Evaluation of treatment simplification strategies in patients living with HIV with multi-drug resistance.

Background: Patients living with HIV (PLWH) with multi-drug resistance (MDR) and prior episodes of virologic failure have few therapeutic options remaining. These patients are often prescribed 'salvage' antiretroviral therapy (ART) regimens with high pill burdens, leading to potential decreased medication adherence and increased side effects and drug-drug interactions. Materials & Methods: In this retrospective, observational cohort study, we included adult patients with a diagnosis of HIV-1 who received care at our institution's Ryan White Clinic and who received 'salvage' ART, defined as three of more antiretroviral agents from at least three different HIV drug classes. Patients were grouped into two cohorts, simplified ART cohort and non-simplified ART cohort, based on whether their ART regimen was reduced by at least one tablet daily. The primary outcome was the percentage of patients who had their viral load suppressed (HIV-1 RNA <50 copies/ml) at their most recent clinic visit. Secondary outcomes were virologic failure (HIV-1 RNA ⩾200 copies/ml), percentage of time patients were virologically suppressed over the past 2 years, and the emergence of new treatment-resistant mutations. Results: There were 50 patients included in the final analysis, 28 in the simplified ART cohort and 22 in the non-simplified ART cohort. The percentage of patients who had their HIV-1 viral load suppressed at their most recent clinic visit was n = 24 (86%) in the simplified ART cohort and n = 16 (73%) in the non-simplified ART cohort (p = 0.302). There were no statistically significant differences between the two cohorts in terms of the secondary outcomes. Conclusion: Our study found that simplification of ART regimens based on HIV genotype in PLWH with a history of MDR and prior virologic failures, regardless of the presence of HIV-1 viremia at the time of simplification, resulted in similar rates of virologic suppression and virologic failure as non-simplified ART regimens.

Safety and Efficacy of Prophylactic Amiodarone After Left Ventricular Assist Device.

The prophylactic use of amiodarone to reduce the incidence of postoperative arrhythmias is effective for patients undergoing general cardiac surgeries; however, no data exists for the use of prophylactic amiodarone to prevent postoperative arrhythmias after CF-LVAD. This single-center, retrospective analysis compared patients with CF-LVADs placed between April 2014 and June 2020 who received prophylactic postoperative amiodarone to those who did not. Based on institution practice at the respective times, patients with a CF-LVAD placed between April 2014 and June 2018 were included in the group receiving postoperative amiodarone arrhythmia prophylaxis and patients with a CF-LVAD placed July 2018 to June 2020 were included in the group not receiving arrhythmia prophylaxis. The primary outcome was the incidence of first occurring atrial or ventricular arrhythmia from CF-LVAD placement to 21 days or hospital discharge. Sixty patients received amiodarone for arrhythmia prophylaxis and 27 patients did not receive prophylaxis. The primary outcome occurred in 40% of the prophylaxis group and 66.7% in the no prophylaxis group (RR, 0.60; 95% CI, 0.40-0.90; p = 0.038). In patients receiving CF-LVADs, the use of prophylactic amiodarone was associated with a reduction in the incidence of postoperative arrhythmias, which was driven primarily by a reduction in postoperative atrial arrhythmias, without significantly increasing the rate of amiodarone-related adverse events.

Alemtuzumab in Renal Retransplantation - Transplant Outcomes and Associated Infections.

Renal retransplant patients have decreased graft survival compared with primary renal transplant patients. Alemtuzumab induction is often used at the time of retransplant; however, the literature surrounding alemtuzumab induction in renal retransplant patients is limited. In this single-center, retrospective, observational study, we aimed to determine the 1-year incidence of infections and transplant outcomes in renal retransplant patients who received alemtuzumab induction. Thirty-four patients who received alemtuzumab met inclusion criteria and were included in the final analysis. Twenty-two (64.7%) of these patients acquired infections. Of these, 7 patients (31.8%) acquired infections that resulted in hospitalization or intravenous antibiotics. The most common infections were urinary tract infections (n = 10; 29.4%), cytomegalovirus DNAemia (n = 7; 20.6%), and BK virus (n = 6; 17.6%). The use of steroid maintenance therapy after alemtuzumab induction did not increase the number of infections compared with patients with a steroid-free interval after alemtuzumab induction. The number of patients who developed de novo donor-specific antibodies (DSA) was 11 (32.4%) with only 1 of these patients having DSA before retransplantation. The incidence of acute cellular rejection was 2.9% (n = 1). There was no graft loss, and patient survival was 97% (n = 33). There were no significant differences in infection rate or DSA development between alemtuzumab and the other induction agents, antithymocyte globulin and basiliximab, among retransplanted patients. Alemtuzumab induction in renal retransplant patients resulted in similar bacterial and viral infection rates as previously reported in the literature and did not negatively impact graft and patient survival.

Overcoming anti-PEG antibody mediated accelerated blood clearance of PEGylated liposomes by pre-infusion with high molecular weight free PEG.

Antibodies that specifically bind polyethylene glycol (PEG), i.e. anti-PEG antibodies (APA), are associated with reduced efficacy and increased risk of serious adverse events for several PEGylated therapeutics. Here, we explored the concept of using free PEG molecules to saturate circulating APA. Surprisingly, we found that 40 kDa free PEG effectively restored the prolonged circulation of PEGylated liposomes in the presence of high titers of pre-existing APA for at least 48 h in mice. In contrast, lower molecular weight free PEG (≤10 kDa) failed to restore circulation beyond a few hours. These in vivo results were consistent with estimates from a minimal physiologically based pharmacokinetic model. Importantly, the infusion of free PEG appeared to be safe in mice previously sensitized by injection of PEGylated liposomes, and free PEG did not elicit excess APA production even in mice with pre-existing adaptive immunity against PEG. Our results support further investigation of high molecular weight free PEG as a potential method to control and overcome high titers of APA, restoring the prolonged circulation of PEGylated liposomes and possibly other PEGylated therapeutics.