Prevalence of transmitted HIV-1 drug resistance in HIV-1-infected patients in Italy: evolution over 12 years and predictors.

Objectives: Transmitted HIV-1 drug resistance (TDR) can reduce the efficacy of first-line antiretroviral therapy.

Patients And Methods: A retrospective analysis was performed to assess the prevalence and correlates of TDR in Italy over time. TDR was defined as the presence of at least one of the mutations present in the surveillance drug resistance mutation (SDRM) list.

Evolution and predictors of HIV type-1 drug resistance in patients failing combination antiretroviral therapy in Italy.

Background: This study aimed to examine the evolution of genotypic drug resistance prevalence in treatment-failing patients in the multicentre, Italian, Antiretroviral Resistance Cohort Analysis (ARCA).

Methods: Patients with a drug resistance genotype test performed between 1999 and 2006 at failure of a combination antiretroviral therapy and with complete treatment history were selected. The prevalence of resistance was measured overall, per calendar year, per drug class and per treatment line at failure.

Long-term follow-up of nevirapine-treated patients in a single-centre cohort.

Objectives: We reviewed the safety and efficacy of nevirapine (NVP)-based therapy in all patients initiating NVP-containing combined antiretroviral therapy [cART (>or=3 drugs)] in our clinic since 1994.

Methods: Patient characteristics and laboratory values from the start of the NVP-based cART regimen to the last available follow-up or to NVP discontinuation were retrieved from an observational database.

Results: Five hundred and seventy-three patients were treated with NVP-based cART for a median of 18.

Pharmacokinetic variability of antiretroviral drugs and correlation with virological outcome: 2 years of experience in routine clinical practice.

Objectives: To assess the inter-individual and intra-individual plasma concentration variabilities of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in routine clinical practice and to investigate their relationships with virological failure.

Methods: We retrospectively enrolled HIV-infected patients undergoing therapeutic drug monitoring (TDM) of NNRTIs and PIs during routine outpatient visits. Plasma drug concentrations were measured by HPLC-UV and were considered therapeutic if above the proposed minimum efficacy trough concentration.

Are mutations in HIV type-1 reverse transcriptase 245 codon predictive of abacavir hypersensitivity reaction?

Background: HLA-B*5701 is strongly related to abacavir hypersensitivity reactions (HSRs). Polymorphisms at position 245 of HIV type-1 (HIV-1) reverse transcriptase (RT) show an association with HLA-B*5701 suggesting that viral genotyping performed for antiretroviral drug resistance testing could reduce human leukocyte antigen (HLA) screening necessity to prevent abacavir HSR.

Methods: To further test the validity of 245 codon analysis results for predicting HSR, we analysed 1,179 sequences from 752 HIV-1-infected patients.

Virological suppression reduces clinical progression in patients with multiclass-resistant HIV type 1.

The virological and immunological outcomes in patients carrying multiclass-resistant HIV-1, their predictors, and their impact on disease progression were investigated. Antiretroviral-experienced patients carrying at least one primary resistance mutation (IAS-USA 2006) to two to three classes of antiretroviral drugs were analyzed for achieving an HIV-1 RNA <50 copies/ml, a CD4 count increase of >200 cells/microl from baseline, and progression to an AIDS-defining event or death. Survival analysis was performed using the Kaplan-Meier estimates and predictors of different outcomes were analyzed using Cox's regression models.

Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis.

Objective: To establish the effectiveness of cidofovir for AIDS-related progressive multifocal leukoencephalopathy (PML) in patients concomitantly receiving combination antiretroviral therapy.

Design: Analysis of raw data pooled from one prospective and five cohort studies.

Setting: Tertiary care centers for the treatment of HIV-associated complications.

Atazanavir and lopinavir with ritonavir alone or in combination: analysis of pharmacokinetic interaction and predictors of drug exposure.

Objectives: Studies on the pharmacokinetic interaction between atazanavir and lopinavir with ritonavir (lopinavir/ritonavir) report contradictory results. We aimed to establish the in vivo interaction between these two protease inhibitors as well as the variables influencing drug exposure.

Methods: Pharmacokinetic parameters were investigated in HIV-infected patients treated with atazanavir 300 mg with ritonavir 100 mg q24h (group A) or lopinavir/ritonavir 400/100 mg q12h (group B) or atazanavir 300 mg q24h with lopinavir/ritonavir 400/100 mg q12h (group C).

Genotypic resistance profile and clinical progression of treatment-experienced HIV type 1-infected patients with virological failure.

We explored the relationship between HIV-1 drug resistance in treatment-experienced patients and disease progression in a cohort of patients undergoing resistance testing to guide treatment decisions. A total of 601 treatment-failing individuals tested for genotypic HIV-1 drug resistance between 1998 and 2004 were selected. At genotypic testing, median HIV-1 RNA levels and CD4 counts were 3.

Cardiovascular risk score change in HIV-1-infected patients switched to an atazanavir-based combination antiretroviral regimen.

Background: We aimed to establish whether the limited impact of atazanavir on the plasma lipid profile could translate into a reduction in the predicted cardiovascular risk in antiretroviral (ARV)-experienced patients switching to an atazanavir-containing regimen.

Methods: HIV-1-infected treatment-experienced patients, switched to atazanavir for whatever reason and without prior major cardiovascular events, were selected and followed for at least 1 month. An individual cardiovascular risk score (10-year risk of major cardiovascular events) based on validated events and measurable risk factors in Italian cardiovascular cohorts was calculated using software available online.

Improved interpretation of genotypic changes in the HIV-1 reverse transcriptase coding region that determine the virological response to didanosine.

Background: Consensus on the interpretation of mutations in the human immunodeficiency virus (HIV)-1 reverse transcriptase (RT) gene that predict the response to didanosine treatment is needed.

Methods: Baseline HIV-1 RT genotypes and 12-week virological outcomes for patients undergoing didanosine-containing salvage regimens were extracted from prospective studies. Existing didanosine genotypic-resistance interpretation rules were validated in the entire-patient data set.

Characterization of JC virus in cerebrospinal fluid from HIV-1 infected patients with progressive multifocal leukoencephalopathy: insights into viral pathogenesis and disease prognosis.

Objectives: To analyze virological and immunological features of AIDS-related progressive multifocal leukoencepalophathy (PML) and their association to disease prognosis.

Methods: In HIV-infected patients with virologically confirmed PML, JC virus (JCV) DNA load and levels of Macrophage Chemoattractant Protein (MCP)-1 were determined in cerebrospinal fluid. JCV genotypes, rearrangements and JCV DNA binding sites for cellular transcription factors were analyzed by sequencing the viral VP1 region and regulatory region (RR).

Declining prevalence of HIV-1 drug resistance in treatment-failing patients: a clinical cohort study.

Objectives: A major barrier to successful viral suppression in HIV type 1 (HIV-1)-infected individuals is the emergence of virus resistant to antiretroviral drugs. We explored the evolution of genotypic drug resistance prevalence in treatment-failing patients from 1999 to 2005 in a clinical cohort.

Patients And Methods: Prevalence of major International AIDS Society-USA HIV-1 drug resistance mutations was measured over calendar years in a population with treatment failure and undergoing resistance testing.

Genotypic resistance to lopinavir and fosamprenavir with or without ritonavir of clinical isolates from patients failing protease inhibitors-containing HAART regimens: prevalence and predictors.

The aim of this study was to establish the prevalence and predictors of genotypic resistance of HIV-1 to lopinavir and fosamprenavir from patients failing protease inhibitors (PI)-based regimens. We selected 643 HIV-1-infected patients with available treatment history who underwent genotypic resistance assays for virological failure from a clinical site and from the Stanford database. According to the genotypic resistance interpretation of the Stanford algorithm, proportions of viruses showing full susceptibility to fosamprenavir and lopinavir were 32% and 34%, respectively (p =ns).

Association of HIV-1 replication capacity with treatment outcomes in patients with virologic treatment failure.

Background: The extent to which HIV-1 replication capacity (RC) influences the response to therapy remains to be established.

Methods: Phenotypic susceptibility and RC of baseline isolates (n = 139) from patients enrolled in the ARGENTA trial were measured and correlated to treatment outcomes over 36 months.

Results: RC in baseline isolates correlated with the number of phenotypically active drugs (R = 0.

Adherence and plasma drug concentrations are predictors of confirmed virologic response after 24-week salvage highly active antiretroviral therapy.

Data from 197 patients for whom highly active antiretroviral therapy (HAART) failed, who started a new regimen chosen under the guide of resistance testing results interpreted by experts, were retrospectively studied, provided that at least 2 determinations of adherence and plasma drug concentrations were performed during the follow-up. Univariate and multivariable logistic regression analyses were conducted, using confirmed virologic response at week 24 as outcome measure (i.e.

Influence of viral chronic hepatitis co-infection on plasma drug concentrations and liver transaminase elevations upon therapy switch in HIV-positive patients.

It is still controversial whether viral hepatitis co-infection can influence antiretroviral plasma drug concentrations and whether drug concentrations are correlated with liver enzyme elevations during highly active antiretroviral therapy. An analysis of data from a cohort of 220 human immunodeficiency virus (HIV)-infected patients was conducted. Univariate and multivariate logistic analyses were performed to identify predictors of plasma drug concentrations.

Lopinavir/ritonavir or efavirenz plus two nucleoside analogues as first-line antiretroviral therapy: a non-randomized comparison.

Background: Although efavirenz (EFV) and lopinavir/ ritonavir (LPV/r) are both recommended antiretroviral agents for combination therapy in drug-naive HIV-infected patients, no randomized comparison of their efficacy and tolerability is available yet. A multi-cohort prospective observational comparative study was performed.

Methods: Efficacy was examined comparing time to virological failure, CD4 recovery and clinical progression.

Three-year clinical outcomes of resistance genotyping and expert advice: extended follow-up of the Argenta trial.

Objective: To investigate the influence of genotypic resistance-guided HIV-treatment decisions on long-term clinical and virological outcomes in patients failing antiretroviral therapy by a prospective 30-month observation following a 6-month randomized study (Argenta trial).

Methods: Patients (n=174) with virological failure on highly active antiretroviral therapy (HAART) were initially randomized (1:1) to receive empirical therapy or guidance by genotypic resistance results. After month 6, all patients with HIV RNA >1,000 copies/ml received genotypic resistance tests and expert advice.

A comparison between abacavir and efavirenz as the third drug used in combination with a background therapy regimen of 2 nucleoside reverse-transcriptase inhibitors in patients with initially suppressed viral loads.

Background: Our objective was to compare the rate of viral rebound and therapy failure in patients receiving abacavir or efavirenz as the third drug (in addition to 2 non-abacavir nucleosides) in combination antiretroviral therapy (cART) and to compare the rate of metabolic alteration associated with these regimens.

Methods: We conducted a multicohort prospective observational study of human immunodeficiency virus-infected patients who had attained viral loads < or = 80 copies/mL while receiving cART, without having previously received antiretrovirals. The rates of virological rebound, therapy failure, and lipid-level alteration during follow-up were calculated as the number of events divided by person-years of follow-up (PYFU).

Frequency and treatment-related predictors of thymidine-analogue mutation patterns in HIV-1 isolates after unsuccessful antiretroviral therapy.

We investigated, in patients tested between 1991 and 2004, the patterns of mutually exclusive human immunodeficiency virus-1 thymidine-analogue mutations (TAMs) in 4039 reverse-transcriptase sequences with > or = 1 TAM. TAM pattern 1, which included M41L and L210W and excluded K70R and is coupled with more-extensive cross-resistance to drugs, became the most frequent pattern after 1996. In 1465 genotypes from 684 patients in whom highly active antiretroviral therapy (HAART) was unsuccessful, predictors of this pattern were the number of previous HAART regimens undergone (adjusted odds ratio [OR], 1.

Reduced rate of diagnostic positive detection of JC virus DNA in cerebrospinal fluid in cases of suspected progressive multifocal leukoencephalopathy in the era of potent antiretroviral therapy.

Fifty-nine human immunodeficiency virus (HIV)-infected patients with suspected progressive multifocal leukoencephalopathy and 224 controls were tested for JC virus (JCV) DNA in cerebrospinal fluid by PCR. The diagnostic positive detection rate dropped from 89.5% (95% confidence intervals of 75.

Macrophage chemoattractant protein-1 levels in cerebrospinal fluid correlate with containment of JC virus and prognosis of acquired immunodeficiency syndrome--associated progressive multifocal leukoencephalopathy.

In the highly active antiretroviral therapy (HAART) era, the role of the inflammatory response in acquired immunodeficiency syndrome (AIDS)-related progressive multifocal leukoencephalopathy (PML) remains controversial. In this study, JC virus DNA load and levels of cytokines were determined in cerebrospinal fluid (CSF) from 32 human immunodeficiency virus (HIV)-1-infected patients with confirmed PML who underwent HAART; cytokines were also measured in 12 HIV-positive controls. Predictors of survival were analyzed by Cox's models.

A randomized controlled trial to evaluate antiretroviral salvage therapy guided by rules-based or phenotype-driven HIV-1 genotypic drug-resistance interpretation with or without concentration-controlled intervention: the Resistance and Dosage Adapted Regimens (RADAR) study.

Background: It is not well defined whether concentration-controlled intervention (CCI) and rules-based human immunodeficiency virus (HIV) type 1 genotype drug-resistance interpretation (GI) or virtual phenotype drug-resistance interpretation (VPI) may improve the outcome of HIV salvage therapy.

Methods: In a prospective, randomized, controlled trial, patients were randomized (on a factorial basis) to change treatment after either GI or VPI, and they then were further randomized to the control arm (no CCI) or the CCI arm. Protease inhibitor (PI) and nonnucleoside reverse-transcriptase inhibitor (NNRTI) trough concentration (Ctrough) values were determined at weeks 1, 4, 12, and 24 of the study.

CD4 cell-monitored treatment interruption in patients with a CD4 cell count > 500 x 106 cells/l.

Background: Little is known about CD4 cell count changes in patients with high CD4 cell counts who interrupt antiretroviral therapy, especially in those with a nadir of 250-350 x 10 cells/l.

Methods: Data derived from 139 patients from seven prospective cohorts who had > 12 months highly active antiretroviral therapy (HAART), CD4 cell count nadir of > 250 x 10 cells/l and at pre-interruption of > 500 x 10 cells/l. Endpoint was time to CD4 cell count < 350 x 10 cells/l or reinitiation of treatment.