Comparative evaluation of seven resistance interpretation algorithms and their derived genotypic inhibitory quotients for the prediction of 48 week virological response to darunavir-based salvage regimens.

BACKGROUND: the darunavir genotypic inhibitory quotient (gIQ) has been suggested as one of the predictors of virological response to darunavir-containing salvage regimens. Nevertheless, which resistance algorithm should be used to optimize the calculation of gIQ is still debated. The aim of our study was to compare seven different free-access resistance algorithms and their derived gIQs as predictors of 48 week virological response to darunavir-based salvage therapy in the clinical setting. METHODS: patients placed on two nucleoside reverse transcriptase inhibitors + 600/100 mg of darunavir/ritonavir twice daily  ±â€Š enfuvirtide were prospectively evaluated. Virological response was assessed at 48 weeks. Darunavir resistance interpretation was performed according to seven different algorithms, of which two were weighted algorithms. Analysis of other factors potentially associated with virological response at 48 weeks was performed. RESULTS: fifty-six treatment-experienced patients were included. Overall, 35 patients (62.5%) had a virological response at 48 weeks. Receiver operator characteristic curve analysis showed that De Meyer's weighted score (WS) and its derived gIQ (gIQ WS) were the most accurate parameters defining virological response, and related cut-offs showed the best sensitivity/specificity pattern. In univariate logistic regression analysis, baseline log viral load (P = 0.028), optimized background score ≥ 2 (P = 0.048), WS >5 (P = 0.001) and WS gIQ ≥ 600 (P < 0.0001) were independently associated with virological response. In multivariate analysis, only baseline log viral load (P = 0.008) and WS gIQ ≥ 600 (P < 0.0001) remained in the model. CONCLUSIONS: in our study, although different resistance interpretation algorithms and derived gIQs were associated with virological response, gIQ WS was the most accurate predictive model for achieving a successful virological response.

New macrocyclic amines showing activity as HIV entry inhibitors against wild type and multi-drug resistant viruses.

Considering as a lead molecule the chemokine CXCR4 receptor antagonist AMD-3100, which shows significant anti-HIV activity in vitro and in vivo, we investigated a series of structurally related macrocyclic polyamines incorporating o,o'-phenanthroline or 2,2'-bipyridyl scaffolds as potential antiviral agents with lower toxicity and increased activity against both wild type X4-tropic and dual tropic HIV strains. The antiviral activity of these compounds was evaluated by susceptibility assays in PBMC (Peripheral Blood Mononuclear Cells) and compared to that of AMD-3100. The newly investigated compounds showed IC(50)s values in the low micromolar range and significantly inhibited the viral replication of wild type X4-tropic isolate and dual tropic strains. These macrocyclic polyamines constitute a promising class of HIV entry inhibitors.

Evolution of the HIV-1 protease region in heavily pretreated HIV-1 infected patients receiving Atazanavir.

BACKGROUND: Previous in vitro studies indicated that Atazanavir (ATV) has a distinct resistance profile than other protease inhibitors (PIs). In treatment-experienced patients ATV resistance is characterised by the accumulation of at least four mutations among those that confer cross-resistance to the PIs. OBJECTIVE: We studied the evolution of PIs resistance mutations in 10 HAART-failed patients undergoing ATV enrolled in an early access program. STUDY DESIGN: Virus genotypic resistance was determined from plasma collected at baseline and during treatment. HIV-RNA was extracted and the pol region amplified and sequenced. Genotypic data were used to determine drug susceptibility. Phylogenetic analysis was performed. RESULTS: At baseline, genotypic data showed cross-resistance patterns to approved PIs in 6 patients. In two of these subjects new mutations (I54V and A71V) conferring cross-resistance emerged after 3 months of therapy. The I50L mutation was evidenced in one subject after 12 months of treatment. The "virtual" phenotype analysis mirrored the resistance profiles to ATV and other PIs and evidenced differences with tipranavir and darunavir. CONCLUSION: Genotype evolution within the protease region did not emerge at significant levels during salvage therapy of multidrug-experienced patients. ATV exhibited certain/same virologic effect on the majority of our patients.

Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy.

Patients with inefficient CD4+ T-cell recovery on virogically suppressive highly active antiretroviral therapy constitute a major clinical hurdle given the threat of HIV/AIDS disease progression. We show heightened circulating lipopolysaccharide associated with plasma enterobacterial DNA and highly activated Ki67+CD4+CD8+ in 24 immunologic-nonresponders (CD4+ T-cell < or = 200; HIV-RNA < or = 50) compared with 11 full responders (CD4+ T-cell > or= 400; HIV-RNA < or = 50). These data provide novel insight into INRs pathogenesis, since they correlate augmented systemic translocation of microbial bioproducts with T-cell hyperactivation.