activator (uPA) and its receptor (uPAR) play important physiological functions in extracellular proteolysis, as well as cell adhesion and migration. Through dysregulation of these functions, the uPA/uPAR system might be involved in the pathogenesis of AIDS dementia complex (ADC), and, in fact, uPAR has been found to be overexpressed in the cerebrospinal fluid (CSF) and brain tissues of patients with ADC. On the other hand, its ligand uPA has been shown to down-regulate HIV replication in vitro.