Temesgen, Zelalem

AbstractBackgroundClostridioides difficile infection (CDI) is a significant cause of morbidity and mortality in recipients of solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). In retrospective single center analyses, severe disease and relapse are common. We undertook an international, prospective cohort study to estimate the response to physician determined antibiotic treatment for CDI in patients with SOT and HSCT.MethodsAdults with a first episode of CDI within the first 2 years of SOT or HSCT were enrolled. Demographics, comorbidities, and medication history were collected, and over 90 days of follow‐up clinical cure, recurrences, and complications were assessed. Logistic regression was used to study associations of baseline predictors of clinical cure and recurrence. Odds ratios (ORs) and 95% confidence intervals (CIs) are cited.ResultsA total of 132 patients, 81 SOT and 51 HSCT (32 allogeneic), were enrolled with a median age of 56 years; 82 (62%) were males and 128 (97%) were hospitalized at enrollment. One hundred and six (80.3%) were diagnosed by DNA assay. CDI occurred at a median of 20 days post‐transplant (interquartile range, IQR: 6–133). One hundred and eight patients (81.8%) were on proton pump inhibitors; 126 patients (95.5%) received antibiotics within the 6 weeks before CDI. The most common initial CDI treatments prescribed, on or shortly before enrollment, were oral vancomycin alone (50%) and metronidazole alone (36%). Eighty‐three percent (95% CI: 76, 89) of patients had clinical cure; 18% (95% CI: 12, 27) of patients had recurrent CDI; global clinical cure occurred in 65.2%. Of the 11 patients who died, two (1.5% of total) were related to CDI. In multivariable logistic regression analyses, the type of initial treatment was associated with clinical cure (p = .009) and recurrence (p = .014). A history of cytomegalovirus (CMV) after transplant was associated with increased risk of recurrence (44% with versus 13% without CMV history; OR: 5.7, 95% CI: 1.5, 21.3; p = .01).ConclusionsAmong adults who develop CDI after SOT or HSCT, despite their immunosuppressed state, the percentage with clinical cure was high and the percentage with recurrence was low. Clinical cure and recurrence varied by type of initial treatment, and CMV viremia/disease was associated with an increased risk of recurrence.

Purpose of review To date, more than 30 antiretroviral drugs have been approved by the Food and Drug Administration for the treatment of HIV infection. As new drugs with better efficacy and safety profile become available for clinical practice, older drugs are either withdrawn from the market or become no longer actively prescribed. We review hepatotoxicity associated with contemporary antiretroviral drugs, with emphasis on data from the past 3 years. Recent findings Although less robust data exists for side effects of contemporary antiretroviral medications recently approved for the management of HIV (i.e., doravirine, ibalizumab, fostemsavir, cabotegravir), the risks of substantial hepatotoxicity appears to be minimal with these agents. Summary Although newer antiretroviral drugs are better tolerated than their earlier counterparts, they are not completely devoid of adverse drug reactions, including hepatotoxicity. Monitoring patients on antiretroviral therapy for treatment-emergent liver injury should continue to be part of routine clinical care.

Contemporary antiretroviral agents afford enhanced potency and safety for patients living with HIV. Newer antiretroviral drugs are often better tolerated than those initially approved in the early stages of the HIV epidemic. While the safety profile has improved, adverse drug reactions still occur. We have segregated the antiretroviral agents used in contemporary practice into class groupings based on their mechanism of antiviral activity (non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, and entry inhibitors) while providing a review and discussion of the hepatoxicity seen in the most relevant clinical literature published to date. Clinical literature for individual agents is discussed and agent comparisons afforded within each group in tabular format. Our review will provide a summative overview of the incidence and medications associated with hepatic adverse reactions linked to the use of contemporary antiretroviral drugs.

Background: Persistent inflammation and incomplete immune recovery among persons with HIV (PHIV) are associated with increased disease risk. We hypothesized that the angiotensin receptor blocker (ARB) losartan would reduce inflammation by mitigating nuclear factor (NF)κB responses and promote T-cell recovery via inhibition of transforming growth factor-beta (TGFβ)-mediated fibrosis. Methods: Losartan (100 mg) versus placebo over 12 months was investigated in a randomized (1 : 1) placebo-controlled trial, among PHIV age at least 50 years, receiving antiretroviral therapy (ART), with HIV RNA less than 200 copies/ml and CD4+ cell count 600 cells/μl or less. Inflammation, fibrosis and myocardial biomarkers were measured in blood using ELISA, electrochemiluminescence and immunoturbidimetric methods, and T-cell and monocyte phenotypes were assessed with flow cytometry among a subset of participants. Changes over follow-up in (log-2 transformed) biomarkers and cell phenotypes (untransformed) were compared between losartan and placebo arms using linear mixed models. Results: Among 108 PHIV (n = 52 to losartan; n = 56 to placebo), 97% had a month 12 visit. Median age was 57 years and baseline CD4+ cell count was 408 cells/μl. Losartan treatment was not associated with an improvement in interleukin-6 levels, or other blood measures of inflammation, immune activation, fibrosis activity or myocardial function. CD4+ and CD8+ T cells also did not differ by treatment group. Losartan reduced SBP and DBP by 6 and 5 mmHg, respectively. Conclusion: Among older PHIV with viral suppression, losartan did not improve blood measures of inflammation nor T-cell immune recovery. Losartan treatment is unlikely to reduce inflammation associated comorbidities to a clinically meaningful degree, beyond the benefits from lowering blood pressure. ClinicalTrials.gov: NCT02049307.

Background:There are limited data on the outcomes of acute myocardial infarction–cardiogenic shock (AMI-CS) in patients with HIV infection and AIDS.Setting:Twenty percent sample of all US hospitals.Methods:A retrospective cohort of AMI-CS during 2000–2017 from the National Inpatient Sample was evaluated for concomitant HIV and AIDS. Outcomes of interest included in-hospital mortality and use of cardiac procedures. A subgroup analysis was performed for those with and without AIDS within the HIV cohort.Results:A total 557,974 AMI-CS admissions were included, with HIV and AIDS in 1321 (0.2%) and 985 (0.2%), respectively. The HIV cohort was younger (54.1 vs. 69.0 years), more often men, of non-White race, uninsured, from a lower socioeconomic status, and with higher comorbidity (allP< 0.001). The HIV cohort had comparable multiorgan failure (37.8% vs. 39.0%) and cardiac arrest (28.7% vs. 27.4%) (P> 0.05). The cohorts with and without HIV had comparable rates of coronary angiography (70.2% vs. 69.0%;P= 0.37) but less frequent early coronary angiography (hospital day zero) (39.1% vs. 42.5%;P< 0.001). The cohort with HIV had higher unadjusted but comparable adjusted in-hospital mortality compared with those without [26.9% vs. 37.4%; adjusted odds ratio 1.04 (95% confidence interval: 0.90 to 1.21);P= 0.61]. In the HIV cohort, AIDS was associated with higher in-hospital mortality [28.8% vs. 21.1%; adjusted odds ratio 4.12 (95% confidence interval: 1.89 to 9.00);P< 0.001].Conclusions:The cohort with HIV had comparable rates of cardiac procedures and in-hospital mortality; however, those with AIDS had higher in-hospital mortality.

Understanding temporal dynamics of COVID-19 symptoms could provide fine-grained resolution to guide clinical decision-making. Here, we use deep neural networks over an institution-wide platform for the augmented curation of clinical notes from 77,167 patients subjected to COVID-19 PCR testing. By contrasting Electronic Health Record (EHR)-derived symptoms of COVID-19-positive (COVID pos ; n = 2,317) versus COVID-19-negative (COVID neg ; n = 74,850) patients for the week preceding the PCR testing date, we identify anosmia/dysgeusia (27.1-fold), fever/chills (2.6-fold), respiratory difficulty (2.2-fold), cough (2.2-fold), myalgia/arthralgia (2-fold), and diarrhea (1.4-fold) as significantly amplified in COVID pos over COVID neg patients. The combination of cough and fever/chills has 4.2-fold amplification in COVID pos patients during the week prior to PCR testing, in addition to anosmia/dysgeusia, constitutes the earliest EHR-derived signature of COVID-19. This study introduces an Augmented Intelligence platform for the real-time synthesis of institutional biomedical knowledge. The platform holds tremendous potential for scaling up curation throughput, thus enabling EHR-powered early disease diagnosis.

Abstract Background: Antiretroviral therapy for HIV-1 infection has become increasingly complex. The availability of new and potent drugs and progress in understanding the pathogenesis of HIV-1 infection have led to the establishment of new treatment paradigms. The varying dosing regimens, associated toxicities, and the potential for drug-drug and food-drug interactions further complicate treatment. This complexity contributes to patient nonadherence. Because clinicians have no tools to monitor adherence or drug-drug interactions and because response requires that therapy exceed the known inhibiting concentration, serum monitoring of antiretroviral therapy may play a role in improving treatment of HIV-1 infection. We report methods to quantify serum concentrations of antiretroviral drugs used to treat HIV-1 infection, precision and interference studies of these methods, and results observed in a pilot evaluation of blood serum concentrations from 12 human subjects. Methods: HPLC offers adequate sensitivity to measure peak or trough serum concentrations of delavirdine, lamivudine, nevirapine, indinavir, nelfinavir, ritonavir, and saquinavir and peak serum concentrations of stavudine, zidovudine, and didanosine with reasonable precision. Results: Peak indinavir serum concentrations in most patients were in the range of 1–10 mg/L, and trough concentrations were in the range of 0.1–0.5 mg/L. Peak stavudine concentrations were in the range of 0.3–1.3 mg/L, and trough concentrations were in the range of 0.1–0.5 mg/L. Peak zidovudine concentrations were in the range of 0.1–1.1 mg/L. Conclusions: Because this was a blood serum concentration-seeking pilot study to evaluate analytic performance, we do not report on the correlation of drug response to blood concentration. However, the concentrations observed in patients are generally consistent with blood concentrations reported from studies of monotherapy.