Investigating Perampanel Antiepileptic Drug by DFT Calculations and SERS with Custom Spinning Cell.

SERS, a clinical practice where medical doctors can monitor the drug concentration in biological fluids, has been proposed as a viable approach to therapeutic drug monitoring (TDM) of the antiepileptic drug Perampanel. The adoption of an acidic environment during the SERS experiments was found to be effective in enhancing the spectroscopic signal. In this work, we combine SERS experiments, conducted with a custom spinning cell in controlled acidic conditions, with DFT calculations aimed at investigating the possible protonated forms of Perampanel. The DFT-simulated Raman spectra of protonated Perampanel accounts for most of the observed SERS signals, thus explaining the effective role of protonation of the analyte. Our results suggest protonation as a viable approach to fostering SERS of alkaline drugs.

Early discontinuation of DTG/ABC/3TC and BIC/TAF/FTC single-tablet regimens: a real-life multicenter cohort study.

Background: Data regarding the efficacy and tolerability of DTG/ABC/3TC/and BIC/TAF/FTC in switching strategies are still scarce. The rates and reasons of early discontinuation within 24 weeks from the switch to dolutegravir (DTG) or bictegravir (BIC) single-tablet regimens (STRs) were compared.Methods: This is a multicenter cohort study. Persons living with HIV (PLWH) with HIV-1 RNA <50 copies/mL switching to BIC-STR or DTG-STR were included and followed-up 24 weeks. Major outcome was the analysis of (quantitative assessment of) discontinuation due to adverse events and self-suspension (EDAEs). Second, we assessed virologic failure (VF), and all-cause discontinuation (EDAC). Cox model for regression analysis was employed.Results: We included 786 PLWH: 524 with DTG, 262 with BIC. At week 24, we observed 70 EDAC: 5 for VF (1 with BIC and 4 with DTG; p = 0.6276), 10 simplifications, more frequently with BIC than DTG (n = 5, 1.9% and n = 5, 0.9%; p = 0.072) and 55 EDAEs, 7 (2.7%) with BIC, 48 (9.2%) with DTG (p = 0.0323). EDAEs due to neurological and gastrointestinal toxicity were similar (p = 0.2398 and p = 0.1160, respectively). There were no significant differences in the rates of VF and EDAC. EDAEs rate was significantly higher for DTG than for BIC. The adjusted HR for EDAEs in DTG group was 3.28 (95% CI: 1.34-8.00; p = 0.009). We identified an association between EDAE in the DTG group and having an age >60 and having switched from a regimen without ABC.Conclusions: PLWH who received DTG or BIC do not show differences in VF or EDAC rates. However, EDAEs is more frequent with DTG especially in the over-sixties and in those who come from regimens without abacavir.

Short Communication: Comparing Lamivudine+Dolutegravir and Bictegravir/Emtricitabine/Tenofovir Alafenamide as Switch Strategies: Preliminary Results from Clinical Practice.

We tried to investigate and compare the safety of a dual therapy (DT) with dolutegravir+lamivudine (DTG +3TC) versus bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). We performed a retrospective analysis in a cohort of virologically suppressed HIV+ pts switching to DT or BIC in our center. Primary endpoint was to evaluate time to treatment discontinuation (TD) for any cause. Survival analysis was employed to determine time to TD and its predictors were analyzed by Cox regression. Moreover, we collected viro-immunological parameters as well as markers of renal function and lipid profile at baseline and after 24 weeks and assessed changes through nonparametric tests. We analyzed 476 patients: 350 starting a DT and 126 starting BIC. Overall, we registered 21 TD: 15 in the DT group during 170 patient-years of follow-up (PYFU) (a rate of 8.8 per 100 PYFU) and 6 in the BIC one during 48 PYFU (12.5 per 100 PYFU). Estimated probabilities of maintaining study regimen after 24 weeks were 95.5% [standard deviation (SD) ±1.1] in the DT group and 94.9% (SD ±2.0) in the BIC group, with no significant differences between them (log-rank p = .639). Concerning metabolic profile, in the DT group, after 24 weeks, triglycerides decreased significantly (median change -14 mg/dL, p < .001), whereas high-density lipoprotein cholesterol increased (+3 mg/dL, p = .031). In the BIC group, meanwhile, we observed a significant decrease in low-density lipoprotein cholesterol after 24 weeks (-13 mg/dL, p = .026). Both optimization strategies showed high tolerability in the short term in experienced pts, with few differences between them. Further studies are needed to properly assess the matter.

Integrase Inhibitors Use and Cytomegalovirus Infection Predict Immune Recovery in People Living With HIV Starting First-Line Therapy.

BACKGROUND: We explored predictors of CD4/CD8 ratio improvement and optimal immunological recovery (OIR) after initiation of antiretroviral therapy (ART) in naive people living with HIV (PLWH). METHODS: Retrospective multicenter study including naive PLWH starting ART with 2 nucleos(t)ide reverse transcriptase inhibitors + 1 integrase strand transfer inhibitor (InSTI) or non-NRTI or protease inhibitor (PI). PLWH were followed from the time of ART initiation (baseline) to the discontinuation of first-line regimen, virological failure, death, or loss to follow-up. Estimated incidence and predictors of time to CD4/CD8 ratio normalization (defined as ≥1) and OIR (defined as CD4/CD8 ratio ≥ 1 plus CD4 ≥ 500 cells/µL plus CD4% ≥ 30%) were explored by Kaplan-Meier curves and Cox regression analysis. RESULTS: Overall, 1428 PLWH (77.8% males, median age 39 years, 55.1% with positive cytomegalovirus (CMV) antibodies, median HIV-RNA 4.80 log copies/mL, median CD4 323 cells/µL, median CD4/CD8 ratio 0.32) were included, of which 21.5% (n = 307), 44.5% (n = 636), and 34% (n = 485) treated with InSTI-, PI-, and NNRTI-based regimens, respectively. The estimated proportion of CD4/CD8 normalization and OIR at 36 months was 38.6% and 32.9%, respectively. Multivariate analysis showed that InSTI-based regimens had a higher probability of CD4/CD8 ratio normalization and OIR both in the total population (P < 0.001 versus PI) and in advanced naive PLWH (P ≤ 0.001 versus PI and NNRTI). Moreover, subjects with positive CMV serology showed a lower probability of CD4/CD8 ratio normalization and OIR (P < 0.001). CONCLUSIONS: InSTI-based regimens showed a better immune recovery, suggesting that the type of first-line ART can influence immune reconstitution. PLWH with positive CMV serology showed an increased risk of suboptimal immune recovery.

Kaposi-like manifestations in a newly diagnosed AIDS transgendered patient with silicone embolism syndrome and disseminated tuberculosis.

The use of liquid silicone for cosmetic procedures can yield serious sequelae including embolization and pneumonia. We describe a recent case of silicone embolism syndrome occurring together with systemic tuberculosis in a transgendered patient newly diagnosed with AIDS. She presented with fever, hematochezia, lymphadenopathies, purple nodular lesions and lower limb edema. HIV test was positive. A chest X-Ray showed interstitial infiltrates and a tomography showed necrotic lymph nodes and pulmonary nodules with blurred borders, suggesting Kaposi sarcoma. Psychomotor impairment then occurred in the absence of tomographic signs of acute neurological events. The Mycobacterium tuberculosis genome was isolated from stool and bronchial washing samples. Histological examination of a necrotic lymph node showed lymphoadenopathy due to silicone accumulation. Moreover, the patient presented fever and swelling of lower limbs; a tomography showed multiple foreign body granulomas. After starting antitubercular, antiretroviral and antibiotic treatment she reported symptomatic improvement including a mild recovery of motor-slowing. There are few reports about silicone-induced pulmonary disease in HIV-1 infected patients and, as far as we know, none of them describes an overlapping pulmonary involvement due to Mycobacterium tuberculosis infection. Even if extensive clinical and radiologic evidence is suggestive of Kaposi sarcoma (fever, severe immunodeficiency, multiple cutaneous nodules, hematochezia, diffuse lymphoadenopathies), it is possible to see Kaposi-like manifestations in patients with systemic silicone embolization. With this article we wish to stress the attention on the possible overlap of more than one concurrent disease in an immunocompromised host.

Long-Term Serological Response to 13-Valent Pneumococcal Conjugate Vaccine Versus 23-Valent Polysaccharide Vaccine in HIV-Infected Adults.

INTRODUCTION: Long-term comparative immunologic response to 13-valent pneumococcal conjugate vaccine (PCV13) versus 23-valent polysaccharide vaccine (PPV23) among HIV-infected adults has not yet been investigated. METHODS: In this prospective pilot study, we quantified in HIV-positive adults serotype-specific IgG concentrations of the 12 pneumococcal serotypes shared by both vaccines 5 years after vaccination with two doses of PCV13 8 weeks apart (group 1) or one dose of PPV23 (group 2) and compared them with those assessed prior to vaccination (BL) and after 1 year (T1). Comparison of immunogenicity was based on geometric mean concentration (GMC), proportion of individuals with ≥ twofold increase from BL in specific antibody concentration against ≥ 2 serotypes and percentage of individuals with serotype-specific IgG ≥ 0.35 µg/ml, ≥ 1 µg/ml and ≥ individual serotype-specific correlates of protection. RESULTS: We included 91 subjects (median CD4+ 650 cells/µl, > 90% with HIV-RNA < 50 copies/ml); patients in groups 1 (n = 42) and 2 (n = 49) were homogeneous for the main characteristics. GMCs were significantly higher in the PCV13 group than in the PPV23 group for serotype 19F (p = 0.003). Both vaccines revealed higher significant GMCs to most serotypes compared with BL, i.e., eight in group 1 vs. seven in group 2. With respect to T1, GMCs decreased significantly in the PCV13 group for eight vs. ten serotypes in the PPV23 group. More participants in the PCV13 group had ≥ 2 increase from BL in antibody levels to ≥ 2 serotypes compared with the PPV23 group (78.6% vs. 59.2%, p = 0.042). Overall, the percentage of subjects with serotype-specific IgG ≥ 0.35 µg/ml, ≥ 1 µg/ml and ≥ individual serotype-specific correlates of protection was similar between groups. CONCLUSION: In this study with HIV-positive adults with a favorable viro-immunologic profile, both vaccines were shown to achieve a long-term durable serologic response. We found minor differences in immunogenicity between the two vaccines, which favored PCV13 over PPV23 5 years after immunization. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02123433.