M. Prosperi

Determinants of survival in progressive multifocal leukoencephalopathy

Background: We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML). Methods: We recorded the clinical outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood. Results: Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV− patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for death = 0.47, 95% confidence interval [CI] 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/μL at PML diagnosis compared to 67% in those with CD4 >200/μL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival. Conclusions: The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML. CE = contrast enhancement; CI = confidence interval; CTL = cytotoxic T-lymphocytes; HR = hazard ratio; IQR = interquartile range; IRIS = immune reconstitution inflammatory syndrome; JCV = JC virus; PBMC = peripheral blood mononuclear cells; PML = progressive multifocal leukoencephalopathy.

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 (≥3 drugs)] in our clinic since 1994.

Stochastic modelling of genotypic drug-resistance for human immunodeficiency virus towards long-term combination therapy optimization

MOTIVATION Several mathematical models have been investigated for the description of viral dynamics in the human body: HIV-1 infection is a particular and interesting scenario, because the virus attacks cells of the immune system that have a role in the antibody production and its high mutation rate permits to escape both the immune response and, in some cases, the drug pressure. The viral genetic evolution is intrinsically a stochastic process, eventually driven by the drug pressure, dependent on the drug combinations and concentration: in this article the viral genotypic drug resistance onset is the main focus addressed. The theoretical basis is the modelling of HIV-1 population dynamics as a predator-prey system of differential equations with a time-dependent therapy efficacy term, while the viral genome mutation evolution follows a Poisson distribution. The instant probabilities of drug resistance are estimated by means of functions trained from in vitro phenotypes, with a roulette-wheel-based mechanisms of resistant selection. Simulations have been designed for treatments made of one and two drugs as well as for combination antiretroviral therapies. The effect of limited adherence to therapy was also analyzed. Sequential treatment change episodes were also exploited with the aim to evaluate optimal synoptic treatment scenarios. RESULTS The stochastic predator-prey modelling usefully predicted long-term virologic outcomes of evolved HIV-1 strains for selected antiretroviral therapy combinations. For a set of widely used combination therapies, results were consistent with findings reported in literature and with estimates coming from analysis on a large retrospective data base (EuResist).

Evolutionary Fuzzy Modelling for Drug Resistant HIV-1 Treatment Optimization

Fuzzy relational models for genotypic drug resistance analysis in Human Immunodeficiency Virus type 1 (HIV-1) are discussed. Fuzzy logic is introduced to model high-level medical language, viral and pharmacological dynamics. In-vitro experiments of genotype/phenotype pairs and in-vivo clinical data bases are the base for the knowledge mining. Fuzzy evolutionary algorithms and fuzzy evaluation functions are proposed to mine resistance rules, to improve computational performances and to select relevant features.

Single-tablet regimen is associated with reduced efavirenz withdrawal in antiretroviral naïve or switching for simplification HIV-infected patients

Efavirenz (EFV) is still discussed for its high rate of interruption due to adverse event, in particular central nervous system side effects (CNS‐SE). Aim of the study was to define if better drug formulations up to single tablet regimen (STR), including (EFV) plus NRTI backbone (tenofovir‐emtricitabine), reduced the risk of interruption.