Atazanavir/ritonavir with lamivudine as maintenance therapy in virologically suppressed HIV-infected patients: 96 week outcomes of a randomized trial.

Objectives: To investigate the long-term safety and efficacy of a treatment switch to dual ART with atazanavir/ritonavir + lamivudine versus continuing a standard regimen with atazanavir/ritonavir + 2NRTI in virologically suppressed patients. Methods: ATLAS-M is a 96 week open-label, randomized, non-inferiority (margin -12%) trial enrolling HIV-infected adults on atazanavir/ritonavir + 2NRTI, with stable HIV-RNA <50 copies/mL and CD4 counts >200 cells/mm3. At baseline, patients were randomized 1:1 to switch to atazanavir/ritonavir + lamivudine or to continue the previous regimen. Here, we report the 96 week efficacy and safety data. The study was registered with ClinicalTrials.gov, number NCT01599364. Results: Overall, 266 subjects were enrolled (133 in each arm). At 96 weeks, in the ITT population, patients free of treatment failure totalled 103 (77.4%) with atazanavir/ritonavir + lamivudine and 87 (65.4%) with triple therapy (difference +12.0%, 95% CI +1.2/+22.8, P = 0.030), demonstrating the superiority of dual therapy. Two (1.5%) and 9 (6.8%) virological failures occurred in the dual-therapy arm and the triple-therapy arm, respectively, without development of resistance to any study drug. Clinical adverse events occurred at similar rates in both arms. A higher frequency of grade 3-4 hyperbilirubinemia (66.9% versus 50.4%, P = 0.006) and hypertriglyceridaemia (6.8% versus 1.5%, P = 0.031) occurred with dual therapy, although this never led to treatment discontinuation. A significant improvement in renal function and lumbar spine bone mineral density occurred in the dual-therapy arm. The evolution of CD4, HIV-DNA levels and neurocognitive performance was similar in both arms. Conclusions: In this randomized study, a treatment switch to atazanavir/ritonavir + lamivudine was superior over the continuation of atazanavir/ritonavir + 2NRTI in virologically suppressed patients, with a sustained benefit in terms of improved renal function and bone mineral density.

Incidence of DAA failure and the clinical impact of retreatment in real-life patients treated in the advanced stage of liver disease: Interim evaluations from the PITER network.

BACKGROUND: Few data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure. AIM: To evaluate DAA failure incidence and the retreatment clinical impact in patients treated in the advanced liver disease stage. METHODS: Data on HCV genotype, liver disease severity, and first and second line DAA regimens were prospectively collected in consecutive patients who reached the 12-week post-treatment and retreatment evaluations from January 2015 to December 2016 in 23 of the PITER network centers. RESULTS: Among 3,830 patients with advanced fibrosis (F3) or cirrhosis, 139 (3.6%) failed to achieve SVR. Genotype 3, bilirubin levels >1.5mg/dl, platelet count <120,000/mm3 and the sofosbuvir+ribavirin regimen were independent predictors of failure by logistic regression analysis. The failure rate was 7.6% for patients treated with regimens that are no longer recommended or considered suboptimal (sofosbuvir+ribavirin or simeprevir+sofosbuvir±ribavirin), whereas 1.4% for regimens containing sofosbuvir combined with daclatasvir or ledipasvir or other DAAs. Of the patients who failed to achieve SVR, 72 (51.8%) were retreated with a second DAA regimen, specifically 38 (52.7%) with sofosbuvir+daclatasvir, 27 (37.5%) with sofosbuvir+ledipasvir, and 7 (9.7%) with other DAAs ±ribavirin. Among these, 69 (96%) patients achieved SVR12 and 3 (4%) failed. During a median time of 6 months (range: 5-14 months) between failure and the second DAA therapy, the Child-Pugh class worsened in 12 (16.7%) patients: from A to B in 10 patients (19.6%) and from B to C in 2 patients (10.5%), whereas it did not change in the remaining 60 patients. Following the retreatment SVR12 (median time of 6 months; range: 3-12 months), the Child-Pugh class improved in 17 (23.6%) patients: from B to A in 14 (19.4%) patients, from C to A in 1 patient (1.4%) and from C to B in 2 (2.9%) patients; it remained unchanged in 53 patients (73.6%) and worsened in 2 (2.8%) patients. Of patients who were retreated, 3 (4%) had undergone OLT before retreatment (all reached SVR12 following retreatment) and 2 (2.8%) underwent OLT after having achieved retreatment SVR12. Two (70%) of the 3 patients who failed to achieve SVR12 after retreatment, and 2 (2.8%) of the 69 patients who achieved retreatment SVR12 died from liver failure (Child-Pugh class deteriorated from B to C) or HCC complications. CONCLUSIONS: Failure rate following the first DAA regimen in patients with advanced disease is similar to or lower than that reported in clinical trials, although the majority of patients were treated with suboptimal regimens. Interim findings showed that worsening of liver function after failure, in terms of Child Pugh class deterioration, was improved by successful retreatment in about one third of retreated patients within a short follow-up period; however, in some advanced liver disease patients, clinical outcomes (Child Pugh class, HCC development, liver failure and death) were independent of viral eradication.

Diabetic Foot Infection: Preliminary Results of a Fast-Track Program with Early Endovascular Revascularization and Local Surgical Treatment.

BACKGROUND: To demonstrate that a fast-track program consisting in early endovascular revascularization and local surgical treatment saves tissue in patients with diabetic foot infection (DFI). METHODS: Between January and December 2014, 48 patients with DFI underwent early endovascular revascularization and local surgical treatment at our Diabetic Foot Center. In all cases, endovascular revascularization and local surgical treatment were performed within 1 week from the diagnosis of infection and during the same hospital stay. One-year outcomes were evaluated in terms of survival, primary patency, primary-assisted patency, secondary patency, absence of target lesion restenosis (TLR), and limb salvage. RESULTS: The patients were predominantly males (34 of 48, 70.8%) with a mean age of 72.4 years (range, 51-91). The target vessel was a tibial artery in 34 cases (70.8%). Surgical treatment consisted of debridement without bone resection in 27 cases (56.2%), toe and/or ray amputation in 15 cases (31.2%), Lisfranc amputation in 2 cases (4.2%), transmetatarsal amputation in 2 cases (4.2%). In the remaining 2 cases, a leg amputation was necessary with an overall 30-day major amputation rate of 4.2%. During the follow-up (mean duration 6.9 months, range 1-12) healing of the lesions was obtained in 30 cases (62.5%). Estimated 12-month survival, primary patency, primary-assisted patency, secondary patency, absence of TLR, and limb salvage rates were 83.5%, 53.4%, 65%, 65%, 60.7%, and 86.6%, respectively. CONCLUSIONS: A fast-track program consisting in early endovascular revascularization and local surgical treatment contributes to our experience in limiting amputation levels in patients with DFI. A multidisciplinary approach and adoption of diabetic foot triage are essential to achieve these outcomes.

Simplification to atazanavir/ritonavir+lamivudine in virologically suppressed HIV-infected patients: 24-weeks interim analysis from ATLAS-M trial.

INTRODUCTION: We report interim 24-weeks efficacy data of ATLAS-M trial, a phase IV, multicentre, open-label, randomized study designed to show 48-weeks, non-inferior efficacy (margin of -12%) of treatment simplification to atazanavir/ritonavir (ATV/r)+lamivudine (3TC) versus maintaining 3-drugs ATV/r-based cART. METHODS: Subjects on ATV/r+2 NRTIs, without previous treatment failure (TF), with HIV-RNA <50copies/mL for >3 months and CD4>200 cells/mm(3) for >6 months were eligible. At baseline, patients were randomized to switch to ATV/r+3TC (arm one) or to maintain the original 3-drug regimen (arm two). PRIMARY ENDPOINT: proportion of patients free of TF at week 48. TF was defined as treatment modification for any reason, including virological failure (VF=two consecutive HIV-RNA>50 copies/mL or a single value >1000 copies/mL). Enrollment of 266 patients was planned. RESULTS: A total of 266 patients (78% males, median age 44 years, median CD4 603 cells/µL, 79% treated with a tenofovir-containing backbone) were enrolled. At the time of analysis, 24 weeks data were available for 84 and 87 patients in arm one and two, respectively. At baseline, subjects in the two arms did not differ for the main characteristics. At 24 weeks, at the intention to treat analysis the proportion of patients free of TF was 91.7% (95% CI 85.8-97.6) and 85.1% (95% CI 77.6-92.6) in arm one and two, respectively (difference +6.6%, 95% CI -2.9/+16.1). VF was observed in two patients randomized to arm one (one at baseline, before treatment simplification) and one to arm two without resistance mutations. Clinical and laboratory adverse events occurred at similar rates in the two arms. At week 24, patients in arm one showed a greater increase in CD4 (mean change +90 vs +10 cells/µL, p=0.007). A greater increase in total cholesterol (+18 vs -2 mg/dL, p<0.001), HDL (+4 vs +0 mg/dL, p=0.001) and LDL (+12 vs +0 mg/dL, p=0.001) was also observed in arm one without differences in other lipid parameters. Renal function showed a significant improvement in arm one (mean change in eGFR +5 vs -2 mL/min/1.73m(2) in arm two, p=0.001). No significant differences in bilirubin levels or other laboratory parameters were observed between the two arms. CONCLUSIONS: This interim analysis suggests a 24-weeks non-inferior efficacy of treatment simplification to ATV/rit+3TC as compared to continuation of ATV/rit +2 NRTI in virologically suppressed patients. Follow-up until 48-weeks is scheduled to confirm these data.

Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients.

OBJECTIVES: Prolonged treatment with linezolid may cause toxicity. The purpose of this study was to define pharmacodynamic thresholds for improving safety outcomes of linezolid. METHODS: We performed a retrospective study of patients who had trough (C(min)) and peak (C(max)) plasma levels measured during prolonged linezolid treatment. Dosage adjustments were performed when C(min) ≥10 mg/L and/or AUC24 ≥400 mg/L ·â€Šh. Patients were divided into two subgroups according to the absence or presence of co-treatment with rifampicin (the linezolid group and the linezolid + rifampicin group, respectively). Data on demographic characteristics, disease, microbiology and haematochemical parameters were collected and outcomes in relation to drug exposure were compared between groups. RESULTS: A total of 45 patients were included. Dosage adjustments were needed in 40% versus 0% of patients in the linezolid group (n = 35) versus the linezolid + rifampicin group (n = 10), respectively. Patients in the linezolid group had either significantly higher C(min) [3.71 mg/L (1.43-6.38) versus 1.37 mg/L (0.67-2.55), P < 0.001] or AUC24 [212.77 mg/L ·â€Šh (166.67-278.42) versus 123.33 mg/L ·â€Šh (97.36-187.94), P < 0.001]. Thrombocytopenia appeared in 51.4% versus 0% of cases in the linezolid group versus the linezolid + rifampicin group, respectively. In 33.3% of those patients who were experiencing thrombocytopenia, therapeutic drug monitoring (TDM)-guided dosage reductions allowed recovery from toxicity and prosecution of therapy with good outcome. A logistic regression model for thrombocytopenia estimated a probability of 50% in the presence of C(min) of 6.53 mg/L and/or of AUC24 of 280.74 mg/L ·â€Šh. CONCLUSIONS: Maintenance over time of C(min) between 2 and 7 mg/L and/or of AUC24 between 160 and 300 mg/L ·â€Šh may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.